WO2025042787A2 - Methods and compositions for inhibiting ape2 in cancer cells - Google Patents

Abstract

Described herein are methods of treating cancer in a subject in need thereof, more specifically the treatment of cancer cells through the inhibition of APE2, as well as the co-inhibition of APE2 and PARE in HR-deficient cancers.

Description

METHODS AND COMPOSITIONS FOR INHIBITING APE2 IN CANCER CELLS CROSS-REFERENCE TO RELATED APPLICATIONS This International PCT Application claims the benefit of and priority to U.S. Provisional Application No.63/520,423 filed August 18, 2023, the specification, claims and drawings of which are incorporated herein by reference in their entirety. SEQUENCE LISTING The instant application contains contents of the electronic sequence listing (90245.01061- Sequence-Listing.xml; Size: 27,813 bytes; and Date of Creation: August 13, 2024) is herein incorporated by reference in its entirety. TECHNICAL FIELD The present invention is directed to methods of treating cancer in a subject in need thereof, more specifically the treatment of cancer cells through the inhibition of APE2, as well as the co- inhibition of APE2 and PARP in HR-deficient cancers. BACKGROUND Mutations in DNA repair genes, which are frequent in cancers, participate in genomic instability and tumorigenesis. These defects can however be exploited in cancer therapy, as they lead to cellular addiction to alternative repair mechanisms. The most prominent example is the treatment of homologous recombination deficient (HRD) cancers with inhibitors of the DNA damage sensor PARP. PARP inhibitors (PARPi) have been FDA-approved for ovarian and breast cancers and show promising results against prostate and metastatic pancreatic cancer in clinical trials. In all, over 300,000 patients annually receive PARPi. However, the success of PARPi in increasing progression-free survival is limited by the frequent emergence of drug resistance. There is currently no treatment available against these resistant tumors, and it is therefore urgent to develop complementary or alternative therapies to counteract PARPi resistance. Cancers that are deficient for homologous recombination account for approximately 25% of breast cancers and half of ovarian cancers among other types. Among its functions, HR repairs DNA double strand breaks (DSBs) that arise during replication (Fig. 1A). To cope with lack of HR, these cancer cells upregulate a backup pathway, microhomology-mediated end-joining (MMEJ, also referred to as Alt-EJ) (Fig.1B). Because MMEJ is intrinsically mutagenic and prone to generate genomic rearrangements, individuals with compromised HR, such as mutated BRCA genes, have elevated risk of ovarian, breast, prostate, and pancreatic cancers. Similarly, somatic mutations or epigenetic repression of HR are commonly found in cancers. For instance, HR is deficient in over half of high grade ovarian cancers. While MMEJ participates in tumorigenesis, it also constitutes the Achille’s heel of HRD cancers: Since cells with compromised HR solely rely on MMEJ to repair replication-induced DSBs, suppression of MMEJ is lethal in HRD cells (Fig. 1C). Hence, inhibition of MMEJ has a strong therapeutic potential to circumvent the problem of PARPi resistance. The development of MMEJ inhibitors for cancer treatment is however limited by our incomplete understanding of the MMEJ pathway. To address this need, the present inventors identified APE2, a nuclease known previously to participate in the repair of single strand breaks and the removal of 3’ blocking lesions. The present inventors demonstrated that APE2 is an essential component of the MMEJ repair pathway and is critical for the survival of HRD cells. As described below, inhibition of APE2 could serve as a novel therapeutic strategy to eliminate HRD cancers and circumvent the problem of resistance to PARP inhibitors. BRIEF SUMMARY OF THE INVENTION The present invention in specific embodiments includes systems, methods, and compositions for the inhibition of expression of APE2 (SEQ ID NO.1), preferably in a cancer cell. The invention in further embodiments includes systems, methods, and compositions for the inhibition of the activity of APE2 (SEQ ID NO.2), preferably in a cancer cell. The present invention in specific embodiments further includes methods of treating cancer in a subject in need thereof, which includes the inhibition of expression of APE2 (SEQ ID NO.1, 2), preferably in a cancer cell. The present invention in specific embodiments includes methods of treating cancer in a subject in need thereof, which includes the inhibition of activity of APE2 (SEQ ID NO. 2), preferably in a cancer cell. The present invention in specific embodiments includes methods of treating cancer in a subject in need thereof, comprising the step of administering a therapeutically effective amount of an APE2 inhibitor. The present invention in specific embodiments includes methods of treating cancer in a subject in need thereof, comprising the step of administering a therapeutically effective amount of an APE2 inhibitor, and a therapeutically effective amount of a PARP inhibitor (PARPi), wherein preferably said cancer is homologous-recombination (HR) deficient. Other embodiments of the invention will be apparent from the detailed description, figures, and claims provided herewith. BRIEF DESCRIPTION OF DRAWINGS Figure 1: Repair of replication induced DSBs. A. At replication forks, NHEJ is inactive, and HR is the dominant repair pathway. B. HR-deficient cells rely on MMEJ to repair replication- induced (ri)DSBs. C. When both HR and MMEJ are NHEJ compromised, riDSBs cannot be repaired, leading to cell death. Figure 2: A dual CRISPR-Cas9 screens identifies MMEJ genes and APEX2, CIP2A and ALC1. A. Schematic of the dual CRISPR-Cas9 screen. B. Result of the BRCA1 (B) and PALB2 (C) synthetic lethality screens. Log fold changes and p values are calculated based on guide RNA representation in the BRCA1^KO (B) or PALB2^KO (C) cells compared to parental HT1080 cells. Most significant genes (-Log Fold change>1 or -1, -Log10 p value >2) are colored in red/orange (Log Fold change>-1) or green (Log Fold change>1). D. Plot of the MAGeCK -Log10 depletion scores of BRCA2^KO vs PALB2^KO. E. Result of the growth competition assay at day 24. Values are % of RFP+ cells / % of GFP+ cells, normalized to day 0.3 biological replicates. Data are mean ± s.d. Figure 3. APE2 is required for MMEJ-mediated fusions of deprotected telomeres. A. Western Blot of Ku80, TRF2 and Actin in parental and XRCC5^KO TERF2^F/- upon treatment with 4OHT (1µM). B. Percentage of fused telomeres in XRCC5^WT and XRCC5^KO TERF2^F/- MEFs upon treatment with tamoxifen (4OHT, 1µM), DNA-PKcs-inhibitor (NU7441, 1µM), PARP inhibitor (Olaparib, 20µM), or Polθ inhibitor (ART558, 1µM). 3 independent experiments. n=20 metaphases counted for each condition, each replica. Data are mean ± s.d. C. Representative images of metaphase spreads analyzed in d. Red: DNA (DNA - DAPI), Green: telomere FISH. Scale bar: 5µm. D-E-F. Quantification of telomere fusions in XRCC5^KO (D-E) or XRCC5^WT (F) TERF2^F/- MEFs transduced with iCas9 and the indicated sgRNA, and treated with doxycycline (1µg/ml), 4OHT (1µM), and PARPi (D) (Olaparib, 20µM).3 independent experiments. Data are mean ± s.e.m. Statistical analysis for B, D, E and F: One-way ANOVA. ****p<0.0001. Figure 4. APE2 is a key effector of the MMEJ repair pathway. A. Schematic of the MMEJ repair reporter. Upon induction of a DSB by ISce1 and repair using annealing of the indicated microhomologies, the mCherry cassette is reconstituted. B-C-D. MMEJ quantification using the DNA reporter in: (B) parental HT1080 and indicated APEX2^KO and POLQ^KO clones, (C) parental HT1080 and APEX2^KO clones complemented with empty vector (EV) or hAPE2, and (D) parental HT1080 and APEX2^KO clones with iCas9 and sgNT (non-targeting gRNA) or sgPOLQ. mCherry+ cells (MMEJ+) were scored in the BFP+ population (I-Sce1+). Values are normalized to WT (B), WT+EV (C) or WT+sgNT (D). Data are mean ± s.e.m. F. Schematic of the MMEJ sequence. G. Depiction of the most frequent repair outcomes obtained upon DSB induction with Cas9 followed by amplicon sequencing of the MMEJ sequence. G. Quantification of the most frequent repair outcomes in parental HT1080 (WT) or APEX2^KO clones untreated or treated with Polθ inhibitor (ART558, 1µM). Data represent % of total edited sequences. Three biological replicates were performed with parental cells, while APEX2^KO replicates were obtained from four different clones (A29, A37, A42 and A46). Data are mean ± s.e.m. Statistical analysis for B, C, D and G: One-way ANOVA. *p<0.05, **p<0.01, ****p<0.0001. Figure 5. Involvement of APE2’s domains in its MMEJ activity. A. Schematic of wild type and mutants APE2. Amino acids mutated or deleted are indicated for both human and mouse APE2. B. Quantification of telomere fusion in XRCC5^KO TERF2^F/- MEFs transduced with iCas9, sgAPEX2#1, and the indicated mAPE2 construct, and treated with doxycycline (1µg/ml) and 4OHT (1µM). EV: empty vector. 3 independent experiments. Data are mean ± s.e.m. C. MMEJ quantification using the MMEJ reporter in HT1080-APEX2^KO clone A2.4 complemented with indicated hAPE2. mCherry+ cells (MMEJ+) were scored in the BFP+ population (I-Sce1+). Values are normalized to WT.4 independent experiments. Data are mean ± s.e.m. D. Schematic of hAPE2 amino acid conservation. Two uncharacterized conserved regions are indicated. E. Schematic of APE2 CR1 and CR2 deletion mutants. Deleted amino acids are indicated for both human and mouse APE2. F. Quantification of telomere fusion in XRCC5^KO TERF2^F/- MEFs transduced with iCas9, sgAPEX2#1, and the indicated mAPE2 construct, and treated with doxycycline (1µg/ml) and 4OHT (1µM). EV = empty vector.3 independent experiments. Data are mean ± s.e.m. G. MMEJ quantification using the MMEJ repair reporter in HT1080-APEX2^KO clone A2.4 complemented with indicated hAPE2. mCherry+ cells (MMEJ+) were scored in the BFP+ population (I-Sce1+). Values are normalized to WT. 4 independent experiments. Data are mean ± s.e.m. Statistical analysis for B, C, F and G: One-way ANOVA. Grey: vs empty vector, Black: vs WT. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Figure 6. APE2 domains’ requirement for MMEJ predicts their necessity for survival in HR- deficient cells. A. Schematic and experimental timeline of the growth competition assay. HRD cells are transduced with sgNT (non-targeting) and GFP or with sgAPEX2#1, RFP and the indicated hAPE2 or empty vector (EV). B. Growth competition assay in HT1080-BRCA1^KO cells and HT1080-PALB2^KO cells. Values are % of RFP+ cells / % of GFP+ cells, averaged on days 6, 8 and 10 and normalized to day 0.3 independent experiments. Data are mean ± s.e.m. Statistical analysis: One-way ANOVA. Grey: vs empty vector, Black: vs WT. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Figure 7: PARPi-resistant cells remain sensitive to APE2 inhibition. A. Dose response to Olaparib (PARP inhibitor) of PEO1 (HRD ovarian cancer cells) and PEO1-OR (corresponding cells that acquired resistance to Olaparib). B. PEO1-OR cells (PARPi-resistant) are as sensitive to APE2 suppression as PEO1 (PARP sensitive). Competitive survival assay: PEO1 or PEO1-OR cells expressing either GFP and a non-targeting sgRNA or RFP and an APEX2 guide RNA were mixed 1:1 and the RFP/GFP ratio was measured every 2 days after Cas9 induction. DETAILED DESCRIPTION OF INVENTION In one aspect, the present invention include systems, methods, and compositions for the inhibition of APE2. As noted above, APE2 is a deoxyribo-endonuclease. Suppression of APE2 is lethal in cells that lack homologous recombination (HR). As further described below, the present inventors demonstrate that APE2 is essential for DNA repair by MMEJ, a pathway that is critical in HR-deficient cells. Thus, suppression of MMEJ through APE2 inhibition kills HR-deficient cancers. These cancers are commonly treated with inhibitors of PARP1/2, but most cancers become resistant and relapse. Indeed, the present inventors demonstrate that HR-deficient cells that became resistant to PARP inhibitors remain sensitive to APE2 suppression. In another aspect, the present invention include systems, methods, and compositions for the inhibition of the expression of APE2 in a cancer cell, and preferably an HR-deficient cancer and/or a cancer cell that is resistant to PARPi. In another aspect, inhibition of the expression of APE2 can be coupled with the inhibition of the expression of PARP. More specifically, a therapeutically effective amount of an APE2 expression inhibitor can be co-administered a therapeutically effective amount of a PARPi to synergistically kill HR-deficient cancer cells and prevent drug resistance. In another aspect, the present invention include systems, methods, and compositions for the inhibition of the activity, and preferably the catalytic activity, of APE2 in a cancer cell, and preferably an HR-deficient cancer and/or a cancer cell that is resistant to PARPi. In another aspect, inhibition of the activity of APE2 can be coupled with the inhibition of the activity of PARP. More specifically, a therapeutically effective amount of an APE2 activity inhibitor can be co- administered a therapeutically effective amount of a PARPi to synergistically kill HR-deficient cancer cells and prevent drug resistance. Other further aspects of the invention provide for the treatment of disease ameliorated by the inhibition of APE2, and/or optionally APE2 and PARP, such as HR-deficient and/or PARP resistant cancer cells, comprising administering to a subject in need of treatment a therapeutically- effective amount of an APE2 inhibitor and/or PARPi as defined herein, preferably in the form of a pharmaceutical composition, and optionally in combination, with ionizing radiation, surgical, intervention, or other chemotherapeutic agents. The term “treatment”, as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. The terms “prevent,” “preventing” and “prevention” (and grammatical variations thereof) refer to prevention and/or delay of the onset of a disease, disorder and/or a clinical symptom(s) in a subject and/or a reduction in the severity of the onset of the disease, disorder and/or clinical symptom(s) relative to what would occur in the absence of the methods of the disclosure. The prevention can be complete, e.g., the total absence of the disease, disorder and/or clinical symptom(s). The prevention can also be partial, such that the occurrence of the disease, disorder and/or clinical symptom(s) in the subject and/or the severity of onset is less than what would occur in the absence of the present disclosure. The term “therapeutically effective amount” as used herein refers to that amount of a compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and/or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer. As used herein, “subject” refers to a human or animal subject. In certain preferred embodiments, the subject is a human. As used herein, “PARP inhibitors” refer to pharmacological inhibitors of poly ADP ribose polymerase and include, but are not limited to, anticancer agents, alkylating agents, antibiotic agents, antimetabolic agents, hormonal agents, plant-derived agents, and biologic agents. PARP inhibitors have been developed for a variety of indications, including the treatment of cancer. PARP1 is a protein that is important for repairing single strand breaks ("gaps" in DNA). If this gap is not repaired until the DNA is replicated (necessarily before cell division), replication itself can lead to the formation of double-strand breaks. Drugs that inhibit PARP1 form multiple double- strand breaks in this way, and in certain tumors (such as those with BRCA1, BRCA2, or PALB2 mutations), these double-strand breaks are not efficiently repaired, resulting in cell death. Normal cells do not replicate their DNA as frequently as cancer cells, and BRCA1 or BRCA2, which lack any mutations, still have a homologous repair function, enabling them to survive PARP inhibition. In addition to preventing its catalytic effects, PARP inhibitors also result in capture of PARP proteins on DNA. It interferes with replication, preferentially causing cell death in cancer cells that grow faster than non-cancer cells. PARP inhibitors include, but are not limited to, talazoparib, velipari, pamiparib, olaparib, lucapanib, CEP9822, nilapanib, E7016, iniparib, 3-aminobenzamide, Tarazol panil, rukapanib, Veliparib, and Olaparib. In one embodiment, the APE2 inhibitor, or an APE2 inhibitor and a PARPi can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition. As used herein, “pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of the disclosed compound(s) together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and/or optionally other biologically active ingredients. Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (19th Edition). In one embodiment, a pharmaceutical composition of the invention may include a quantity of a composition that inhibits APE2 expression or activity, also referred to herein as an “APE2 inhibitor,” or “active compound,” and a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable excipient or carriers. Such pharmaceutical compositions/formulations are useful for administration to a subject, in vivo or ex vivo. Pharmaceutical compositions and formulations include carriers or excipients for administration to a subject. Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, “Handbook of Pharmaceutical Additives”, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, N.Y., USA), “Remington's Pharmaceutical Sciences”, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and “Handbook of Pharmaceutical Excipients”, 2nd edition, 1994. As used herein the terms “pharmaceutically acceptable” and “physiologically acceptable” mean a biologically compatible formulation, gaseous, liquid, or solid, or mixture thereof, which is suitable for one or more routes of administration, in vivo delivery, or contact. Such formulations include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration or in vivo contact or delivery. Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents. Such pharmaceutically acceptable carriers include tablets (coated or uncoated), capsules (hard or soft), microbeads, powder, granules, and crystals. Supplementary active compounds (e.g., preservatives, antibacterial, antiviral, and antifungal agents) can also be incorporated into the compositions. The formulations may, for convenience, be prepared or provided as a unit dosage form. In general, formulations are prepared by uniformly and intimately associating the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. For example, a tablet may be made by compression or molding. Compressed tablets may be prepared by compressing, in a suitable machine, an active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be produced by molding, in a suitable apparatus, a mixture of powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide a slow or controlled release of the active ingredient therein. Pharmaceutical formulations and delivery systems appropriate for the compositions and methods of the invention are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (2003) 20.sup.th ed., Mack Publishing Co., Easton, Pa.; Remington's Pharmaceutical Sciences (1990) 18.sup.th ed., Mack Publishing Co., Easton, Pa.; The Merck Index (1996) 12.sup.th ed., Merck Publishing Group, Whitehouse, N.J.; Pharmaceutical Principles of Solid Dosage Forms (1993), Technonic Publishing Co., Inc., Lancaster, Pa.; Ansel and Stoklosa, Pharmaceutical Calculations (2001) 11.sup.th ed., Lippincott Williams & Wilkins, Baltimore, Md.; and Poznansky et al., Drug Delivery Systems (1980), R. L. Juliano, ed., Oxford, N.Y., pp. 253-315). For example, pharmaceutical compositions can optionally be formulated to be compatible with a particular route of administration. Exemplary routes of administration include administration to a biological fluid, an immune cell (e.g., T or B cell) or tissue, mucosal cell or tissue (e.g., mouth, buccal cavity, labia, nasopharynx, esophagus, trachea, lung, stomach, small intestine, vagina, rectum, or colon), neural cell or tissue (e.g., ganglia, motor or sensory neurons) or epithelial cell or tissue (e.g., nose, fingers, ears, cornea, conjunctiva, skin or dermis). Thus, pharmaceutical compositions include carriers (excipients, diluents, vehicles, or filling agents) suitable for administration to any cell, tissue, or organ, in vivo, ex vivo (e.g., tissue or organ transplant) or in vitro, by various routes and delivery, locally, regionally, or systemically. The active compound or pharmaceutical composition comprising the APE2 inhibitor, as well as in some embodiments also a PARPi may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary, shaping the product. Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, losenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols. Formulations suitable for oral administration (e.g., by ingestion) may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste. A tablet may be made by conventional means, e.g., compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. Formulations suitable for topical administration (e.g., transdermal, intranasal, ocular, buccal, and sublingual) may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil. Alternatively, a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents. Formulations suitable for topical administration in the mouth include losenges comprising the active compound in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier. Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound. Formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the active compound. Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurized pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichorotetrafluoroethane, carbon dioxide, or other suitable gases. Formulations suitable for topical administration via the skin include ointments, creams, and emulsions. When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active compounds may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues. When formulated as a topical emulsion, the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Suitable emulgents and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration (e.g., by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal), include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer’ s Solution, or Lactated Ringer’ s Injection. Typically, the concentration of the active compound in the solution is from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 μg/ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs. It will be appreciated that appropriate dosages of the active compounds, and compositions comprising the active compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. In general, a suitable dose of the active compound is in the range of about 100 μg to about 250 mg per kilogram body weight of the subject per day. Where the active compound is a salt, an ester, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately. INHIBITION OF APE2 BY INHIBITORY NUCLEIC ACIDS In some embodiments, a nucleic acid molecule may be used to inhibit, downregulate, or disrupt expression or activity of APE2. In certain aspects, the nucleic acid molecule may be RNAi, ribozyme, antisense, DNA enzyme or other nucleic acid-related compositions for manipulating (typically decreasing) a target’s expression or activity. Some embodiments of the invention make use of materials and methods for effecting knockdown of APE2 by means of RNA interference (RNAi). RNAi is a process of sequence-specific post-transcriptional gene repression which can occur in eukaryotic cells. In general, this process involves degradation of an mRNA of a particular sequence induced by double-stranded RNA (dsRNA) that is homologous to that sequence. Any selected gene may be repressed by introducing a dsRNA which corresponds to all or a substantial part of the mRNA for that gene. It appears that when a long dsRNA is expressed, it is initially processed by a ribonuclease III into shorter dsRNA oligonucleotides of as few as 21 to 22 base pairs in length. Accordingly, RNAi may be effected by introduction or expression of relatively short homologous dsRNAs. The double stranded oligonucleotides used to effect RNAi are preferably less than 30 base pairs in length and, more preferably, comprise about 25, 24, 23, 22, 21, 20, 19, 18 or 17 base pairs of ribonucleic acid. Optionally the dsRNA oligonucleotides of the invention may include 3' overhang ends. Exemplary 2-nucleotide 3' overhangs may be composed of ribonucleotide residues of any type and may even be composed of 2'-deoxythymidine resides, which lowers the cost of RNA synthesis and may enhance nuclease resistance of siRNAs in the cell culture medium and within transfected cells (see Elbashir et al. (2001) Nature 411: 494-8). Longer dsRNAs of 50, 75, 100 or even 500 base pairs or more may also be utilized in certain embodiments of the invention to inhibit APE2. Exemplary concentrations of dsRNAs for effecting RNAi are about 0.05 nM, 0.1 nM, 0.5 nM, 1.0 nM, 1.5 nM, 25 nM or 100 nM, although other concentrations may be utilized depending upon the nature of the cells treated, the gene target and other factors readily discernable the skilled artisan. Exemplary dsRNAs may be synthesized chemically or produced in vitro or in vivo using appropriate expression vectors. Exemplary synthetic RNAs include 21 nucleotide RNAs chemically synthesized using methods known in the art (e.g., Expedite RNA phophoramidites and thymidine phosphoramidite (Proligo, Germany). Synthetic oligonucleotides are preferably deprotected and gel-purified using methods known in the art (see e.g., Elbashir et al. (2001) Genes Dev.15: 188-200). Longer RNAs may be transcribed from promoters, such as T7 RNA polymerase promoters, known in the art. A single RNA target, placed in both possible orientations downstream of an in vitro promoter, will transcribe both strands of the target to create a dsRNA oligonucleotide of the desired target sequence. Any of the above RNA species will be designed to include a portion of nucleic acid sequence for APE2, sometimes also referred to as the “target gene,” such as, for example, a nucleic acid that hybridizes, under stringent and/or physiological conditions to a mRNA of APE2. The specific sequence utilized in design of the oligonucleotides may be any contiguous sequence of nucleotides contained within the expressed gene message of the target. Programs and algorithms, known in the art, may be used to select appropriate target sequences. In addition, optimal sequences may be selected utilizing programs designed to predict the secondary structure of a specified single stranded nucleic acid sequence and allowing selection of those sequences likely to occur in exposed single stranded regions of a folded mRNA. Methods and compositions for designing appropriate oligonucleotides may be found, for example, in U.S. Pat. No.6,251,588, the contents of which are incorporated herein by reference. Messenger RNA (mRNA) is generally thought of as a linear molecule which contains the information for directing protein synthesis within the sequence of ribonucleotides, however studies have revealed a number of secondary and tertiary structures that exist in most mRNAs. Secondary structure elements in RNA are formed largely by Watson-Crick type interactions between different regions of the same RNA molecule. Important secondary structural elements include intramolecular double stranded regions, hairpin loops, bulges in duplex RNA and internal loops. Tertiary structural elements are formed when secondary structural elements come in contact with each other or with single stranded regions to produce a more complex three-dimensional structure. A number of researchers have measured the binding energies of a large number of RNA duplex structures and have derived a set of rules which can be used to predict the secondary structure of RNA (see e.g., Jaeger et al. (1989) Proc. Natl. Acad. Sci. USA 86:7706 (1989); and Turner et al. (1988) Annu. Rev. Biophys. Biophys. Chern. 17:167). The rules are useful in identification of RNA structural elements and, in particular, for identifying single stranded RNA regions which may represent preferred segments of the mRNA to target for silencing RNAi, ribozyme or antisense technologies. Accordingly, preferred segments of the mRNA target can be identified for design of the RNAi mediating dsRNA oligonucleotides as well as for design of appropriate ribozyme and hammerhead ribozyme compositions related to the targets of the invention. The dsRNA oligonucleotides may be introduced into the cell by transfection with using carrier compositions such as liposomes, which are known in the art as described by the manufacturer for adherent cell lines. Transfection of dsRNA oligonucleotides for targeting genes may be carried out using Oligofectamine. Transfection efficiency may be checked using fluorescence microscopy for mammalian cell lines after co-transfection of hGFP-encoding pAD3 (Kehlenback et al. (1998) J Cell BioI 141: 863-74). The effectiveness of the RNAi may be assessed by any of a number of assays following introduction of the dsRNAs. These include Western blot analysis using antibodies which recognize APE2 expression following sufficient time for turnover of the endogenous pool after new protein synthesis is repressed, reverse transcriptase polymerase chain reaction and Northern blot analysis to determine the level of existing target mRNA. Further compositions, methods and applications of RNAi technology are provided in U.S. patent application Nos.6,278,039, 5,723,750 and 5,244,805, which are incorporated herein by reference. Ribozyme molecules designed to catalytically cleave, for example APE2 mRNA transcripts can also be used to prevent translation of subject mRNAs and/or expression of said genes in a cancer cell, preferably in a subject in need thereof (see, e.g., PCT International Publication W090111364, published Oct.4, 1990; Sarver et al. (1990) Science 247:1222-1225 and U.S. Pat. No. 5,093,246). Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. (For a review, see Rossi (1994) Current Biology 4: 469-471). The mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by an endonucleolytic cleavage event. The composition of ribozyme molecules preferably includes one or more sequences complementary to a target mRNA, and the well-known catalytic sequence responsible for mRNA cleavage or a functionally equivalent sequence (see, e.g., U.S. Pat. No.5,093,246, which is incorporated herein by reference in its entirety). In addition to ribozymes that cleave mRNA at site specific recognition sequences, hammerhead ribozymes can also be used to destroy target APE2 mRNAs. Hammerhead ribozymes cleave mRNAs at locations dictated by flanking regions that form complementary base pairs with the target mRNA. Preferably, the target APE2 mRNA has the following sequence of two bases: 5'-mUG-3'. The construction and production of hammerhead ribozymes is well known in the art and is described more fully in Haseloff and Gerlach ((1988) Nature 334:585-591; and see PCT Appln. No. W089/05852, the contents of which are incorporated herein by reference). Hammerhead ribozyme sequences can be embedded in a stable RNA such as a transfer RNm (tRNA) to increase cleavage efficiency in vivo (Perriman et al. (1995) Proc. Natl. Acad. Sci.mUSA, 92: 6175-79; de Feyter, and Gaudron, Methods in Molecular Biology, Vol. 74, Chapter 43, “Expressing Ribozymes in Plants”, Edited by Turner, P. C, Humana Press Inc., Totowa, N.J.). In particular, RNA polymerase HI-mediated expression of tRNA fusion ribozymes are well known in the art (see Kawasaki et al. (1998) Nature 393: 284-9; Kuwabara et al. (1998) Nature Biotechnol. 16: 961-5; and Kuwabara et al. (1998) Mol. Cell 2: 61727; Koseki et al. (1999) J Virol 73: 1868- 77; Kuwabara et al. (1999) Proc Natl Acad Sci USA 96:m1886-91; Tanabe et al. (2000) Nature 406: 473-4). There are typically a number of potential hammerhead ribozyme cleavage sites within a given target cDNA sequence. Preferably the ribozyme is engineered so that the cleavage recognition site is located near the 5' end of the target mRNA--to increase efficiency and minimize the intracellular accumulation of non-functional mRNA transcripts. Furthermore, the use of any cleavage recognition site located in the target sequence encoding different portions of the C- terminal amino acid domains of, for example, long and short forms om target would allow the selective targeting of one or the other form of the target, and thus, have a selective effect on one form of the APE2 gene product. Gene targeting ribozymes necessarily contain a hybridizing region complementary to two regions, each of at least 5 and preferably each 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleotides in length of an APE2 mRNA. In addition, ribozymes possess highly specific endoribonuclease activity, which autocatalytically cleaves the target sense mRNA. The present invention extends to ribozymes which hybridize to a sense mRNA encoding a APE2 thereby hybridizing to the sense mRNA and cleaving it, such that it is no longer capable of being translated to synthesize a functional polypeptide product. Ribozymes can be composed of modified oligonucleotides (e.g., for improved stability, targeting, etc.) and should be delivered to cells which express the target gene in vivo. A preferred method of delivery involves using a DNA construct “encoding” the ribozyme under the control of a strong constitutive pol III or pol II promoter, so that transfected cells will produce sufficient quantities of the ribozyme to destroy endogenous target messages and inhibit translation. Because ribozymes, unlike antisense molecules, are catalytic, a lower intracellular concentration is required for efficiency. A further aspect of the invention relates to the use of the isolated “antisense” nucleic acids to inhibit expression of APE2, e.g., by inhibiting transcription and/or translation of APE2 nucleic acids. The antisense nucleic acids may bind to the APE2 mRNA, for example, by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix. In general, these methods refer to the range of techniques generally employed in the art and include any methods that rely on specific binding to oligonucleotide sequences. An antisense construct of the present invention can be delivered, for example, as an expression plasmid which, when transcribed in the cell, produces RNA which is complementary to at least a unique portion of the cellular mRNA which encodes an APE2 polypeptide of the invention, or other other methods known in the art, such as various pharmaceutical compositions as described herein. Alternatively, the antisense construct is an oligonucleotide probe, which is generated ex vivo and which, when introduced into the cell causes inhibition of expression by hybridizing with the mRNA and/or genomic sequences of an APE2 gene nucleic acid. Such oligonucleotide probes are preferably modified oligonucleotides, which are resistant to endogenous nucleases, e.g., exonucleases and/or endonucleases, and are therefore stable in vivo. Exemplary nucleic acid molecules for use as antisense oligonucleotides are phosphoramidate, phosphothioate and methylphosphonate analogs of DNA (see also U.S. Pat. Nos. 5,176,996; 5,264,564; and 5,256,775). Additionally, general approaches to constructing oligomers useful in antisense therapy have been reviewed, for example, by Van der Krol et al. (1988) BioTechniques 6:958- 976; and Stein et al. (1988) Cancer Res 48:2659- 2668. Antisense approaches involve the design of oligonucleotides (either DNA or RNA) that are complementary to mRNA encoding an APE2 polypeptide. The antisense oligonucleotides may bind to the mRNA transcripts and prevent translation. Absolute complementarity, although preferred, is not required. In the case of double-stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the longer the hybridizing nucleic acid, the more base mismatches with an RNA it may contain and still form a stable duplex (or triplex, as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex. Oligonucleotides that are complementary to the 5' end of the mRNA, e.g., the 5’] untranslated sequence up to and including the AUG initiation codon, should work most efficiently at inhibiting translation. However, sequences complementary to the 3’ untranslated sequences of mRNAs have been shown to be effective at inhibiting translation of mRNAs as well. Therefore, oligonucleotides complementary to either the 5’ or 3’ untranslated, non-coding regions of an APE2 gene could be used in an antisense approach to inhibit translation of that mRNA. Oligonucleotides complementary to the 5’ untranslated region of the mRNA should include the complement of the AUG start codon. Antisense oligonucleotides complementary to mRNA coding regions are less efficient inhibitors of translation but could also be used in accordance with the invention. Whether designed to hybridize to the 5’, 3’ or coding region of mRNA, antisense nucleic acids should be at least six nucleotides in length and are preferably less that about 100 and more preferably, less than about 50, 25, 17 or 10 nucleotides in length. The antisense oligonucleotides can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, hybridization, etc. The oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors), or compounds facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci. U.S.A.86:6553- 6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci.84:648-652; PCT Publication No. W088/09810, published Dec.15, 1988) or the blood- brain barrier (see, e.g., PCT Publication No. W089110134, published Apr. 25, 1988), hybridization-triggered cleavage agents. (See, e.g., Krol et al., 1988, BioTechniques 6:958- 976) or intercalating agents. (See, e.g., Zon, 1988, Pharm. Res.5 :539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization- triggered cleavage agent, etc. The antisense oligonucleotide may comprise at least one modified base moiety which is selected from the group including but not limited to: 5-fluorouracil, 5-bromouracil, 5- chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxytiethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N 6-isopentenyladenine, 1-methylguanine, III methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5- methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5- methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4- thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5- methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. The antisense oligonucleotide may also comprise at least one modified sugar moiety selected from the group including but not limited to: arabinose, 2-fluoroarabinose, xylulose, and hexose. The antisense oligonucleotide can also contain a neutral peptide-like backbone. Such molecules are termed peptide nucleic acid (PNA)-oligomers and are described, e.g., in Perry- O'Keefe et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93:14670 and in Eglom et al. (1993) Nature 365:566. One advantage of PNA oligomers is their capability to bind to complementary DNA essentially independently from the ionic strength of the medium due to the neutral backbone of the DNA. In yet another embodiment, the antisense oligonucleotide comprises at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof. A further aspect of the invention relates to the use of DNA enzymes to inhibit expression of APE2 of the invention. DNA enzymes incorporate some of the mechanistic features of both antisense and ribozyme technologies. DNA enzymes are designed so that they recognize a particular target nucleic acid sequence, much like an antisense oligonucleotide, however much like a ribozyme they are catalytic and specifically cleave the target nucleic acid. There are currently two basic types of DNA enzymes, and both of these were identified by Santoro and Joyce (see, for example, U.S. Pat. No. 6,110,462). The 10-23 DNA enzyme comprises a loop structure which connect two arms. The two arms provide specificity by recognizing the particular target nucleic acid sequence while the loop structure provides catalytic function under physiological conditions. Briefly, to design an ideal DNA enzyme that specifically recognizes and cleaves a target nucleic acid, one of skill in the art must first identify the unique target sequence. This can be done using the same approach as outlined for antisense oligonucleotides. Preferably, the unique or substantial portion of the sequence is a G/C rich of approximately 18 to 22 nucleotides. High G/C content helps insure a stronger interaction between the DNA enzyme and the target sequence. When synthesizing the DNA enzyme, the specific antisense recognition sequence that will target the enzyme to the message is divided so that it comprises the two arms of the DNA enzyme, and the DNA enzyme loop is placed between the two specific arms. Methods of making and administering DNA enzymes can be found, for example, in U.S. Pat. No. 6,110,462. Similarly, methods of delivery of DNA ribozymes in vitro or in vivo include methods of delivery of RNA ribozyme, as outlined in detail above. Additionally, one of skill in the art will recognize that, like antisense oligonucleotide, DNA enzymes can be optionally modified to improve stability and improve resistance to degradation. Antisense RNA and DNA, ribozyme, RNAi constructs of the invention may be prepared by any method known in the art for the synthesis of DNA and RNA molecules, including techniques for chemically synthesizing oligodeoxyribonucleotides and oligoribonucleotides well known in the art such as for example solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors which incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines. Moreover, various well-known modifications to nucleic acid molecules may be introduced as a means of increasing intracellular stability and half-life. Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the oligodeoxyribonucleotide backbone. INHIBITION OF APE2 BY ANTIBODIES OR APTAMERS The present invention also encompasses reagents, compounds, agents or molecules which specifically bind the target molecules, whether they be polypeptides or polynucleotides. As used herein, the term “specifically binding,” refers to the interaction between binding pairs (e.g., an antibody and an antigen or aptamer and its target). In some embodiments, the interaction has an affinity constant of at most 10-6 moles/liter, at most 10-7 moles/liter, or at most 10-8 moles/liter. In other embodiments, the phrase “specifically binds” refers to the specific binding of one protein to another (e.g., an antibody, fragment thereof, or binding partner to an antigen), wherein the level of binding, as measured by any standard assay (e.g., an immunoassay), is statistically significantly higher than the background control for the assay. For example, when performing an immunoassay, controls typically include a reaction well/tube that contain antibody or antigen binding fragment alone (i.e., in the absence of antigen), wherein an amount of reactivity (e.g., non-specific binding to the well) by the antibody or antigen binding fragment thereof in the absence of the antigen is considered to be background. Binding can be measured using a variety of methods standard in the art including enzyme immunoassays (e.g., ELISA), immunoblot assays, etc.). The molecules that may bind to APE2 include antibodies, aptamers and antibody derivatives or fragments. As used herein, the term “antibody” refers to an immunoglobulin molecule capable of binding an epitope present on an antigen. The term is intended to encompass not only intact immunoglobulin molecules such as monoclonal and polyclonal antibodies, but also bi-specific antibodies, humanized antibodies, chimeric antibodies, anti-idiopathic (anti-ID) antibodies, single-chain antibodies, Fab fragments, F(ab') fragments, fusion proteins and any modifications of the foregoing that comprise an antigen recognition site of the required specificity. As used herein, an aptamer is a non-naturally occurring nucleic acid molecule or peptide having a desirable action on a target, including, but not limited to, binding of the target, catalytically changing the target, reacting with the target in a way which modifies/alters the target or the functional activity of the target, covalently attaching to the target as in a suicide inhibitor, facilitating the reaction between the target and another molecule. In one embodiment, the antibodies, antibody derivatives or fragments, or aptamers specifically bind to a component that is a fragment, modification, precursor or successor of one or more target molecules. Antibodies that target APE2 may be prepared by any suitable means known in the art. For example, antibodies may be prepared by immunizing an animal host with the target or an immunogenic fragment thereof (conjugated to a carrier, if necessary). Adjuvants (e.g., Freund's adjuvant) optionally may be used to increase the immunological response. Sera containing polyclonal antibodies with high affinity for the antigenic determinant can then be isolated from the immunized animal and purified. Alternatively, antibody-producing tissue from the immunized host can be harvested and a cellular homogenate prepared from the organ can be fused to cultured cancer cells. Hybrid cells which produce monoclonal antibodies specific to a target can be selected. Alternatively, the antibodies of the invention can be produced by chemical synthesis or by recombinant expression. For example, a polynucleotide that encodes the antibody can be used to construct an expression vector for the production of the antibody. The antibodies of the present invention can also be generated using various phage display methods known in the art. Antibodies or aptamers that specifically bind APE2 can be used, for example, in methods for detecting levels of APE2 using methods and techniques well-known in the art. In some embodiments, for example, the antibodies are conjugated to a detection molecule or moiety (e.g., a dye, and enzyme) and can be used in ELISA or sandwich assays to detect APE2 in a cell or assay context. In another embodiment, antibodies or aptamers against APE2 can be used to assay a tissue sample for the target. The antibodies or aptamers can specifically bind APE2, if any, present in the tissue sections and allow the localization of the target in the tissue. Similarly, antibodies or aptamers labeled with a radioisotope may be used for in vivo imaging or treatment applications. In some embodiments, the APE2 inhibitory agent protein is an antibody specifically reactive with a target protein or polypeptide, which is effective for decreasing a biological activity of the target protein or polypeptide. For example, by using immunogens derived from a target protein or polypeptide, e.g., based on the cDNA sequences, anti-protein/anti-peptide antisera or monoclonal antibodies can be made by standard protocols. A mammal, such as a mouse, a hamster or rabbit can be immunized with an immunogenic form of APE2 protein or polypeptide or an antigenic fragment which is capable of eliciting an antibody response, or a fusion protein). Techniques for conferring immunogenicity on a protein or peptide include conjugation to carriers or other techniques well known in the art. An immunogenic portion of a target protein or polypeptide, such as APE2, can be administered in the presence of adjuvant. The progress of immunization can be monitored by detection of antibody titers in plasma or serum. Standard ELISA or other immunoassays can be used with the immunogen as antigen to assess the levels of antibodies. In a preferred embodiment, the subject antibodies are immunospecific for antigenic determinants of a target protein or polypeptide, such as APE2, of a mammal. In one example, following immunization of an animal with an antigenic preparation of APE2 protein or polypeptide, anti- APE2 or anti- APE2 antisera can be obtained and, if desired, polyclonal anti- APE2 or anti- APE2 antibodies can be isolated from the serum. To produce monoclonal antibodies, antibody- producing cells (lymphocytes) can be harvested from an immunized animal and fused by standard somatic cell fusion procedures with immortalizing cells such as myeloma cells to yield hybridoma cells. Again, such techniques are well known in the art. Hybridoma cells can be screened immunochemically for production of antibodies specifically reactive with a mammalian APE2 or APE2 protein or polypeptide and monoclonal antibodies isolated from a culture comprising such hybridoma cells. In certain preferred embodiments, an antibody of the invention is a monoclonal antibody, and in certain embodiments the invention makes available methods for generating novel antibodies. For example, a method for generating a monoclonal antibody that binds specifically to a APE2 protein or polypeptide may comprise administering to a mouse an amount of an immunogenic composition comprising the APE2 protein or polypeptide effective to stimulate a detectable immune response, obtaining antibody-producing cells (e.g., cells from the spleen) from the mouse and fusing the antibody-producing cells with myeloma cells to obtain antibody- producing hybridomas, and testing the antibody-producing hybridomas to identify a hybridoma that produces a monoclonal antibody that binds specifically to the APE2 protein or polypeptide. Once obtained, a hybridoma can be propagated in a cell culture, optionally in culture conditions where the hybridoma-derived cells produce the monoclonal antibody that binds specifically to the APE2 protein or polypeptide. The monoclonal antibody may be purified from the cell culture. One characteristic that influences the specificity of an antibody:antigen interaction is the affinity of the antibody for the antigen. Although the desired specificity may be reached with a range of different affinities, generally preferred antibodies will have an affinity (a dissociation constant) of about 10- 6,10-7,10-8,10-9 or less. In addition, the techniques used to screen antibodies in order to identify a desirable antibody may influence the properties of the antibody obtained. For example, an antibody to be used for certain therapeutic purposes will preferably be able to target a particular cell type or extra- cellular location. Accordingly, to obtain antibodies of this type, it may be desirable to screen for antibodies that bind to cells that express the antigen of interest (e.g., by fluorescence activated cell sorting). Likewise, if an antibody is to be used for binding an antigen in solution or extra-cellularly, it may be desirable to test this type of binding. A variety of different techniques are available for testing antibody:antigen interactions to identify particularly desirable antibodies. Such techniques include ELISAs, surface plasmon resonance binding assays sandwich, western blots, immunoprecipitation assays and immunohistochemistry. INHIBITION OF APE2 BY GENE EDITING A further aspect of the invention relates to the use of DNA editing compositions and methods to inhibit, alter, disrupt expression and/or knock-out or replace APE2 (SEQ ID NO.1). In various embodiments, the APE2 gene may be altered through CRISPR/Cas-9, TALAN or Zinc (Zn2+) finger nuclease systems. In some embodiments, the agent for altering gene expression is CRISPR-Cas9, or a functional equivalent thereof, together with an appropriate RNA molecule arranged to the APE2 gene, such, or a variant or homologue thereof. For example, one embodiment of the present invention may include the introduction of one or more guide RNAs (gRNAs) to be utilized by CRISPR/Cas9 system to disrupt, replace, or alter the expression or activity of APE2. In this context, the gene-editing CRISPR/cas-9 technology is an RNA-guided gene-editing platform that makes use of a bacterially derived protein (Cas9) and a synthetic guide RNA to introduce a double strand break at a specific location within the genome. Editing is achieved by transfecting a cell, such as a cancer cell, with the Cas9 protein along with a specially designed guide RNA (gRNA) that directs the cut through hybridization with its matching genomic sequence. By making use of this technology, it is possible to introduce specific genetic alterations in one or more target genes. In some embodiments, this CRISPR/cas-9 may be utilized to replace one or more existing wild- type genes with a modified version, while additional embodiments may include the addition of genetic elements that alter, reduce, increase or knock-out the expression of APE2. In some embodiments, the agent for altering APE2 expression is a zinc finger, or zinc finger nuclease or other equivalent. The term “zinc finger nuclease” or “zinc finger nuclease as used herein, refers to a nuclease comprising a nucleic acid cleavage domain conjugated to a binding domain that comprises a zinc finger array. In some embodiments, the cleavage domain is the cleavage domain of the type II restriction endonuclease FokI. Zinc finger nucleases can be designed to target virtually any desired sequence in a given nucleic acid molecule for cleavage, and the possibility to design zinc finger binding domains to bind unique sites in the context of complex genomes allows for targeted cleavage of a single genomic site in living cells, for example, to achieve a targeted genomic alteration of therapeutic value. Targeting a double-strand break to a desired genomic locus can be used to introduce frame-shift mutations into the coding sequence of a gene due to the error-prone nature of the non-homologous DNA repair pathway. Zinc finger nucleases can be generated to target a site of interest by methods well known to those of skill in the art. For example, zinc finger binding domains with a desired specificity can be designed by combining individual zinc finger motifs of known specificity. The structure of the zinc finger protein Zif268 bound to DNA has informed much of the work in this field and the concept of obtaining zinc fingers for each of the 64 possible base pair triplets and then mixing and matching these modular zinc fingers to design proteins with any desired sequence specificity has been described (Pavletich NP, Pabo Colo. (May 1991). “Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 A”. Science 252 (5007): 809-17, the entire contents of which are incorporated herein). In some embodiments, separate zinc fingers that each recognizes a 3 base pair DNA sequence are combined to generate 3-, 4-, 5-, or 6-finger arrays that recognize target sites ranging from 9 base pairs to 18 base pairs in length. In some embodiments, longer arrays are contemplated. In other embodiments, 2-finger modules recognizing 6-8 nucleotides are combined to generate 4-, 6-, or 8-zinc finger arrays. In some embodiments, bacterial or phage display is employed to develop a zinc finger domain that recognizes a desired nucleic acid sequence, for example, a desired nuclease target site of 3-30 bp in length. Zinc finger nucleases, in some embodiments, comprise a zinc finger binding domain and a cleavage domain fused or otherwise conjugated to each other via a linker, for example, a polypeptide linker. The length of the linker determines the distance of the cut from the nucleic acid sequence bound by the zinc finger domain. If a shorter linker is used, the cleavage domain will cut the nucleic acid closer to the bound nucleic acid sequence, while a longer linker will result in a greater distance between the cut and the bound nucleic acid sequence. In some embodiments, the cleavage domain of a zinc finger nuclease has to dimerize in order to cut a bound nucleic acid. In some such embodiments, the dimer is a heterodimer of two monomers, each of which comprise a different zinc finger binding domain. For example, in some embodiments, the dimer may comprise one monomer comprising zinc finger domain A conjugated to a FokI cleavage domain, and one monomer comprising zinc finger domain B conjugated to a FokI cleavage domain. In this non- limiting example, zinc finger domain A binds a nucleic acid sequence on one side of the target site, zinc finger domain B binds a nucleic acid sequence on the other side of the target site, and the dimerize FokI domain cuts the nucleic acid in between the zinc finger domain binding sites. The term “zinc finger,” as used herein, refers to a small nucleic acid-binding protein structural motif characterized by a fold and the coordination of one or more zinc ions that stabilize the fold. Zinc fingers encompass a wide variety of differing protein structures (see, e.g., Klug A, Rhodes D (1987). “Zinc fingers: a novel protein fold for nucleic acid recognition”. Cold Spring Harb. Symp. Quant. Biol. 52: 473-82, the entire contents of which are incorporated herein by reference). Zinc fingers can be designed to bind a specific sequence of nucleotides, and zinc finger arrays comprising fusions of a series of zinc fingers, can be designed to bind virtually any desired target sequence. Such zinc finger arrays can form a binding domain of a protein, for example, of a nuclease, e.g., if conjugated to a nucleic acid cleavage domain. Different types of zinc finger motifs are known to those of skill in the art, including, but not limited to, Cys2His2, Gag knuckle, Treble clef, Zinc ribbon, Zn2/Cys6, and TAZ2 domain-like motifs (see, e.g., Krishna S, Majumdar I, Grishin N V (January 2003). “Structural classification of zinc fingers: survey and summary”. Nucleic Acids Res.31 (2): 532-50). Typically, a single zinc finger motif binds 3 or 4 nucleotides of a nucleic acid molecule. Accordingly, a zinc finger domain comprising 2 zinc finger motifs may bind 6-8 nucleotides, a zinc finger domain comprising 3 zinc finger motifs may bind 9-12 nucleotides, a zinc finger domain comprising 4 zinc finger motifs may bind 12-16 nucleotides, and so forth. Any suitable protein engineering technique can be employed to alter the DNA-binding specificity of zinc fingers and/or design novel zinc finger fusions to bind virtually any desired target sequence from 3-30 nucleotides in length (see, e.g., Pabo C O, Peisach E, Grant RA (2001). “Design and selection of novel cys2H is 2 Zinc finger proteins”. Annual Review of Biochemistry 70: 313-340; Jamieson A C, Miller J C, Pabo C O (2003). “Drug discovery with engineered zinc- finger proteins”. Nature Reviews Drug Discovery 2 (5): 361-368; and Liu Q, Segal D J, Ghiara J B, Barbas C F (May 1997). “Design of polydactyl zinc-finger proteins for unique addressing within complex genomes”. Proc. Natl. Acad. Sci. U.S.A.94 (11); the entire contents of each of which are incorporated herein by reference). Fusions between engineered zinc finger arrays and protein domains that cleave a nucleic acid can be used to generate a “zinc finger nuclease.” A zinc finger nuclease typically comprises a zinc finger domain that binds a specific target site within a nucleic acid molecule, and a nucleic acid cleavage domain that cuts the nucleic acid molecule within or in proximity to the target site bound by the binding domain. Typical engineered zinc finger nucleases comprise a binding domain having between 3 and 6 individual zinc finger motifs and binding target sites ranging from 9 base pairs to 18 base pairs in length. Longer target sites are particularly attractive in situations where it is desired to bind and cleave a target site that is unique in a given genome. In some embodiments, the agent for altering APE2 is a TALEN system or its equivalent. The term TALEN or “Transcriptional Activator-Like Element Nuclease” or “TALE nuclease” as used herein, refers to an artificial nuclease comprising a transcriptional activator like effector DNA binding domain to a DNA cleavage domain, for example, a FokI domain. A number of modular assembly schemes for generating engineered TALE constructs have been reported (Zhang, Feng; et. al. (February 2011). “Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription”. Nature Biotechnology 29 (2): 149-53; Geibler, R.; Scholze, H.; Hahn, S.; Streubel, J.; Bonas, U.; Behrens, S. E.; Boch, J. (2011), Shiu, Shin-Han. ed. “Transcriptional Activators of Human Genes with Programmable DNA-Specificity”. PLoS ONE 6 (5): e19509; Cermak, T.; Doyle, E. L.; Christian, M.; Wang, L.; Zhang, Y.; Schmidt, C.; Baller, J. A.; Somia, N. V. et al. (2011). “Efficient design and assembly of custom TALEN and other TAL effector- based constructs for DNA targeting”. Nucleic Acids Research; Morbitzer, R.; Elsaesser, J.; Hausner, J.; Lahaye, T. (2011). “Assembly of custom TALE-type DNA binding domains by modular cloning”. Nucleic Acids Research; Li, T.; Huang, S.; Zhao, X.; Wright, D. A.; Carpenter, S.; Spalding, M. H.; Weeks, D. P.; Yang, B. (2011). “Modularly assembled designer TAL effector nucleases for targeted gene knockout and gene replacement in eukaryotes”. Nucleic Acids Research.; Weber, E.; Gruetzner, R.; Werner, S.; Engler, C.; Marillonnet, S. (2011). Bendahmane, Mohammed. ed. “Assembly of Designer TAL Effectors by Golden Gate Cloning”. PLoS ONE 6 (5): e19722; each of which is incorporated herein by reference). Those of skill in the art will understand that TALE nucleases can be engineered to target virtually any genomic sequence with high specificity, and that such engineered nucleases can be used in embodiments of the present technology to manipulate the genome of a cell, e.g., by delivering the respective TALEN via a method or strategy disclosed herein under circumstances suitable for the TALEN to bind and cleave its target sequence within the genome of the cell. In some embodiments, the APE2 is altered by a nuclease delivered to the cell via a strategy or method disclosed herein, e.g., CRISPR/cas-9, a TALEN, or a zinc-finger nuclease, or a plurality or combination of such nucleases. In some embodiments, a single- or double-strand break is introduced at a specific site within the genome by the nuclease, resulting in a disruption of the target genomic sequence. Methods to integrate a polynucleotide sequence, such as one that results in the addition of, or knock-out of APE2, within a specific chromosomal site of, preferably a cancer cell via homologous recombination have been described within the art. For instance, site specific integration as described in US Patent Application Publication No.2009/0111188 A1 describes the use of recombinases or integrases to mediate the introduction of a donor polynucleotide sequence into a chromosomal target. In addition, International Patent Application No. WO 2008/021207 describes zinc finger mediated-homologous recombination to integrate one or more donor polynucleotide sequences within specific locations of the genome. The use of recombinases such as FLP/FRT as described in U.S. Pat. No. 6,720,475 or CRE/LOX as described in U.S. Pat. No. 5,658,772 can be utilized to integrate a polynucleotide sequence into a specific chromosomal site. Finally, the use of meganucleases for targeting donor polynucleotides into a specific chromosomal location was described in Puchta et al., PNAS USA 93 (1996) pp.5055-5060. The following terms are used in the description herein and the appended claims: Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the detailed description herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein “cancer” refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one. As used herein, “inhibits,” "inhibition" refers to the decrease in active of APE2 product relative to the normal wild type level. Inhibition may result in a decrease in activity of a target APE2, by less than 10%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. By “levels” or “expression” means the amount of a protein or RNA present in a cell. By “activity,” means an activity of molecules, such as a protein in a cell. Protein has “homology” or is “homologous” to a second protein if the amino acid sequence encoded by a gene has a similar amino acid sequence to that of the second gene. Alternatively, a protein has homology to a second protein if the two proteins have “similar” amino acid sequences. (Thus, the term “homologous proteins” is defined to mean that the two proteins have similar amino acid sequences). More specifically, in certain embodiments, the term “homologous” with regard to a contiguous nucleic acid sequence, refers to contiguous nucleotide sequences that hybridize under appropriate conditions to the reference nucleic acid sequence. For example, homologous sequences may have from about 75%-100, or more generally 80% to 100% sequence identity, such as about 81%; about 82%; about 83%; about 84%; about 85%; about 86%; about 87%; about 88%; about 89%; about 90%; about 91%; about 92%; about 93%; about 94% about 95%; about 96%; about 97%; about 98%; about 98.5%; about 99%; about 99.5%; and about 100%. The property of substantial homology is closely related to specific hybridization. For example, a nucleic acid molecule is specifically hybridizable when there is a sufficient degree of complementarity to avoid non-specific binding of the nucleic acid to non-target sequences under conditions where specific binding is desired, for example, under stringent hybridization conditions, and would fall within the range of a homolog. As used herein, “gene editing,” “gene edited” “genetically edited” and “gene editing effectors” refer to the use of homing technology with naturally occurring or artificially engineered nucleases, also referred to as “molecular scissors”, “homing endonucleases,” or “targeting endonucleases.” The nucleases create specific double-stranded chromosomal breaks (DSBs) at desired locations in the genome, which in some cases harnesses the cell's endogenous mechanisms to repair the induced break by natural processes of homologous recombination (HR) and/or nonhomologous end-joining (NHEJ). Gene editing effectors include Zinc Finger Nucleases (ZENs), Transcription Activator-Like Effector Nucleases (TALENs), the Clustered Regularly Interspaced Short Palindromic Repeats/CAS9 (CRISPR/Cas9) system, and meganucleases (e.g., meganucleases re-engineered as homing endonucleases). The terms also include the use of transgenic procedures and techniques, including, for example, where the change is a deletion or relatively small insertion (typically less than 20 nt) and/or does not introduce DNA from a foreign species. The term also encompasses progeny such as those created by sexual crosses or asexual propagation from the initial gene edited cell. For example, the edited chromosomal sequence of a target cancer cell may be (1) inactivated, (2) modified, or (3) comprise an integrated sequence resulting in a null mutation. An inactivated chromosomal sequence is altered such that a protein function as it relates to production of secondary metabolites is impaired, reduced or eliminated. Thus, a genetically edited animal comprising an inactivated chromosomal sequence may be termed a “knock out” or a “conditional knock out.” “Knockout” means disruption of the structure or regulatory mechanism of a gene. Knockouts may be generated through homologous recombination of targeting vectors, replacement vectors or hit-and-run vectors or random insertion of a gene trap vector resulting in complete, partial or conditional loss of gene function. As used herein, “homologous recombination” refers to a reaction between any pair of nucleotide sequences having corresponding sites containing a similar nucleotide sequence through which the two nucleotide sequences can interact (recombine) to form a new, recombinant DNA sequence. The sites of similar nucleotide sequence are each referred to herein as a “homology sequence.” Generally, the frequency of homologous recombination increases as the length of the homology sequence increases. Thus, while homologous recombination can occur between two nucleotide sequences that are less than identical, the recombination frequency (or efficiency) declines as the divergence between the two sequences increases. Recombination may be accomplished using one homology sequence on each of the donor and target molecules, thereby generating a “single crossover” recombination product. Alternatively, two homology sequences may be placed on each of the target and donor nucleotide sequences. Recombination between two homology sequences on the donor with two homology sequences on the target generates a “double crossover” recombination product. If the homology sequences on the donor molecule flank a sequence that is to be manipulated (e.g., a sequence of interest), the double-crossover recombination with the target molecule will result in a recombination product wherein the sequence of interest replaces a DNA sequence that was originally between the homology sequences on the target molecule. The exchange of DNA sequence between the target and donor through a double-crossover recombination event is termed “sequence replacement.” By “RNA interference” (RNAi) means a phenomenon where double-stranded RNA homologous to a target mRNA leads to degradation of the targeted mRNA (e.g., a APE2 mRNA). RNAi is more broadly defined as degradation of target mRNAs by homologous siRNAs. By “siNA” means small interfering nucleic acids. One exemplary siNA is composed of ribonucleic acid (siRNA). siRNAs can be 21-25 nt RNAs derived from processing of linear double- stranded RNA. siRNAs assemble in complexes termed RISC (RNA-induced silencing complex) and target homologous RNA sequences for endonucleolytic cleavage. Synthetic siRNAs also recruit RISCs and are capable of cleaving homologous RNA sequences. The term “operably linked,” when used in reference to a regulatory sequence and a coding sequence, means that the regulatory sequence affects the expression of the linked coding sequence. “Regulatory sequences,” or “control elements,” refer to nucleotide sequences that influence the timing and level/amount of transcription, RNA processing or stability, or translation of the associated coding sequence. Regulatory sequences may include promoters; translation leader sequences; introns; enhancers; stem-loop structures; repressor binding sequences; termination sequences; polyadenylation recognition sequences; etc. Particular regulatory sequences may be located upstream and/or downstream of a coding sequence operably linked thereto. Also, particular regulatory sequences operably linked to a coding sequence may be located on the associated complementary strand of a double-stranded nucleic acid molecule. As used herein, the term “promoter” refers to a region of DNA that may be upstream from the start of transcription, and that may be involved in recognition and binding of RNA polymerase and other proteins to initiate transcription. A promoter may be operably linked to a coding sequence for expression in a cell, or a promoter may be operably linked to a nucleotide sequence encoding a signal sequence which may be operably linked to a coding sequence for expression in a cell. An “inducible” promoter may be a promoter which may be under environmental control. Tissue-specific, tissue-preferred, cell type specific, and inducible promoters constitute the class of “non-constitutive” promoters. A “constitutive” promoter is a promoter which may be active under most environmental conditions or in most cell or tissue types. As used herein, the term “transformation” or “genetically modified” refers to the transfer of one or more nucleic acid molecule(s) into a cell. A yeast cell is “transformed” or “genetically modified” by a nucleic acid molecule transduced into the cell when the nucleic acid molecule becomes stably replicated by the cell. As used herein, the term “transformation” or “genetically modified” encompasses all techniques by which a nucleic acid molecule can be introduced into, such as a yeast cell, including both transient and stable transformation. Transformation methods and techniques are readily known to those of ordinary skill in the art and further are readily reproduced through commercially available kits for the same. The term “vector” refers to some means by which DNA, RNA, a protein, or polypeptide can be introduced into a host. The polynucleotides, protein, and polypeptide which are to be introduced into a host can be therapeutic or prophylactic in nature; can encode or be an antigen; or can be regulatory in nature, etc. There are various types of vectors including viruses, plasmid, bacteriophages, cosmids, and bacteria. An “expression vector” is nucleic acid capable of replicating in a selected host cell or organism. An expression vector can replicate as an autonomous structure, or alternatively can integrate, in whole or in part, into the host cell chromosomes or the nucleic acids of an organelle, or it is used as a shuttle for delivering foreign DNA to cells, and thus replicate along with the host cell genome. Thus, an expression vector are polynucleotides capable of replicating in a selected host cell, organelle, or organism, e.g., a plasmid, virus, artificial chromosome, nucleic acid fragment, and for which certain genes on the expression vector (including genes of interest) are transcribed and translated into a polypeptide or protein within the cell, organelle or organism; or any suitable construct known in the art, which comprises an “expression cassette.” In contrast, as described in the examples herein, a “cassette” is a polynucleotide containing a section of an expression vector of this invention. The use of a cassette assists in the assembly of the expression vectors. An expression vector is a replicon, such as plasmid, phage, virus, chimeric virus, or cosmid, and which contains the desired polynucleotide sequence operably linked to the expression control sequence(s). As is known in the art, different organisms preferentially utilize different codons for generating polypeptides. Such “codon usage” preferences may be used in the design of nucleic acid molecules encoding the proteins and chimeras of the invention in order to optimize expression in a particular host cell system. For example, all nucleotides of the present invention may be optimized for expression in a select organism, such as a mammals, yeast, algae, fungi, and bacteria. A polynucleotide sequence is operably linked to an expression control sequence(s) (e.g., a promoter and, optionally, an enhancer) when the expression control sequence controls and regulates the transcription and/or translation of that polynucleotide sequence. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), the complementary (or complement) sequence, and the reverse complement sequence, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (see e.g., Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). Because of the degeneracy of nucleic acid codons, one can use various different polynucleotides to encode identical polypeptides. The Table below contains information about which nucleic acid codons encode which amino acids. Amino acid Nucleic acid codons Amino Acid Nucleic Acid Codons Ala/A GCT, GCC, GCA, GCG Arg/R CGT, CGC, CGA, CGG, AGA, AGG Asn/N AAT, AAC Asp/D GAT, GAC Cys/C TGT, TGC Gln/Q CAA, CAG Glu/E GAA, GAG Gly/G GGT, GGC, GGA, GGG His/H CAT, CAC Ile/I ATT, ATC, ATA Leu/L TTA, TTG, CTT, CTC, CTA, CTG Lys/K AAA, AAG Met/M ATG Phe/F TTT, TTC Pro/P CCT, CCC, CCA, CCG Ser/S TCT, TCC, TCA, TCG, AGT, AGC Thr/T ACT, ACC, ACA, ACG Trp/W TGG Tyr/Y TAT, TAC Val/V GTT, GTC, GTA, GTG Moreover, because the proteins are described herein, one can chemically synthesize a polynucleotide which encodes these polypeptides/chimeric proteins. Oligonucleotides and polynucleotides that are not commercially available can be chemically synthesized e.g., according to the solid phase phosphoramidite triester method first described by Beaucage and Caruthers, Tetrahedron Letts.22:1859-1862 (1981), or using an automated synthesizer, as described in Van Devanter et al., Nucleic Acids Res. 12:6159- 6168 (1984). Other methods for synthesizing oligonucleotides and polynucleotides are known in the art. Purification of oligonucleotides is by either native acrylamide gel electrophoresis or by anion-exchange HPLC as described in Pearson & Reanier, J. Chrom.255:137-149 (1983). The term “expression,” as used herein, or “expression of a coding sequence” (for example, a gene or a transgene) refer to the process by which the coded information of a nucleic acid transcriptional unit (including, e.g., genomic DNA or cDNA) is converted into an operational, non- operational, or structural part of a cell, often including the synthesis of a protein. Gene expression can be influenced by external signals; for example, exposure of a cell, tissue, or organism to an agent that increases or decreases gene expression. Expression of a gene can also be regulated anywhere in the pathway from DNA to RNA to protein. Regulation of gene expression occurs, for example, through controls acting on transcription, translation, RNA transport and processing, degradation of intermediary molecules such as mRNA, or through activation, inactivation, compartmentalization, or degradation of specific protein molecules after they have been made, or by combinations thereof. Gene expression can be measured at the RNA level or the protein level by any method known in the art, including, without limitation, Northern blot, RT-PCR, Western blot, or in vitro, in situ, or in vivo protein activity assay(s). The term “nucleic acid” or “nucleic acid molecules” include single- and double-stranded forms of DNA; single-stranded forms of RNA; and double-stranded forms of RNA (dsRNA). The term “nucleotide sequence” or “nucleic acid sequence” refers to both the sense and antisense strands of a nucleic acid as either individual single strands or in the duplex. The term “ribonucleic acid” (RNA) is inclusive of iRNA (inhibitory RNA), dsRNA (double stranded RNA), siRNA (small interfering RNA), mRNA (messenger RNA), miRNA (micro-RNA), hpRNA (hairpin RNA), tRNA (transfer RNA), whether charged or discharged with a corresponding acetylated amino acid), and cRNA (complementary RNA). The term “deoxyribonucleic acid” (DNA) is inclusive of cDNA, genomic DNA, and DNA-RNA hybrids. The term “gene” or “sequence” refers to a coding region operably joined to appropriate regulatory sequences capable of regulating the expression of the gene product (e.g., a polypeptide or a functional RNA) in some manner. A gene includes untranslated regulatory regions of DNA (e.g., promoters, enhancers, repressors, etc.) preceding (up-stream) and following (down-stream) the coding region (open reading frame, ORF) as well as, where applicable, intervening sequences (i.e., introns) between individual coding regions (i.e., exons). The term “structural gene” as used herein is intended to mean a DNA sequence that is transcribed into mRNA which is then translated into a sequence of amino acids characteristic of a specific polypeptide. It should be noted that any reference to a SEQ ID, or sequence specifically encompasses that sequence, as well as all corresponding sequences that correspond to that first sequence. For example, for any amino acid sequence identified, the specific specifically includes all compatible nucleotide (DNA and RNA) sequences that give rise to that amino acid sequence or protein, and vice versa. A nucleic acid molecule may include either or both naturally occurring and modified nucleotides linked together by naturally occurring and/or non-naturally occurring nucleotide linkages. Nucleic acid molecules may be modified chemically or biochemically, or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those of skill in the art. Such modifications include, for example, labels, methylation, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications (e.g., uncharged linkages: for example, methyl phosphonates, phosphotriesters, phosphoramidates, carbamates, etc.; charged linkages: for example, phosphorothioates, phosphorodithioates, etc.; pendent moieties: for example, peptides; intercalators: for example, acridine, psoralen, etc.; chelators; alkylators; and modified linkages: for example, alpha anomeric nucleic acids, etc.). The term “nucleic acid molecule” also includes any topological conformation, including single-stranded, double-stranded, partially duplexed, triplexed, hair-pinned, circular, and padlocked conformations. The term “sequence identity” or “identity,” as used herein in the context of two nucleic acid or polypeptide sequences, refers to the residues in the two sequences that are the same when aligned for maximum correspondence over a specified comparison window. The terms “approximately” and “about” refer to a quantity, level, value, or amount that varies by as much as 30%, or in another embodiment by as much as 20%, and in a third embodiment by as much as 10% to a reference quantity, level, value or amount. As used herein, the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. The singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, the term “about” as used herein when referring to a measurable value such as an amount, dose, time, temperature, and the like, is meant to encompass variations of ± 20%, ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified amount. Also as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). The invention now being generally described will be more readily understood by reference to the following examples, which are included merely for the purposes of illustration of certain embodiments of the present invention. The examples are not intended to limit the invention, as one of skill in the art would recognize from the above teachings and the following examples that other techniques and methods can satisfy the claims and can be employed without departing from the scope of the claimed invention. Indeed, while this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. EXAMPLES Example 1: APE2 is required for MMEJ-mediated fusions of deprotected telomeres. To discover potentially uncharacterized effectors of MMEJ, Applicants exploited the synthetic lethality observed when cells lose both HR and MMEJ (Ceccaldi et al., 2015; Mateos- Gomez et al., 2015). To identify genes that are synthetically lethal with HRD in general, rather than with one gene in particular, they compared the genetic interactions of two HR genes, BRCA1 and PALB2 (Venkitaraman, 2001; Xia et al., 2006; Zhang et al., 2009). They created isogenic cell lines by knocking out BRCA1 or PALB2 in HT1080 fibrosarcoma HR-proficient cells. Applicants next performed genome-wide CRISPR-Cas9 dropout screens (Doench et al., 2016) in the HT1080, HT1080-BRCA1^KO and HT1080-PALB2^KO cells, which identified genes that are synthetically lethal with loss of BRCA1 or with PALB2 (Fig. 2A-C). Plotting the depletion scores of both dropout screens against each other revealed those genes whose depletion conferred synthetic lethality in both HR-deficient lines (Figure 2D). Among the top candidates, they found PARP1, XRCC1, NBN (encoding Nbs1), LIG3 and POLQ (encoding Polθ), which are already known to participate in MMEJ repair (Audebert et al., 2004; Ceccaldi et al., 2015; Dutta et al., 2017; Liang et al., 2005; Mateos-Gomez et al., 2015; Sfeir and Symington, 2015; Truong et al., 2013; Wang et al., 2006). In addition to the previously reported MMEJ genes, Applicants found CIP2A, ALC1 and APEX2 (encoding APE2) as significant hits (Fig.2D) and confirmed that deletion of these three genes is lethal in BRCA1^KO and PALB2 ^KO HT1080s but does not affect cellular fitness in the parental cells (Fig.2E). To determine whether these three genes are required for MMEJ repair, Applicants first exploited fusion of telomeres, which is a readout of MMEJ in cells depleted for TRF2 and Ku (Fig. 3 A-B). Using inducible Cas9 and two different small guide RNAs (sgRNA) per gene, Applicants knocked out APEX2, CIP2A and ALC1 in XRCC5^KO TERF2^F/- MEFs and induced telomere fusions with tamoxifen driven deletion of TERF2 (Fig. 3C-D). Treatment with Olaparib or POLQ knockout were used as positive controls of MMEJ inhibition. Deletion of CIP2A or ALC1 did not reduce MMEJ-mediated telomere fusions, indicating that these proteins are dispensable for MMEJ. In contrast, knockout of APEX2 significantly repressed telomere fusions by MMEJ to the same extent as knockout of POLQ. Furthermore, inhibition of Polθ did not further reduce the fusions in sgAPEX2 cells (Fig.3E), indicating that APE2 and Polθ function in the same pathway. By contrast, suppression of APE2 did not affect NHEJ-mediated telomere fusions (Fig.3F). Example 2: APE2 is a key effector of the MMEJ repair pathway. To test the function of APE2 in MMEJ beyond telomere fusions, Applicants first turned to fluorescent MMEJ DNA repair reporter assays in APEX2^KO clones. Applicants created an MMEJ DNA repair reporter that consists of a lentiviral mCherry cassette interrupted by an ISCe1 site flanked by a 10 bp microhomology. Upon expression of ISce1, repair of the cut site by microhomology annealing leads to reconstitution of the mCherry cassette and fluorescence expression (Fig. 4A). Applicants found that MMEJ was significantly reduced in all APEX2^KO clones when compared to the parental cells, and that the reduction in mCherry+ cells was comparable to that observed in POLQ^KO clones (Fig.4B) . To exclude potential off-target effects or clonal divergences, Applicants complemented the parental cells and the APEX2 knockout clones containing the MMEJ reporter with an empty vector (EV) or with exogenous APE2. While exogenous expression of APE2 had no effect on MMEJ activity in the parental cells compared to the cells transduced with an empty vector, re-expression of APE2 significantly increased the percentage of mCherry+ cells in the APEX2^KO clones (Fig.4C). Further knock-out of POLQ had no additional effect, indicating, again, that both genes function in the same pathway (Fig. 4D). Finally, Applicants recapitulated these results using amplicon sequencing on a genome- inserted sequence containing an 11 bp microhomology spaced by 10 bp and where the DSB was induced using Cas9 (Fig.4E-G). Collectively, these data demonstrate that APE2 is a required for MMEJ repair of DSBs. Example 3: Domains of APE2 that are required for MMEJ. APE2 belongs to the ExoIII family of nucleases (Hadi and Wilson 2000). Its catalytic domain, which possesses endonuclease, 3’-5’ exonuclease, and phosphodiesterase activities (EEP), is related to the base excision repair (BER) AP endonuclease APE1, but APE2 displays stronger exonuclease and weaker AP endonuclease activities (Unk, Haracska et al. 2000, Unk, Haracska et al. 2001, Hadi, Ginalski et al. 2002). To test whether APE2’s function in MMEJ depends on the EEP domain, Applicants introduced two mutations, D196N (CD1) and D276A (CD2), that suppress all three catalytic activities of APE2 (Hadi, Ginalski et al.2002, Burkovics, Szukacsov et al. 2006, Alvarez-Quilon, Wojtaszek et al. 2020) (Fig. 5A). They stably complemented the XRCC5^KO TERF2^F/- iCas9-sgAPEX2 MEFs with empty vector (EV) or with Doxycycline-inducible wild-type or mutant mouse APE2 and tested the capacity of the catalytic dead APE2 mutants to rescue MMEJ-mediated telomere fusions (Fig. 5B). As expected, they observed very few telomere fusions in sgAPEX2 cells without complementation (~5% fused telomeres), while exogenous wildtype APE2 expression restored the levels of fusions to that observed in wildtype cells (~20%). Expression of catalytic dead APE2 mutants could not rescue the levels of fusions, indicating that the catalytic activity of APE2 is critical for its role in MMEJ. Beyond its catalytic domain, APE2 also possesses a C-terminal domain that is absent in APE1, which contains a PCNA interacting peptide (PIP) box and a zinc-finger motif (Zf-GRF). The interaction of APE2 with PCNA through its PIP-box facilitates its recruitment to sites of oxidated DNA damage (Burkovics, Hajdu et al.2009). In vitro, PCNA promotes APE2’s activity at 3’ resected DNA and at 3’ blocks (Unk, Haracska et al. 2002, Burkovics, Hajdu et al. 2009, Wallace, Berman et al.2017). Applicants complemented APE2 suppression in their fusion assay with a mutant carrying a deletion of the PIP-box (∆PIP) and observed that expression APE2∆PIP fully rescued telomere fusions (Fig. 5B), showing that the PIP-box is dispensable for MMEJ- mediated fusions. The Zinc-finger motif promotes the recruitment of APE2 to ssDNA and its subsequent PCNA-mediated exonuclease activity (Wallace, Berman et al. 2017) and directly interacts with PCNA in Xenopus (Lin, Bai et al. 2018). Expression of APE2∆Zf-GRF led to an intermediate phenotype (Fig. 5B), suggesting that MMEJ-driven repair is only partially dependent on a functional Zf-GRF. Finally, to determine whether the PIP and the zinc-finger motifs could have a redundant role in the recruitment of APE2 to DSBs and its MMEJ function, Applicants complemented cells with an exogenous mAPE2 that carried both the PIP-box deletion and the zinc-finger mutation (APE2∆PIP-Zf^mut), or the double deletion and (APE2∆PIP-∆Zf) (Figures 5B). They found that deletion of the PIP-box had no additional effect on telomere fusions compared to the zinc-finger mutant or deletion alone, suggesting that the PCNA-interacting property of these motifs is not required for MMEJ repair. To extend these observations to intra-chromosomal break repair, Applicants created a series of mutants in human APE2 and tested whether they could complement APEX2 knockout in their MMEJ reporter system (Fig.5C). They obtained similar results as with the telomere fusion assay. Collectively, these data show that MMEJ repair requires APE2 nuclease activity but neither its PIP-box nor its Zinc-finger motif. To identify potentially uncharacterized regions of APE2 that could function in MMEJ, Applicants analyzed APE2’s sequence for conserved regions. They discovered that, beyond the already known EEP, PIP and Zf-GRF domains, two other amino acid stretches showed a high level of conservation (Fig. 5D). To test whether these conserved regions, which they named CR1 and CR2, are involved in MMEJ, they created CR1 and CR2 deletion mutants and tested their capacity to complement APEX2 knockout in telomere fusion assays and DNA reporter assays (Fig.5E-G). They found that both CR1 and CR2 are required for MMEJ activity at deprotected telomeres and intra-chromosomal DSBs. Example 4: APE2 motifs participation in MMEJ predicts their requirement for HRD cell survival. Applicants sought to determine whether the dependence of HRD cell on APE2 is due to its MMEJ repair function, by testing whether the domains that are required or dispensable for MMEJ activity are similarly necessary or dispensable for survival in HRD cells. They performed a fluorescent growth competition assay in BRCA1^KO and PALB2^KO cells after complementation of sgAPEX2 with the different hAPE2 mutants (Figure 6A-B). They found that the catalytic activity of APE2 as well as the two CR domains, which are required for MMEJ, are similarly essential for survival of HRD cells. The zinc-finger mutants showed an intermediate phenotype, similar to what was observed for MMEJ activity. Importantly, Applicants found that APE2∆PIP could fully rescue cellular survival, indicating that it is dispensable for both MMEJ and survival of HRD cells. Finally, as for MMEJ activity, the double ∆PIP-Zf^mut mutant displayed a similar impact on cellular fitness as the zinc-finger mutation alone. Applicants conclude from these results that a domain’s importance in APE2’s MMEJ activity correlates with its requirement for HR-deficient cells survival, which strongly suggest that APE2’s function in MMEJ is critical for the growth of HRD cells. Example 5: HRD cells resistant to PARPi remain sensitive to APE2 suppression Applicants found that cells with HR deficiency are critically dependent on APE2 for survival. Applicants’ preliminary data (Fig.7) also suggest that APE2 suppression is likely to be a successful strategy to treat PARPi resistant cancers. In conclusion, considering that HR-deficient cells are fully dependent on MMEJ and that our data point at APE2 as core component of the MMEJ pathway, APE2 represents a potential therapeutic target to eliminate HRD cancers, either as an alternative to or in combination with POLQ or PARP inhibitors (Zatreanu et al., 2021). In one embodiment, the Applicant can incorporate the use of combinatorial libraries to isolate and characterize small molecules or macromolecules, which bind to or interact with APE2, also referred to herein as a APE2 synthetic inhibitor. The relative binding affinity of these compounds can be compared, and optimum compounds identified using competitive binding studies, which are well known to those of skill in the art. Techniques for making combinatorial libraries and screening combinatorial libraries to isolate molecules that bind a desired target are well known to those of skill in the art. Representative techniques and methods can be found in but are not limited to U.S. Pat. Nos. 5,084,824, 5,288,514, 5,449,754, 5,506,337, 5,539,083, 5,545,568, 5,556,762, 5,565,324, 5,565,332, 5,573,905, 5,618,825, 5,619,680, 5,627,210, 5,646,285, 5,663,046, 5,670,326, 5,677,195, 5,683,899, 5,688,696, 5,688,997, 5,698,685, 5,712,146, 5,721,099, 5,723,598, 5,741,713, 5,792,431, 5,807,683, 5,807,754, 5,821,130, 5,831,014, 5,834,195, 5,834,318, 5,834,588, 5,840,500, 5,847,150, 5,856,107, 5,856,496, 5,859,190, 5,864,010, 5,874,443, 5,877,214, 5,880,972, 5,886,126, 5,886,127, 5,891,737, 5,916,899, 5,919,955, 5,925,527, 5,939,268, 5,942,387, 5,945,070, 5,948,696, 5,958,702, 5,958,792, 5,962,337, 5,965,719, 5,972,719, 5,976,894, 5,980,704, 5,985,356, 5,999,086, 6,001,579, 6,004,617, 6,008,321, 6,017,768, 6,025,371, 6,030,917, 6,040,193, 6,045,671, 6,045,755, 6,060,596, and 6,061,636. In one embodiment, Applicants can use a series of cellular assays to screen a large compound library and identify chemical inhibitors of APE2: (1) Using cell viability as readout, Applicants will identify compounds that specifically kill HR-deficient cells. Applicants’ Crispr/Cas9 screening approach proved to be particularly efficient to identify MMEJ genes and to eliminate many unspecific hits (found in individual BRCA1 and PALB2 screens) (Fig.2). Using previously prepared isogenic cell lines, Applicants can screen for chemical compounds that kill both BRCA1KO and PALB2KO cells but not the parental HR-proficientHT1080. Applicants can next perform secondary and tertiary screenings based on MMEJ activity and APE2 inhibition. Specifically, Applicants can screen the compounds identified in (1) for MMEJ activity inhibition, using the Cas9-mediated MMEJ reporter described in Fig. 3C-left. Applicants can further select compounds that inhibit MMEJ repair (that reduce the percentage of mCherry+ cells uponexpression of Cas9). Applicants’ reporter can be easily used as a screening tool, as it is integrated (no transfection needed), is inducible (Cas9 can be Doxinduced after treatment with the compound library) and the output (fluorescence) is compatible with high throughput screening. (3) Finally, among the compounds which inhibit MMEJ repair (identified in (2)), Applicants can identify those that target APE2. Applicants can further test in cellular assays APE2 inhibitors potential to kill HRD cancer cells. Because ovarian cancers display the largest proportion of HR deficiency, Applicants can work primarily with ovarian cancers as a cellular model and can determine whether APE2 inhibition can synergize with PARP inhibitors, prevent resistance mechanisms, and finally kill resistant cells. To determine the synergistic potential of APE2i and PARPi, Applicants can use previously prepared isogenic cell lines as well as several HRD ovarian cancer cells and measure cellular viability upon treatment with increasing doses of PARPi and APE2i alone or in combination. Applicants can then test whether this double inhibition reduces the occurrence of PARPi resistance, using cellular models of acquired drug resistance. The mechanisms leading to PARPi resistance are multiple and, APE2 inhibition to kill cells with a reverted BRCA mutation, such that Applicants can demonstrate that cells with other types of resistance mechanisms could remain sensitive to APE2 inhibition. Indeed, Applicants found that genetic suppression of APE2 led to cellular mortality in both PARPi-sensitive and -resistant isogenic HRD ovarian cancer cell lines (Figure 5A-B). Applicants can test the sensitivity of wide collection of PARPi-sensitive and -resistant lines with one or more APE2 inhibitors. Example 6: Materials and Methods Cell lines, cell culture and drugs: HT1080 were derived from patient diagnosed with fibrosarcoma and purchased from ATCC (CCL-121). MEFs TRF2F/- Rosa26-CreERT2 were established in the de Lange lab (REF Celli 2005) and obtained from ATCC (CRL-3317). Lenti-X 293T were derived from a transformed human embryonic kidney cell line and purchased from Takara (#632180). All these cell lines and their derivates were maintained in a low oxygen condition (3% O2 and 7.5% CO2) and grown in DMEM medium (Corning # 10-013CV) with 10% Bovine Calf Serum (Seradigm #2100-500),100 μg/mL Penicilin/Streptomycin (Lonza #09-757F) and 1X MEM Nonessentiel Amino Acids (Corning#25-025CI). U2OS were derived from a moderately differentiated sarcoma, purchased from ATCC (HTB-96), and cultured in Dulbecco’s modified Eagle’s medium (DMEM) at 37°C with 5% CO2. Drugs used are Doxycycline (1µg/ml, TCI #D4116), Olaparib (20µM, Selleckchem, AZD2281 #S1060), DNA-PKi (1µM, NU7441, R&D Systems, #3712/10), 4-Hydroxy-tamoxifen (1µM,4OHT, Cayman chemical company #17308) Plasmids: For CRISPR-Cas9 mediated knocks-out, except when stated otherwise, sgRNAs were cloned into pLenti-Guide-iCas9-Blast, a modified form of TLCV2 (Barger et al., 2019) (A gift from Adam Karpf, Addgene #87360) in which eGFP was removed and puromycin was replaced by blasticidin resistance. Guides cloning was done following the golden gate cloning protocol and verified by Sanger sequencing. For APE2 exogenous expression, Myc-tagged codon- optimized human and mouse APEX2 were obtained by DNA synthesis (gBlocks, IDT DNA), and cloned using InFusion (Takara) into pLenti-rtta- Hygro, a modified form of pLIX_403 (A gift from David Root, Addgene #41395) in which Puro was replaced by Hygromycin selection and the bases 547-2297 were replaced by the myc-tagged constructs. All the different mutant versions of APE2 were then obtained by PCR and InFusion cloning. To create the MMEJ reporter (pLenti-Puro-MMEJ_rep), we used a modified form of pLenti- puro (Guan et al., 2011) (A gift from le-Ming Shih, Addgene #39481) in which the bases 2525-2982 were replaced by CMV enhancer/promoter - MMEJ reporter – WPRE. The MMEJ reporter is made of mCherry- T2A-BFP in which the mCherry sequence is interrupted by with an I-SceI restriction site flanked by 10 bp of microhomology. The sequence was obtained by DNA synthesis (IDT DNA), and cloning was performed using InFusion (Takara). The MMEJ Sce1 reporter was further modified to create pLenti-Neo-MMEJ_seq, in which we replaced the puromycin selection by neomycin, and replaced the microhomology-ISce1 site by 10 bp microhomologies flanking 11 bp that can be cut with Cas9. For cloning we used synthetic DNA gBlocks from IDT DNA and InFusion (Takara). All plasmids were verified by restriction digest and Sanger sequencing. Lentiviral transduction and infection: To produce lentivirus, 500,000 Lenti-X 293T cells were in one well of a 6-well plate. The next day, cells were transfected with packaging plasmids (0.5µg pCMV-VSV-G, 1.1µg pD8.9), 0.85µg transfer plasmid, 7.35µg of PEI MAX (Polysciences Inc. - Cat #: 24765-1) and 10mM HEPES. Media was refreshed 24h later with 3ml of complete DMEM. Virus-containing supernatant was collected 48h and 72h post transfection, cleared through a 0.45µm PES Filter membrane (Whatman Uniflo #9914-2504) and directly used to infect cells in the presence of 5 µg.ml polybrene (EMD Millipore #TR-1003-G). Forty- eight hours after infection, cells were washed and selected with 1 μg/ml Puromycin (Alfa Aesar #J61278- MC), 500 μg/ml G418 (neomycinR) (Cornung #30-234-CR), 200μg/ml Hygromycin B (Biosciences #31282-04-9), or 10 μg/ml Blasticidin (RPI #B12200-0.05). Selection was performed until complete death of control uninfected cells. Knock-out cells: For knock-out of BRCA1 and PALB2, HT1080 cells were subjected to three rounds of transfection with pX330 (Cong et al., 2013) (A gift from Feng Zhang, Addgene #42230) containing sgBRCA1 or sgPALB2, using Lipofectamine 2000 (ThermoFisher Scientific #11668027). Individual clones were isolated and pre-screened on sensitivity to Olaparib and by Western blot. Finally, selected clones were verified by allele sequencing: Total genomic DNA was extracted using 30µl of Quick extract (Biosearch Technologies – Cat #: QE09050) and PCR amplified around the Cas9 cut region using KOD master mix (EMD Millipore Corporation – Cat #: 71842-3). The PCR products were cloned into pCR™Blunt II- TOPO™ using the Zero Blunt™ TOPO™ PCR Cloning Kit (ThermoFisher #450245), transformed into DH5 competent cells and at least 12 bacterial clones were analyzed by Sanger sequencing. For knock-out of XRCC5, MEFs TRF2F/- Rosa26 CreERT2 were transduced with pLentiGuide- iCas9-Puro, a modified form of TLCV2 (Barger et al., 2019) (A gift from Adam Karpf, Addgene #87360) in which eGFP was removed, and the XRCC5 gRNA was cloned. Individual cellular clones were isolated and screened by western blot. For knock-out of APEX2 and POLQ, HT1080 cells were transduced with pLentiGuide-iCas9-Blast containing a guide RNA targeting APEX2 or POLQ, individual cellular clones were isolated and analyzed by PCR amplification and TOPO cloning followed by sanger sequencing. CRISPR-Cas9 screens: For each isogenic cell line (Parental HT1080, HT1080- BRCA1^KO, and HT1080-PALB2^KO), 150 million cells were spinfected (Joung et al., 2017) for 2 hours at 1,000g and 33ºC in 24-well plates (3.2 million cells per well in 3 ml of medium and 10 µg/mL of polybrene) with the Brunello genome-wide CRISPR/Cas9 library (Doench et al., 2016) (viral particles were directly obtained from Addgene, #179- LV73) at an MOI of 0.3. 24 hours later, cells were trypsinized and transferred to 15 cm tissue culture petri dishes, then selected the next day with 0.6µg/mL puromycin. Selected cells were then regularly split and counted, with minimal seeding of 45 million cells, and cultured for 12 population doublings after selection. Sequencing and analysis: Genomic DNA were then isolated using QIAamp DNA Blood Kits (QIAGEN #51104), sonicated, guide RNA sequences were captured using the Fli-Seq Library prep kit (Eclipse Bio), and PCR amplified with indexes and adapters for Illumina sequencing. The library was sequenced on an Illumina NovaSeq through Novogene Co. Paired-end reads were aligned used Bowtie 2 (Langmead and Salzberg, 2012), and the gRNA counts were counted using a lab developed Python script. Count files were then analyzed using MAGeCK (Li et al., 2014). Telomeric fusion assay: Six days after treatment with 4-hydroxy-tamoxifen, MEFs were synchronized in metaphase for 3 hours with 0.1 µg/ml colcemid (Gibco KaryoMAX, #15212-012), media and cells were collected and pooled, centrifuged and subjected to hypotonic choc in 10ml 75mM KCl for 30 minutes at 37ºC, then fixed and washed 3 times in methanol::glacial acetic acid 3::1 (v/v). Metaphases were then dropped onto superfrost microscope slides and dried overnight. For FISH, slides were rehydrated 10 min in PBS, fixed with 3.7% formaldehyde for 2min, washed 5 minutes in PBS, then treated 10 minutes at 37ºC with 1 mg/ml pepsin in citric acid pH2, washed 3 times in PBS and fixed again in formaldehyde for 2 min. After three PBS washes, the slides were dehydrated in consecutive ethanol baths (75%, 95% and 100%, 3 minutes each) and allowed to air dry. Slides were then layered with 40 μl of 0.3 ng μl−1 Alexa488-OO- (CCCTAA)3 PNA probe (PNA Bio Inc. #F1001), diluted in 70% (v/v) deionized formamide; 0.25% (v/v) blocking reagent (NEN); 10 mM Tris pH 7.5; 4.1 mM Na2HPO4; 450 μM citric acid; 1.25 mM MgCl2), denatured for 4 min at 76 °C and incubated for 2 h at room temperature. Slides were then washed twice for 15 min in 70% (v/v) formamide; 10 mM TrisHCl pH 7.5 and three times for 5 min in 50 mM TrisHCl pH 7.5; 150 mM NaCl; 0.08% Tween-20. Slides were mounted with Vectashield Plus Dapi (Vector Laboratories H-1900). MMEJ Reporter assay: Parental HT1080, POLQ^KO, and APEX2^KO clones were transduced with pLenti-Puro-MMEJ_rep and selected with puromycin. Parental HT1080s and APEX2^KO clones containing the MMEJ reporter were then transduced with pLenti-rtta-Hygro-EV or pLenti-rtta-Hygro-hApe2, or mutant APE2 constructs (Clone A1.7 only). Cells were then transfected with pCVL.Sce-T2A-BFP (A gift from Andrew Scharenberg obtained from Addgene #32627) using lipofectamine 3000 (following manufacturer’s instructions). Reporter cells were split and passaged for 6 days, then analyzed by FACS for BFP and mCherry expression. The percentage of mCherry+ and BFP+ cells was quantified from gated BFP+ cells that received the I- SceI virus. MMEJ sequence and MiSeq-Sequencing: Clones A1.7 were transduced with pLenti- Neo-MMEJ_seq, selected with G418, then complemented with the pLenti-rtta-Hygro-EV or pLenti-rtta-Hygro-hApe2 and selected with hygromycin. Doxycycline was used to induced hApe2 expression. Three days after dox treatment, cells were transduced with pLenti- CRISPRv2-Puro (Stringer et al., 2019) (a gift from Brett Stringer, Addgene #98290) in which the corresponding guide RNA to cut the MMEJ sequence was cloned. Cells selected with puromycin were then harvested and total genomic DNA was extracted using Quick extract (Biosearch Technologies – Cat #: QE09050). For the first PCR, we used primers amplifying a sequence of 78bp around the Cas9 cut region of the reporter. The first PCR was performed in 25µl reactions, each consisting of 2x KOD master mix (EMD Millipore Corporation – Cat #: 71842-3), 300 ng of template DNA, and 0.25 μM of primers for 30 cycles. PCR purifications were performed using AMPure XP beads (Beckman Coulter Inc – Cat #: A63881) at a ratio of x2. For the second PCR, we diluted the amplicons from the first PCR 20-fold and used these amplicons as a template for the primers that are attached to the Illumina MiSeq adapter sequences and an 8-bp barcode sequence as an index to distinguish each PCR amplicon. The second PCR was performed in 25µl reactions, each consisting of 2x KOD master mix, 1.25 µl of PCR1 and 0.25 μM of primers during 10 cycles. PCR purifications were then performed using AMPure XP beads at a ratio of x1.4. Concentrations were calculated by Qubit dsDNA High Sensitivity Kit (Invitrogen – Cat #: Q32854) and the different amplicons were mixed to obtain a 4nM pooled library solution. The quality and size were analyzed by 2100 BioAnalyzer High Sensitivity DNA kit (Agilent Technologies – Cat #: 5067- 4626). Pooled libraries at 4nM were denatured and diluted to 8pM with 20% PhiX control (Illumina – Cat #: FC-110-3001) per the Illumina Denature and Dilute Libraries Guide Protocol A (Illumina Document # 15039740v10).8pM denatured library and MiSeq Reagent Kit (Illumina – Cat #: MS-103-1002) were loaded into the MiSeq system (Illumina – Cat #: SY-410-1003) per the Illumina MiSeq System Guide (Illumina Document # 15027617v06). Sequencing data was paired- end aligned using the program PEAR (Zhang et al., 2014) with the following options: -j 8. Paired- end aligned reads were then trimmed using the program cutadapt (Martin et al., 2006). Trimmed reads were then sorted, counted, and analyzed using a lab developed Python script. Growth competition assay: Indicated sgRNAs were cloned into LentiGuide-iCas9-Blast- eGFP or LentiGuide-iCas9-Blast-RFP, a modified form of TLCV2 (Barger Cancers 2019) (addegene #87360) in which Cas9-T2A-eGFP and EF1a-Puro were replaced by Cas and EF1a- Blast-T2A-RFP or EF1a- Blast -T2A-eGFP. After lentiviral infection and blasticidin selection, mCherry and GFP-expressing cells were mixed 1:1 (15,000 cells each) and seeded in a 12-well plate with doxycycline (1µg/ml) to induce Cas9 expression. Cells were then harvested for flow cytometry analysis of GFP and mCherry fluorescence on the indicated day, with d0 corresponding to 48 hours post Cas9 induction. Immunoblotting: Whole cell lysates were prepared by scraping cells with cold PBS. Protein extracts were done by using RIPA containing a protease and phosphatase inhibitor cocktail (Roche_05892791001). Protein concentration was measured using the bicinchoninic acid (BCA) protein assay (Thermo Fisher Scientific #23227). Thirty micrograms of total protein extracts were separated on Bolt 4-12% Bis-Tris Plus gels (Invitrogen #NW04120) and transferred onto PVDF membrane (Amersham Hybond P 0.2µm PVDF, GE Healthcare Life science #10600057). Membranes were blocked with 5% skim milk in PBS-Tween for 1 hour, incubated overnight at 4°C with primary antibodies diluted in 5% skim milk in PBS-Tween, washed three times with PBS-T, incubated 1 hour at room temperature with HRP-conjugated secondary antibodies diluted in 5% skim milk in PBS-Tween, and washed three times with PBS-T. Finally, proteins were detected using enhanced chemiluminescence (Super Signal West Pico Plus, Thermo Scientist, # 34580) and chemiluminescence was imaged on a G:Box chemi XX6 (Syngene). Antibodies used: BRCA1 (Cell Signaling, #9010T, diluted at 1:1000), PALB2 (generous gift from Jean-Yves Masson), TRF2 (Novus, #NB110-57130, diluted at 1:1000), Ku80 (Cell Signaling, #2753, diluted at 1:1000), ß-actin (Cell Signaling, #8457, diluted at 1:5000), secondary anti-Mouse-HRP (Cell Signaling, #70765, diluted at 1:3000), and secondary anti- Rabbit-HRP (Cell Signaling, #7074P2, diluted at 1:3000). Immunofluorescence: For immunofluorescence, 15,000 HT1080, HT1080-BRCA1^KO, or HT1080-PALB2^KO cells were plated on coverslips 24 hours prior to treatment. Cells were either irradiated with 8Gy of ionizing radiation or left unirradiated. Cells were allowed to recover for 2 hours, fixed with 10% formalin for 15 mins, washed with 1x PBS, permeabilized with 0.5% Triton- X and 0.2M HCl for 10 minutes, washed again with 1x PBS and blocked with a 4:1 ratio of 10% BSA in PBS-Tween 0.05% and 20% FBS in PBS for 75 minutes. After blocking, cells were rinsed with PBS and incubated with primary antibodies against Rad51 (Mouse Anti-Rad51 monoclonal, Abcam ab213, diluted at 1:500) or γH2AX (Rabbit mAb Phospho-H2A.X S139, Cell Signaling #9718, diluted at 1:1000) overnight at 4°C. The following day the cells were washed with PBS and incubated with secondary AlexaFluors (Goat anti-Mouse IgG (H+L) Secondary Antibody AlexaFluor 568; Goat anti-Rabbit IgG (H+L) Secondary Antibody AlexaFluor 488, diluted at 1:500) in blocking buffer for 1 hour. Cells were again rinsed with PBS and subsequently dH2O. Coverslips were gently dried and fixed onto slides with ProLongGold + DAPI dye and imaged on an ECHO Revolve Light Microscope. Images were compiled and analyzed using ImageJ. The data from biological triplicate experiments were expressed as mean ± SDs and analyzed by ANOVA for bar graphs or Mann-Whitney test for scatter plots. Sample size was indicated in corresponding Figure Legends. 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TABLES Guide RNAs Human hBRCA1 AAGGAGCCAACATAACAGAT (SEQ ID NO.3) hPALB2 TCACCGCAGCTAAAACACTC (SEQ ID NO.4) hApe2-sg1 ATAACCCTCAACGATAGCCA (SEQ ID NO.5) hApe2-sg2 CAACGTGTACTGCCCCCATG (SEQ ID NO.6) hPolq-sg1 CTGACTCCAAAAGCGGTACA (SEQ ID NO.7) hPolq-sg2 GACTTGTCAGGCCACTAGTG (SEQ ID NO.8) hCip2a-sg1 TAAATGTTTAGAACCTACTG (SEQ ID NO.9) hCip2a-sg2 TCAGTGAAGCACTTATGTTG (SEQ ID NO.10) hALC1-sg1 ACAGAAGTAGTGATATACCA (SEQ ID NO.11) hALC1sg2 GTCGCCTGCATATGTTACAC (SEQ ID NO.12) Mouse mXRCC5 CTACGGAAGTGATATCATTC (SEQ ID NO.13) mApe2-sg1 CCAGACTACTTGCATCGCAG (SEQ ID NO.14) mApe2-sg2 ATTTACCAGAATAGCCACTA (SEQ ID NO.15) mPolq-sg1 AGCCCTCACTCCCTTTACAA (SEQ ID NO.16) mPolq-sg2 TAATTGAAATGGGAGTACGG (SEQ ID NO.17) mCip2a-sg1 AGGTAGCCGATTCTGAGTTG (SEQ ID NO.18) m^Cip2a-sg2 _{AAATTGCTGATTATCTGACC (SEQ ID NO. 19)} mALC1-sg1 AGTGGGCATGAACTTAACAG (SEQ ID NO.20) m^ALC1-sg2 _{CAGGACTATATGGACTACAG (SEQ ID NO. 21)} Other MMEJ_seq GGATATTCTGTAACTGACTA (SEQ ID NO.22) 5 MMEJ Reporter Sequencing Fw CCTACACGACGCTCTTCCGATCTGCTAAGTTGAAGGTGACGAAGGG (SEQ ID NO.23) PCR1 Rev GTTCAGACGTGTGCTCTTCCGATCTGCTGGGTGTTTTACGTATGCC (SEQ ID NO.24) F_w ^{AATGATACGGCGACCACCGAGATCTACACNNNNNNNNACACTCTTTCCCTACACGACGCTCTTCCGATCT (SEQ ID} PCR2 NO.25) Rev CAAGCAGAAGACGGCATACGAGATNNNNNNNNGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT (SEQ ID NO. 26) * NNNNNN corresponds to barcode sequences for the different samples.

Claims

CLAIMS What is claimed is: 1. A method of treating cancer in a subject in need thereof, comprising the step of inhibiting the activity or expression of APE2.

2. The method of claim 1, wherein said APE2 comprises the nucleotide sequence according to SEQ ID NO.1, or a sequence having at least 90% sequence homology with SEQ ID NO.1.

3. The method of claim 1, wherein said APE2 comprises the amino acid sequence according to SEQ ID NO.2, or a fragment thereof.

4. The method of claim 1, wherein said of inhibiting comprises inhibiting the catalytic domain of APE2.

5. The method of claim 1, wherein said of inhibiting comprises administering a therapeutically effective amount of an APE2 inhibitor selected from: an APE2 synthetic inhibitor, an inhibitory nucleic acid molecule, an antibody or a biologically active fragment thereof, or an aptamer.

6. The method of claim 5, wherein said inhibitory nucleic acid molecule is selected from: an antisense nucleic acid, an RNAi, an siRNA, an shRNA, and inhibitory RNA, an anti-sense oligonucleotide, a DNA enzyme, and a ribozyme.

7. The method of claim 5, wherein said antibody or a biologically active fragment thereof comprises a monoclonal antibody, or a polyclonal antibody that specifically binds to APE2.

8. The method of claim 5, wherein said aptamer comprises an aptamer that specifically binds to APE2.

9. The method of claim of any of claims 1-8, further comprising administering a therapeutically effective amount of a PARP inhibitor (PARPi).

10. The method of claim of any of claims 1-9, wherein said cancer comprises a cancer that is PARPi resistant, homologous-recombination (HR) deficient, or a combination of both.

11. A method of treating cancer in a subject in need thereof, comprising the step of administering: − a therapeutically effective amount of an APE2 inhibitor; − a therapeutically effective amount of a PARP inhibitor (PARPi); and wherein said cancer is homologous-recombination (HR) deficient.

12. The method of claim 11, wherein said APE2 comprises the nucleotide sequence according to SEQ ID NO.1, or a sequence having at least 90% sequence homology with SEQ ID NO.1.

13. The method of claim 11, wherein said APE2 comprises the amino acid sequence according to SEQ ID NO.2, or a fragment thereof.

14. The method of claim 11, wherein said APE2 inhibitor targets the catalytic domain of APE2.

15. The method of claim 11, wherein said APE2 inhibitor is selected from: an APE2 synthetic inhibitor, an inhibitory nucleic acid molecule, an antibody or a biologically active fragment thereof, or an aptamer.

16. The method of claim 15, wherein said inhibitory nucleic acid molecule is selected from: an antisense nucleic acid, an RNAi, an siRNA, an shRNA, and inhibitory RNA, an anti-sense oligonucleotide, a DNA enzyme, and a ribozyme.

17. The method of claim 15, wherein said antibody or a biologically active fragment thereof comprises an antibody or a biologically active fragment thereof that specifically binds to APE2.

18. The method of claim 15, wherein said aptamer comprises an aptamer that specifically binds to APE2.

19. The method of claim 11, wherein said APE2 inhibitor and said PARPi are co-administered.

20. The method of claim 11, wherein said APE2 inhibitor and said PARPi are administered separately.

21. The method of claim 11, wherein said APE2 inhibitor is administered before the PARPi is administered to the subject.