WO2024263795A2 - Combination treatment to prevent or minimize chemotherapy-induced peripheral neuropathy - Google Patents

Abstract

Compositions and methods are provided for a combination to treat cancer and prevent the occurrence of neurotoxicity or reduce the incidence or severity of CIPN. The combination therapy comprises administration of an effective dose of a chemotherapeutic drug, and an inhibitor of p38α MAP kinase.

Description

COMBINATION TREATMENT TO PREVENT OR MINIMIZE CHEMOTHERAPY-INDUCED

PERIPHERAL NEUROPATHY

CROSS REFERENCE TO OTHER APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/522,662 filed June 22, 2023, the contents of which are hereby incorporated by reference in its entirety.

GOVERNMENT SUPPORT RESEARCH

[0002] This invention was made with Government support under contract NS105092 awarded by the National Institutes of Health. The Government has certain rights in the invention.

BACKGROUND

[0003] Many front-line anticancer drugs are neurotoxic; 40-60% of adult patients treated with anticancer drugs develop chemotherapy-induced peripheral neuropathy (CIPN). CIPN symptoms include tingling or numbness in hands and feet, difficulty walking, and problems completing other activities of daily living, and dramatically impairing quality of life. Children treated with anticancer agents develop CIPN at higher rates than adults (nearly 100%). Moreover, severe and acute-onset CIPN forces clinicians to reduce the intensity of cancer treatments, which implies that CIPN decreases survival.

[0004] Among adult patients who complete their chemotherapy, nearly one-third reported that CIPN symptoms persist more than a year, and patients who develop CIPN are three-times more likely to develop chronic neuropathic pain. Consequently, the healthcare costs of CIPN are substantial: treating patients with CIPN costs $15,000 (in 2006 dollars) more, on average, than those without CIPN. With the number of cancer survivors projected to top 20 million by 2030, preventing CIPN is both a pressing and a growing healthcare challenge.

SUMMARY

[0005] Compositions and methods are provided for a combination drug therapy to treat cancer and prevent the occurrence of neurotoxicity or reduce the incidence or severity of chemotherapy-induced peripheral neuropathy (CIPN). The combination therapy comprises administration of an effective dose of (i) a chemotherapeutic anti-cancer drug, and (ii) an inhibitor of p38a MAP kinase. Findings presented herein show that anti-cancer drugs can activate p38cc MAP kinase, and that drugs that counteract this action have therapeutic value in humans in the reduction of neurotoxicity. The effective dose of a p38a MAPK inhibitor is the dose that reduces symptoms of CIPN relative to the symptoms in the absence of the inhibitor. Preferably the activity of the chemotherapeutic drug is maintained in the therapeutic regimen. [0006] The chemotherapeutic drug and p38 MAPK inhibitor may be administered to an individual subject at the same time, or at different times and on different schedules, provided that the timing permits efficacy of both drugs. The drugs may be co-formulated or separately formulated. For example, the p38 MAPK inhibitor may be administered from about 1 month before, about 21 days, about 14 days, about 10 days, about 7 days, about 5 days, about 3 days, about 2 days, about 1 day or substantially concurrently with the chemotherapeutic drug, or may be administered from about 1 month after, about 21 days, about 14 days, about 10 days, about 7 days, about 5 days, about 3 days, about 2 days, about 1 day after the chemotherapeutic drug. Administration may be daily, semi-weekly, weekly, weekly, etc.

[0007] In some embodiments the chemotherapeutic drug targets microtubules, including without limitation platinum based therapeutics; taxanes, e.g. paclitaxel; vinca alkaloids, e.g. vincristine, etc. In some embodiments the chemotherapeutic drug is a vinca alkyloid, e.g. vinblastine, vincristine, vinorelbine, vindesine and vinflunine. In some embodiments the chemotherapeutic drug is vincristine. In some embodiments the chemotherapeutic drug is paclitaxel.

[0008] In some embodiments the chemotherapeutic drug is a protease inhibitor, e.g. bortezimib.

[0009] In some embodiments a p38a MAP kinase inhibitor is a small molecule that directly inhibits p38oc MAP kinase, e.g. losmapimod; dilmapimod (SB-681323), pirfenidone, ralimetinib; SB-203580; BIRB-796 etc.

[0010] The individual may be treated with additional drugs and regimens as needed, e.g. targeted therapies, immune checkpoint inhibitors, anti-tumor antibodies, surgery, radiation, and the like.

BRIEF DESCRIPTION OF THE DRAWINGS

[001 1] The invention is best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not to-scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures.

[001 ] FIGS. 1A-1 B. Sensory-neuron specific DLK overexpression impairs C. elegans touch sensation. A) Raster plot of 10-touch assay of 25 wild-type (N2) adult worms. Rows are worms and columns are trials; black squares indicate touch-induced reversals. B) Average touch response of animals with or without a transgene driving over-expression of DLK-1 in the TRNs (A/=3, n=75, per genotype). 1 -way ANOVA [F(2, 222)=215.9, p=1e-16\. “ p<0.01 Tukey posthoc test. Error Bars are SEM. [0013] FIGS. 2A-2B. A) Chronic exposure to vincristine (VIN) (100|jM in S-medium + killed NA22 E. coli food, 96hrs) impairs touch sensitivity in controls (bus-17), but not bus-17; pmk-3 mutants (N=3, n=47-75). Bars are mean±SD pooled across three biological replicates, n=54- 75 worms per condition. B) The effect of VIN on touch sensation vs. genotype. Darker shades indicate impairment relative to vehicle-treated controls (bus-17) and are scaled according to the mean response (pooled across three biological replicates, n=54-75 worms per condition. *** p<0.001, t-test VIN(+) vs. VIN(-). All behavioral assays conducted blind to genotype and treatment. All genotypes include bus- 17(br2) which renders the C. elegans cuticle (skin) more permeable to drugs dissolved in liquid media. Notably, this mutation has only minor effects on touch sensation (wild-type: 9.1±0.7; bus-17(br2)\ 8.4±1.1 , mean±s.d., N=2, n=25, p<0.01, t- test).

[0014] FIGS. 3A-3D. A) Darkfield image of four (of 96) single-worm wells. B) Acute exposure of adult worms to VIN (100|uM) impairs movement in control worms after ~2 hrs (arrow). C) VIN treatment does not affect p38 MAPK KO worms (bus-17;pmk-3). D) The effect of VIN on movement vs. genotype. Darker shades indicate impairment. Note: mak-2 mutants are hyperactive; they have higher baseline locomotion than controls. ***p<0.001, *p<0.01, t-test VIN(+) vs. VIN(-)./V=3 biological replicates, n=24 worms per genotype and condition. All assays conducted blind to genotype and condition.

[0015] FIGS. 4A-4D. A) Raw neural traces during stretch in WT (p38a^loxP/loxP ; black) and cKO (p38a^cKO red) afferents after vehicle (VEH). B) Example of an afferent that can entrain 1 :1 to sinusoidal vibration (small arrowhead) and one that cannot (large arrow). C) Afferent static sensitivity as measured by firing rate 3.5s into the hold phase of a 5% Lo stretch after VEH (open) or PTX (filled; Final Static Time or FST; Lo = muscle length where maximum force of twitch contraction is generated). Points are single animals of the indicated genotype & treatment. D) Percent afferents that entrain to vibration as a function of frequency (100 pm peak-to-peak). Entrainment appears to fail at high frequency after PTX in p38a^loxP/loxP (black) but not

Dashed lines VEH, solid lines PTX.

[0016] FIGS. 5A-5B. Intraepidermal nerve fiber (IENF) density in p38a^loxP/loxP (A) and p38a_CKo (B) mice treated with PTX. Nerve fibers labeled with PGP 9.5 (green), epidermis labeled with Ulex Europaeus Agglutinin I (red), and nuclei with DAPI (blue). Average±SD IENF density (counts/mm epidermal border). IENF expressed as count/mm ± Std dev shown in top right (average value from 5 p38a^loxP/loxP and 8 pSSa⁰^ slices from a single 3 mm biopsy). Scale bar is 100 pm.

DETAILED DESCRIPTION

[0017] Before the present methods and compositions are described, it is to be understood that this invention is not limited to particular method or composition described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0018] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0019] Unless defined otherwise, 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 invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supercedes any disclosure of an incorporated publication to the extent there is a contradiction.

[0020] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the peptide" includes reference to one or more peptides and equivalents thereof, e.g. polypeptides, known to those skilled in the art, and so forth.

[0021] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0022] As used herein, compounds which are "commercially available" may be obtained from commercial sources including but not limited to Selleckchem, Houston, TX, Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee Wl, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall U.K.), Lancaster Synthesis (Windham NH), Maybridge Chemical Co. Ltd. (Cornwall U.K.), Parish Chemical Co. (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockville MD), Wako Chemicals USA, Inc. (Richmond VA), Novabiochem and Argonaut Technology.

[0023] Compounds can also be made by methods known to one of ordinary skill in the art. As used herein, "methods known to one of ordinary skill in the art" may be identified though various reference books and databases. Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds of the present invention, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-lnterscience, New York, 1992. Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services.

[0024] "Inhibiting" the onset of a disorder shall mean either lessening the likelihood of the disorder's onset, or preventing the onset of the disorder entirely. In the preferred embodiment, inhibiting the onset of a disorder means preventing its onset entirely.

[0025] "Inhibiting" the expression of a gene in a cell shall mean either lessening the degree to which the gene is expressed, or preventing such expression entirely. "Specifically inhibit" the expression of a protein shall mean to inhibit that protein's expression (a) more than the expression of any other protein, or (b) more than the expression of all but 10 or fewer other proteins.

[0026] "Suitable conditions" shall have a meaning dependent on the context in which this term is used. When used in connection with contacting an agent to a cell, this term shall mean conditions that permit an agent capable of doing so to enter a cell and perform its intended function. In one embodiment, the term "suitable conditions" as used herein means physiological conditions.

[0027] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a mammal being assessed for treatment and/or being treated. In an embodiment, the mammal is a human. The terms “subject,” “individual,” and “patient” thus encompass individuals having cancer. Subjects may be human, but also include other mammals, particularly those mammals useful as laboratory models for human disease, e.g. mouse, rat, etc.

[0028] The definition of an appropriate patient sample encompasses blood and other liquid samples of biological origin, solid tissue samples such as a biopsy specimen or tissue cultures or cells derived there from and the progeny thereof. The definition also includes samples that have been manipulated in any way after their procurement, such as by treatment with reagents; washed; or enrichment for certain cell populations, such as endometrial cells, etc. A sample if interest in bronchial lavage sample. The definition also includes sample that have been enriched for particular types of molecules, e.g., nucleic acids, polypeptides, etc. The term “biological sample” encompasses a clinical sample, and also includes tissue obtained by surgical resection, tissue obtained by biopsy, cells in culture, cell supernatants, cell lysates, tissue samples, organs, bone marrow, blood, plasma, serum, and the like. A “biological sample” includes a sample obtained from a patient’s sample cell, e.g., a sample comprising polynucleotides and/or polypeptides that is obtained from a patient’s sample cell (e.g., a cell lysate or other cell extract comprising polynucleotides and/or polypeptides); and a sample comprising sample cells from a patient. A biological sample comprising a sample cell from a patient can also include normal, non-diseased cells.

[0029] As used herein, the terms “treatment,” “treating,” and the like, refer to administering an agent, or carrying out a procedure for the purposes of obtaining an effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of effecting a partial or complete cure for a disease and/or symptoms of the disease. “Treatment,” as used herein, covers any treatment of cancert and associated peripheral neuropathy in a mammal, particularly in a human, and includes: (a) preventing the development of neuropathy; (b) inhibiting ongoing neuropathy, i.e., arresting its development; and (c) relieving neuropathy.

[0030] Treating may refer to any indicia of success in the treatment or amelioration or prevention of neuropathy, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disease condition more tolerable to the patient; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of an examination by a physician. Accordingly, the term "treating" includes the administration of the compounds or agents of the present invention to prevent or delay, to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with neuropathy. The term "therapeutic effect" refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject.

[0031] "In combination with", "combination therapy" and "combination products" refer, in certain embodiments, to the concurrent administration to a patient of a first therapeutic (i.e., first therapeutic agent) and the compounds as used herein. When administered in combination, each component can be administered at the same time or sequentially in any order at different points in time. Thus, each component can be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.

[0032] "Concomitant administration" of a known therapeutic agent, e.g. chemotherapeutic agent, with a pharmaceutical composition of the present invention means administration of the agents at such time that both will have a therapeutic effect. Such concomitant administration may involve concurrent (i.e. at the same time), prior, or subsequent administration of the drug with respect to the administration of a compound of the present disclosure. A person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compositions of the present disclosure. Therapeutic agents contemplated for concomitant administration according to the methods of the present invention include any other agent for use in the treatment of cancer and neuropathy.

[0033] As used herein, the term “correlates,” or “correlates with,” and like terms, refers to a statistical association between instances of two events, where events include numbers, data sets, and the like. For example, when the events involve numbers, a positive correlation (also referred to herein as a “direct correlation”) means that as one increases, the other increases as well. A negative correlation (also referred to herein as an “inverse correlation”) means that as one increases, the other decreases.

[0034] "Dosage unit" refers to physically discrete units suited as unitary dosages for the particular individual to be treated. Each unit can contain a predetermined quantity of active compound(s) calculated to produce the desired therapeutic effect(s) in association with the required pharmaceutical carrier. The specification for the dosage unit forms can be dictated by (a) the unique characteristics of the active compound(s) and the particular therapeutic effect(s) to be achieved, and (b) the limitations inherent in the art of compounding such active compound(s).

[0035] "Pharmaceutically acceptable excipient "means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.

[0036] The terms "pharmaceutically acceptable", "physiologically tolerable" and grammatical variations thereof, as they refer to compositions, carriers, diluents and reagents, are used interchangeably and represent that the materials are capable of administration to or upon a human without the production of undesirable physiological effects to a degree that would prohibit administration of the composition.

[0037] A "therapeutically effective amount" means the amount that, when administered to a subject for treating a disease, is sufficient to effect treatment for that disease.

[0038] The phrase “determining the treatment efficacy” and variants thereof can include any methods for determining that a treatment is providing a benefit to a subject. The term “treatment efficacy” and variants thereof are generally indicated by alleviation of one or more signs or symptoms associated with the disease and can be readily determined by one skilled in the art. “Treatment efficacy” may also refer to the prevention or amelioration of signs and symptoms of toxicities typically associated with standard or non-standard treatments of a disease. Determination of treatment efficacy is usually indication and disease specific and can include any methods known or available in the art for determining that a treatment is providing a beneficial effect to a patient. For example, evidence of treatment efficacy can include but is not limited to remission of the disease or indication. Further, treatment efficacy can also include general improvements in the overall health of the subject, such as but not limited to enhancement of patient life quality, increase in predicted subject survival rate, decrease in depression or decrease in rate of recurrence of the indication (increase in remission time). (See, e.g., Physicians' Desk Reference (2010).)

Compositions and Methods

[0039] In the present disclosure, a combination therapy of a MAPK inhibitor and a chemotherapeutic drug are administered in doses to maintain anti-mitotic efficacy of the chemotherapeutic drug, while reducing peripheral neuropathy side effects.

[0040] MAPKs are serine/threonine protein kinases that process and regulate cellular properties in response to a wide range of extracellular stimuli. These enzymes phosphorylate the OH group of serine or threonine in proteins and play important roles in the regulation of cell proliferation, differentiation, survival and apoptosis. In mammalian cells, several distinct MAPKs have been identified, including p38 MAPK, c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK 1/2) and ERK 5/BMK-1 . Among MAPKs, p38 MAPK is involved in a wide range of signaling pathways that stimulate different biological functions. P38 MAPK comprises four isoforms (a, p, y and 0). p38a and are approximately 70% identical, whereas p38y and 5 share approximately 60% sequence identity with p38a. Among p38 isoforms, a and p are ubiquitously expressed in most tissues. The alpha isoform is most highly expressed in dorsal root ganglion sensory neurons, whose function is impaired in CIPN.

[0041] P38a (often referred to simply as “p38”) was the first isoform of p38 MAPK to be identified and was first recognized as a stress-induced kinase that can be activated by lipopolysaccharide (LPS) and inflammatory cytokines. p38 MAPK inhibitors are considered drug candidates for inflammation-related diseases. Numerous p38 MAPK inhibitors have been developed and have served as efficient tools for further understanding the roles of this kinase. P38 MAPK inhibitors vary markedly in both chemical structure and binding mode. Many p38 MAPK inhibitors are adenosine triphosphate (ATP)-competitive and bind to the hinge region in p38 MAPK. Other inhibitors do not compete with ATP for the adenosine binding pocket but evoke a conformational reorganization of p38 MAPK that prevents ATP binding. ATI-450 is an inhibitor that prevents activated p38 MAPK from interacting with its kinase target, MK2, see Wang et al. (2015). J Exp Med 7 May 2018; 215 (5): 1315-1325, and Gordon et al. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 in Healthy Subjects: A Placebo-Controlled, Randomized Phase 1 Study. Clin Pharmacol. 2021 Jun 10;13:123-134, each herein specifically incorporated by reference.

[0042] . Examples of MAPK inhibitors are provided below in Table 1 .

Table 1

[0043] In some embodiments a p38a MAP kinase inhibitor is a small molecule that directly inhibits p38a MAP kinase, e.g. losmapimod; dilmapimod (SB-681323), pirfenidone, ralimetinib; SB-203580; BIRB-796 etc. [0044] In some embodiments the p38oc MAPK inhibitor is adenosine triphosphate (ATP)- competitive and binds to the hinge region in p38 MAPK. In some embodiments the the p38oc MAPK inhibitor does not compete with ATP for the adenosine binding pocket but evoke a conformational reorganization of p38 MAPK that prevents ATP binding.

[0045] In some embodiments a p38a MAP kinase inhibitor is a downstream inhibitor, for example an inhibitor of MK2. Mitogen-Activated Protein Kinase- Activated Protein Kinase 2 (MK2) is a protein kinase involved in the regulation of several cellular processes, including inflammation and stress responses. Inhibitors of MK2 are molecules designed to block the activity of this kinase, thereby modulating the associated cellular processes. Inhibitors include, for example, CMPD1 ; PF-3644022 (ATI-450); CC-99677; etc. ATI-450 is an inhibitor that prevents activated p38 MAPK from interacting with its kinase target, MK2.

[0046] The therapeutic dose of a p38 MAPK inhibitors may be at least about 0.01 pg/kg body weight, at least about 0.05 pg/kg body weight; at least about 0.1 pg/kg body weight, at least about 0.5 pg/kg body weight, at least about 1 pg/kg body weight, at least about 2.5 pg/kg body weight, at least about 5 pg/kg body weight, and not more than about 100 pg/kg body weight. It will be understood by one of skill in the art that such guidelines will be adjusted for the molecular weight of the active agent. The dosage may also be varied for localized administration, e.g. intranasal, inhalation, etc., or for systemic administration, e.g. i.m., i.p., i.v., and the like. The dosage will be selected based on the activity of the agent. In some embodiments the dose for a combination therapy is selected to be lower than the dose for anti-cancer therapy, e.g. 90%, 80%, 70%, 60%, 50%, 10%, 5%, 1 %, etc. of the anti-cancer dose.

[0047] In certain embodiments, multiple therapeutically effective doses are administered according to a daily dosing regimen, or intermittently. For example, a therapeutically effective dose can be administered, one day a week, two days a week, three days a week, four days a week, or five days a week, and so forth. By "intermittent" administration is intended the therapeutically effective dose can be administered, for example, every other day, every two days, every three days, once a week, once every two weeks, once every three weeks, once a month, and so forth. For example, in some embodiments, an antibody is administered once every two to four weeks for an extended period of time, such as for 1 , 2, 3, 4, 5, 6, 7, 8, 10, 15, 24 months, and so forth. By "twice-weekly" or "two times per week" is intended that two therapeutically effective doses of the agent in question is administered to the subject within a 7 day period, beginning on day 1 of the first week of administration, with a minimum of 72 hours, between doses and a maximum of 96 hours between doses. By "thrice weekly" or "three times per week" is intended that three therapeutically effective doses are administered to the subject within a 7 day period, allowing for a minimum of 48 hours between doses and a maximum of 72 hours between doses. For purposes of the present invention, this type of dosing is referred to as "intermittent" therapy. In accordance with the methods of the present invention, a subject can receive intermittent therapy for one or more weekly or monthly cycles until the desired therapeutic response is achieved. The agents can be administered by any acceptable route of administration as noted herein below.

[0048] In certain embodiments, multiple therapeutically effective doses are administered according to a daily dosing regimen, or intermittently. For example, a therapeutically effective dose can be administered, one day a week, two days a week, three days a week, four days a week, or five days a week, and so forth. By "intermittent" administration is intended the therapeutically effective dose can be administered, for example, every other day, every two days, every three days, once a week, once every two weeks, once every three weeks, once a month, and so forth. For example, in some embodiments, an antibody is administered once every two to four weeks for an extended period of time, such as for 1 , 2, 3, 4, 5, 6, 7, 8, 10, 15, 24 months, and so forth. By "twice-weekly" or "two times per week" is intended that two therapeutically effective doses of the agent in question is administered to the subject within a 7 day period, beginning on day 1 of the first week of administration, with a minimum of 72 hours, between doses and a maximum of 96 hours between doses. By "thrice weekly" or "three times per week" is intended that three therapeutically effective doses are administered to the subject within a 7 day period, allowing for a minimum of 48 hours between doses and a maximum of 72 hours between doses. For purposes of the present invention, this type of dosing is referred to as "intermittent" therapy. In accordance with the methods of the present invention, a subject can receive intermittent therapy for one or more weekly or monthly cycles until the desired therapeutic response is achieved. The agents can be administered by any acceptable route of administration as noted herein below.

[0049] In some embodiments a chemotherapeutic drug for use in the combination therapy of the disclosure is a microtubule-targeted antimitotic drug. Such drugs include, without limitation, Vinca alkaloids, such as vinblastine, vincristine, vinorelbine, vindesine and vinflunine, cryptophycins, halichondrins, eribulin, ixabepilone, cabazitaxel, enfortumab vedotin, trastuzumab, emtansine, tirbanibulin, estramustine, colchicine and combretastatins; paclitaxel, docetaxel (Taxotere), epothilones, and discodermolide. In some embodiments the chemotherapeutic drug is a vinca alkyloid, e.g. vinblastine, vincristine, vinorelbine, vindesine and vinflunine. Such drugs are administered as clinically appropriate.

[0050] In some embodiments a chemotherapeutic drug for use in the combination therapy of the disclosure is a protease inhibitor, including without limitation bortezomib; atazanavir sulfate; darunavir ethanolate; fosamprenavir calcium; ritonavir; saquinavir mesylate; tipranavir; indinavir sulfate; nelfinavir mesylate. Such drugs are administered as clinically appropriate.

[0051] Additional chemotherapeutic agents may include, for example, Abitrexate (Methotrexate Injection), Abraxane (Paclitaxel Injection), Adcetris (Brentuximab Vedotin Injection), Adriamycin (Doxorubicin), Adrucil Injection (5-FU (fluorouracil)), Afinitor (Everolimus) , Afinitor Disperz (Everolimus) , Alimta (PEMET EXED), Alkeran Injection (Melphalan Injection), Alkeran Tablets (Melphalan), Aredia (Pamidronate), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arzerra (Ofatumumab Injection), Avastin (Bevacizumab), Bexxar (Tositumomab), BiCNU (Carmustine), Blenoxane (Bleomycin), Bosulif (Bosutinib), Busulfex Injection (Busulfan Injection), Campath (Alemtuzumab), Camptosar (Irinotecan), Caprelsa (Vandetanib), Casodex (Bicalutamide), CeeNU (Lomustine), CeeNU Dose Pack (Lomustine), Cerubidine (Daunorubicin), Clolar (Clofarabine Injection), Cometriq (Cabozantinib), Cosmegen (Dactinomycin), CytosarU (Cytarabine), Cytoxan (Cytoxan), Cytoxan Injection (Cyclophosphamide Injection), Dacogen (Decitabine), DaunoXome (Daunorubicin Lipid Complex Injection), Decadron (Dexamethasone), DepoCyt (Cytarabine Lipid Complex Injection), Dexamethasone Intensol (Dexamethasone), Dexpak Taperpak (Dexamethasone), Docefrez (Docetaxel), Doxil (Doxorubicin Lipid Complex Injection), Droxia (Hydroxyurea), DTIC (Decarbazine), Eligard (Leuprolide), Ellence (Ellence (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Elspar (Asparaginase), Emcyt (Estramustine), Erbitux (Cetuximab), Erivedge (Vismodegib), Erwinaze (Asparaginase Erwinia chrysanthemi), Ethyol (Amifostine), Etopophos (Etoposide Injection), Eulexin (Flutamide), Fareston (Toremifene), Faslodex (Fulvestrant), Femara (Letrozole), Firmagon (Degarelix Injection), Fludara (Fludarabine), Folex (Methotrexate Injection), Folotyn (Pralatrexate Injection), FUDR (FUDR (floxuridine)), Gemzar (Gemcitabine), Gilotrif (Afatinib), Gleevec (Imatinib Mesylate), Gliadel Wafer (Carmustine wafer), Halaven (Eribulin Injection), Herceptin (Trastuzumab), Hexalen (Altretamine), Hycamtin (Topotecan), Hycamtin (Topotecan), Hydrea (Hydroxyurea), Iclusig (Ponatinib), Idamycin PFS (Idarubicin), Ifex (Ifosfamide), Inlyta (Axitinib), Intron A alfab (Interferon alfa- 2a), Iressa (Gefitinib), Istodax (Romidepsin Injection), Ixempra (Ixabepilone Injection), Jakafi (Ruxolitinib), Jevtana (Cabazitaxel Injection), Kadcyla (Ado-trastuzumab Emtansine), Kyprolis (Carfilzomib), Leukeran (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Lysodren (Mitotane), Marqibo Kit (Vincristine Lipid Complex Injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib), Mesnex (Mesna), Mesnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mustargen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone), Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), Onxol (Paclitaxel Injection), Panretin (Alitretinoin), Paraplatin (Carboplatin), Perjeta (Pertuzumab Injection), Platinol (Cisplatin), Platinol (Cisplatin Injection), PlatinolAQ (Cisplatin), PlatinolAQ (Cisplatin Injection), Pomalyst (Pomalidomide), Prednisone Intensol (Prednisone), Proleukin (Aldesleukin), Purinethol (Mercaptopurine), Reclast (Zoledronic acid), Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Rituxan (Rituximab), RoferonA alfaa (Interferon alfa-2a), Rubex (Doxorubicin), Sandostatin (Octreotide), Sandostatin LAR Depot (Octreotide), Soltamox (Tamoxifen), Sprycel (Dasatinib), Sterapred (Prednisone), Sterapred DS (Prednisone), Stivarga (Regorafenib), Supprelin LA (Histrelin Implant), Sutent (Sunitinib), Sylatron (Peginterferon Alfa-2b Injection (Sylatron)), Synribo (Omacetaxine Injection), Tabloid (Thioguanine), Taflinar (Dabrafenib), Tarceva (Erlotinib), Targretin Capsules (Bexarotene), Tasigna (Decarbazine), Taxol (Paclitaxel Injection), Taxotere (Docetaxel), Temodar (Temozolomide), Temodar (Temozolomide Injection), Tepadina (Thiotepa), Thalomid (Thalidomide), TheraCys BCG (BCG), Thioplex (Thiotepa), TICE BCG (BCG), Toposar (Etoposide Injection), Torisel (Temsirolimus), Treanda (Bendamustine hydrochloride), Trelstar (Triptorelin Injection), Trexall (Methotrexate), Trisenox (Arsenic trioxide), Tykerb (lapatinib), Valstar (Valrubicin Intravesical), Vantas (Histrelin Implant), Vectibix (Panitumumab), Velban (Vinblastine), Velcade (Bortezomib), Vepesid (Etoposide), Vepesid (Etoposide Injection), Vesanoid (Tretinoin), Vidaza (Azacitidine), Vincasar PFS (Vincristine), Vincrex (Vincristine), Votrient (Pazopanib), Vumon (Teniposide), Wellcovorin IV (Leucovorin Injection), Xalkori (Crizotinib), Xeloda (Capecitabine), Xtandi (Enzalutamide), Yervoy (Ipilimumab Injection), Zaltrap (Ziv-aflibercept Injection), Zanosar (Streptozocin), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zoladex (Goserelin), Zolinza (Vorinostat), Zometa (Zoledronic acid), Zortress (Everolimus), Zytiga (Abiraterone), Nimotuzumab and immune checkpoint inhibitors such as nivolumab, pembrolizumab/MK-3475, pidilizumab and AMP-224 targeting PD-1 ; and BMS-935559, MEDI4736, MPDL3280A and MSB0010718C targeting PD-L1 and those targeting CTLA-4 such as ipilimumab.

Peripheral neuropathy

[0052] Chemotherapy-induced peripheral neurotoxicity (CIPN) is a debilitating adverse side effect of chemotherapy treatment and is a common cause of treatment dose modification. CIPN is characterised by peripheral nerve dysfunction leading to numbness, tingling, weakness and pain in the hands and feet that produces deficits in balance, gait and fine motor function. Long-lasting CIPN has been demonstrated to continue affecting physical function post-treatment, negatively impacting on cancer survivors’ health-related quality of life (QOL). [0053] The methods of the disclosure reduce the level of CIPN in an individual, relative to chemotherapy administered in the absence of a p38 MAPK inhibitor, and may reduce CPIN symptoms by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more.

[0054] Assessing chemotherapy-induced peripheral neuropathy (CIPN) involves a combination of patient-reported symptoms, clinical examinations, and various diagnostic tests. Here are some methods used to assess CIPN in patients:

[0055] Each method provides valuable information, and a combination of these methods is often used to obtain a comprehensive assessment of CIPN in patients. This multimodal approach helps in accurately diagnosing, monitoring the progression, and managing the symptoms of CIPN effectively.

[0056] There remains a lack of consensus on the ideal standardised assessment tool for evaluating CIPN in research settings and clinical practice. Currently, the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) neuropathy subscale is the most widely used measure of CIPN. As set forth in Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, November 2017, National Institutes of Health, National Cancer Institute, there is a scale of 1 -5 for adverse events:

[0057] However, numerous other measures have been proposed to assess CIPN, with approaches including assessing functional impairment, clinical and neurological examination and patient reported questionnaires.

[0058] Patient reported outcome measures (PROMs) are increasingly recognised as a valuable tool to collect CIPN symptom information. CIPN PROMs are predominantly used in research settings to characterise the natural history of neuropathy development and recovery, and as endpoint measures in CIPN treatment and prevention studies. PROMs provide a meaningful measure of CIPN from the patient perspective, essential to capture symptom severity and impact on the patient’s activities of daily living. Such information is also valuable in clinical practice, where treatment modification is often guided by CIPN symptom expression and severity. Cancers

[0059] The types of cancer that can be treated using the subject methods of the present invention include but are not limited to adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, brain cancers, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, cervical cancer, childhood Non-Hodgkin's lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing's family of tumors (e.g. Ewing's sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children's leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin's lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas, melanoma skin cancer, non-melanoma skin cancers, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), transitional cell carcinoma, vaginal cancer, vulvar cancer, mesothelioma, squamous cell or epidermoid carcinoma, bronchial adenoma, choriocarinoma, head and neck cancers, teratocarcinoma, or Waldenstrom's macroglobulinemia.

[0060] Immunotherapy harnesses the body's immune system to eliminate the cancer, and is used to treat advanced stage (IV) non-small cell lung cancer if there is high programmed cell death protein 1 (PD-1 ) or PDL-1 expression.

[0061] Antibiotics, e.g. antibiotics with the classes of aminoglycosides; carbapenems; and the like; penicillins, e.g. penicillin G, penicillin V, methicillin, oxacillin, carbenicillin, nafcillin, ampicillin, etc. penicillins in combination with [3-lactamase inhibitors, cephalosporins, e.g. cefaclor, cefazolin, cefuroxime, moxalactam, etc:; tetracyclines; cephalosporins; quinolones; lincomycins; macrolides; sulfonamides; glycopeptides including the anti-infective antibiotics vancomycin, teicoplanin, telavancin, ramoplanin and decaplanin. Derivatives of vancomycin include, for example, oritavancin and dalbavancin (both lipoglycopeptides). Telavancin is a semi-synthetic lipoglycopeptide derivative of vancomycin (approved by FDA in 2009). Other vancomycin analogs are disclosed, for example, in WO 2015022335 A1 and Chen et al. (2003) PNAS 100(10): 5658-5663, each herein specifically incorporated by reference. Non-limiting examples of antibiotics include vancomycin, linezolid, azithromycin, daptomycin, colistin, eperezolid, fusidic acid, rifampicin, tetracyclin, fidaxomicin, clindamycin, lincomycin, rifalazil, and clarithromycin.

[0062] Radiotherapy means the use of radiation, usually X-rays, to treat illness. X-rays were discovered in 1895 and since then radiation has been used in medicine for diagnosis and investigation (X-rays) and treatment (radiotherapy). Radiotherapy may be from outside the body as external radiotherapy, using X-rays, cobalt irradiation, electrons, and more rarely other particles such as protons. It may also be from within the body as internal radiotherapy, which uses radioactive metals or liquids (isotopes) to treat cancer.

[0001] As used herein, endpoints for treatment will be given a meaning as known in the art and as used by the Food and Drug Administration.

[0002] Overall survival is defined as the time from randomization until death from any cause, and is measured in the intent-to-treat population. Survival is considered the most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint. This endpoint is precise and easy to measure, documented by the date of death. Bias is not a factor in endpoint measurement. Survival improvement should be analyzed as a risk-benefit analysis to assess clinical benefit. Overall survival can be evaluated in randomized controlled studies. Demonstration of a statistically significant improvement in overall survival can be considered to be clinically significant if the toxicity profile is acceptable, and has often supported new drug approval. A benefit of the methods of the invention can include increased overall survival of patients.

[0003] Endpoints that are based on tumor assessments include DFS, ORR, TTP, PFS, and time-to-treatment failure (TTF). The collection and analysis of data on these time-dependent endpoints are based on indirect assessments, calculations, and estimates (e.g., tumor measurements). Disease-Free Survival (DFS) is defined as the time from randomization until recurrence of tumor or death from any cause. The most frequent use of this endpoint is in the adjuvant setting after definitive surgery or radiotherapy. DFS also can be an important endpoint when a large percentage of patients achieve complete responses with chemotherapy.

[0004] Objective Response Rate . ORR is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. Response duration usually is measured from the time of initial response until documented tumor progression. Generally, the FDA has defined ORR as the sum of partial responses plus complete responses. When defined in this manner, ORR is a direct measure of drug antitumor activity, which can be evaluated in a single-arm study.

[0005] Time to Progression and Progression-Free Survival. TTP and PFS have served as primary endpoints for drug approval. TTP is defined as the time from randomization until objective tumor progression; TTP does not include deaths. PFS is defined as the time from randomization until objective tumor progression or death. The precise definition of tumor progression is important and should be carefully detailed in the protocol.

[0063] Determining a therapeutically or prophylactically effective amount of the inhibitor compositions can be done based on animal data using routine computational methods. In one embodiment, the therapeutically or prophylactically effective amount contains between about 0.01 mg and about 1 g of inhibitor, e.g. nucleic acid, protein or peptide, etc., as applicable. In another embodiment, the effective amount contains between about 1 mg and about 100 mg of inhibitor, as applicable. In a further embodiment, the effective amount contains between about 10 mg and about 50 mg of the inhibitor, as applicable.

[0064] Administering the instant compositions can be effected or performed using any of the various methods and delivery systems known to those skilled in the art. The administering can be performed, for example, intravenously, orally, via implant, transmucosally, transdermally, intramuscularly, intrathecally, and subcutaneously. The following delivery systems, which employ a number of routinely used pharmaceutical carriers, are only representative of the many embodiments envisioned for administering the instant compositions.

[0065] Injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can comprise excipients such as solubility-altering agents (e.g. , ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA's). Implantable systems include rods and discs, and can contain excipients such as PLGA and polycaprylactone. Nucleic acids of the invention can also be administered attached to particles using a gene gun.

[0066] Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc).

[0067] Transmucosal delivery systems include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid).

[0068] Dermal delivery systems include, for example, aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions, liposomes, ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon bases and powders, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone). In one embodiment, the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer.

[0069] Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (e.g., gums, xanthans, cellulosics and sugars), humectants (e.g., sorbitol), solubilizers (e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives and Jun. 2,2005 antioxidants (e.g., parabens, vitamins E and C, and ascorbic acid), anti-caking agents, coating agents, and chelating agents (e.g., EDTA).

[0070] The effective dose of a chemotherapeutic drug, or a p38 MAPK inhibitor, may range up to about 30 mg/kg, up to about 20 mg/kg, up to about 10 mg/kg, up to about 5 mg/kg; up to about 1 mg/kg, up to about 0.5 mg/kg; up to about 0.1 mg/kg; up to about 0.05 mg/kg; where the dose may vary with the specific agent and recipient.

[0071] The agents may be administered one or a plurality of days, and in some embodiments is administered daily, every two days, semi-weekly, weekly, etc. for a period of from about 1 , about 2, about 3, about 4, about 5, about 6, about 7 or more weeks, up to a chronic maintenance level of dosing. Therapeutic entities of the present invention are usually administered on multiple occasions. Intervals between single dosages can be weekly, monthly or yearly. Intervals can also be irregular as indicated by measuring blood levels of the therapeutic entity in the patient. Alternatively, therapeutic entities of the present invention can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the polypeptide in the patient.

[0072] In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patent can be administered a prophylactic regime.

[0073] In still yet some other embodiments, for prophylactic applications, pharmaceutical compositions or medicaments are administered to a patient susceptible to, or otherwise at risk of a disease or condition in an amount sufficient to eliminate or reduce the risk, lessen the severity, or delay the outset of the disease, including biochemical, histologic and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. [0074] In still yet some other embodiments, for therapeutic applications, therapeutic entities of the present invention are administered to a patient suspected of, or already suffering from such a disease in an amount sufficient to cure, or at least partially arrest, the symptoms of the disease (biochemical, histologic and/or behavioral), including its complications and intermediate pathological phenotypes in development of the disease. An amount adequate to accomplish therapeutic or prophylactic treatment is defined as a therapeutically- or prophylactically-effective dose. In both prophylactic and therapeutic regimes, agents are usually administered in several dosages until a sufficient response has been achieved.

[0075] According to the present invention, compositions can be administered by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intracranial, intraperitoneal, intranasal, aerosol, or intramuscular means. The most typical route of administration is intravenous although other routes can be equally effective.

[0076] For parenteral administration, compositions of the invention can be administered as injectable dosages of a solution or suspension of the substance in a physiologically acceptable diluent with a pharmaceutical carrier that can be a sterile liquid such as water, oils, saline, glycerol, or ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents, surfactants, pH buffering substances and the like can be present in compositions. Other components of pharmaceutical compositions are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, and mineral oil. In general, glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions. Antibodies and/or polypeptides can be administered in the form of a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained release of the active ingredient. An exemplary composition comprises polypeptide at 1 mg/mL, formulated in aqueous buffer consisting of 10 mM Tris, 210 mM sucrose, 51 mM L-arginine, 0.01 % polysorbate 20, adjusted to pH 7.4 with HCI or NaOH.

[0077] Typically, compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. The preparation also can be emulsified or encapsulated in liposomes or micro particles such as polylactide, polyglycolide, or copolymer for enhanced adjuvant effect, as discussed above. Langer, Science 249: 1527, 1990 and Hanes, Advanced Drug Delivery Reviews 28: 97-1 19, 1997. The agents of this invention can be administered in the form of a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained or pulsatile release of the active ingredient.

[0078] Additional formulations suitable for other modes of administration include oral, intranasal, and pulmonary formulations, suppositories, and transdermal applications.

[0079] For suppositories, binders and carriers include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1%-2%. Oral formulations include excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain 10%-95% of active ingredient, preferably 25%-70%.

[0080] The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration. Preferably, a therapeutically effective dose will provide therapeutic benefit without causing substantial toxicity.

[0081] Toxicity of the inhibitors described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) or the LD100 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in human. The dosage of the inhibitors described herein lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See, e.g., Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch. 1 )-

[0082] Also within the scope of the invention are kits comprising the compositions of the invention and instructions for use. The kit can further contain a least one additional reagent. Kits typically include a label indicating the intended use of the contents of the kit. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.

[0083] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. It is also understood that the terminology used herein is for the purposes of describing particular embodiments

[0084] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or only and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0085] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the appended claims.

EXPERIMENTAL

[0086] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

EXAMPLE 1

[0087] The p38a MAP kinase protein was analyzed as a molecular target for preventing or treating chemotherapy-induced peripheral neuropathy (CIPN), a common and debilitating side effect of cancer treatment that affects millions of cancer survivors. Despite decades of research, no FDA-approved drugs currently exist for CIPN. Filling this therapeutic gap will greatly improve quality of life for cancer survivors, reduce costs associated with cancer treatment, and decrease the incidence of chemotherapy-triggered neuropathic pain that can require treatment with addictive analgesics.

[0088] The research disclosed herein uses three independent biological models, C. elegans worms, human cells (dividing cells and model neurons), and mice, to study the effects of the commonly prescribed chemotherapeutics vincristine and paclitaxel on sensory neuron physiology and morphology and behaviors that depend on touch and proprioception, for validating p38a MAP kinase activity as an effective treatment target. Additionally, existing chemical assets and small-molecule inhibitors are evaluated for suppression of the neurotoxic effects of microtubule targeting chemotherapeutics without compromising their ability to target cancer cells.

[0089] Chemotherapy drugs that are linked to a high incidence of CIPN impair sensory neuron function via activating p38a MAPK downstream of dual-leucine kinase (DLK). In support of this, research in mice, zebrafish, worms, and fruit flies has linked the integrity of the microtubule cytoskeleton to DLK/MAP kinase signaling pathways to neuronal regeneration. This pathway converges onto the conserved transcription factors, basic leucine-zipper (bZIP) domain CCAAT enhancer-binding protein (C/EBP) and activated by mechanical and chemical damage. Activation disrupts the homeostatic balance between sensory neuron regeneration and degeneration. In the setting of chemotherapy drugs the balance favors degeneration and this accounts for the constellation of CIPN symptoms affecting touch, proprioception, and eventually chronic pain.

[0090] Behavior in C. elegans and electrical activity and skin-nerve anatomy in mice is analyzed. In C. elegans we show that activating DLK (by overexpressing it) impairs touch sensation (FIG. 1 ). Shown in FIG. 1A is a Raster plot of 10-touch assay of 25 wild-type (N2) adult worms. Rows are worms and columns are trials; black squares indicate touch-induced reversals. The average touch response of animals with or without a transgene driving overexpression of a short and long isoform of DLK-1 in the TRNs (N=3, n=75, per genotype) is shown in FIG. 1 B, where a significant decrease in touch sensation is associated with activation of DLK.

[0091] As shown in FIG. 2, treating C. elegans with vincristine (a chemotherapy drug that targets microtubules) impairs touch sensation in control animals, but not PMK-3 p38 MAP kinase knockout animals. Members of the MAPK signaling pathway, including (names of human genes in parentheses): TIR-1 (SARM-1 ), DLK-1 (MAP3K15), PMK-3 (p38 MAPK), MAK-2 (MAPKAP-2), CEBP-1 (CEBP-1 ). were tested. We found that PMK-3 prevents vincristine-induced defects in touch impairments, but none of the other mutants have that effect.

[0092] Shown in FIG. 2A, chronic exposure to vincristine (VIN) (100 pM in S-medium, 96 hrs) impairs touch sensitivity in controls (bus-17 , but not bus-17;pmk-3 mutants (N=3, n=47-75 , which have a knockout of the p38 MAPK gene. FIG. 2B shows the effect of VIN on touch sensation vs. genotype. Darker shades indicate impairment and are scaled according to the mean response. These data show that p38 MAPK is critical for the touch impairment.

[0093] Shown in FIG. 3, measurements of the effect of vincristine on movement by C. elegans nematodes has an effect similar to that of the touch sensitivity. Similar to Figure 2, loss of PMK-3 function preserves normal movement better than any of the other mutants, further indicating the important role of p38 MAPK in neural function when exposed to chemotherapy.

[0094] Acute exposure of adult worms to VIN (100pM) impairs movement in control worms after ~2 hrs (arrow), FIG. 3B. VIN treatment does not affect p38 MAPK KO worms (bus- 17;pmk-3). FIG. 3D shows the effect of VIN on movement vs. genotype. Darker shades indicate impairment. [0095] In mice, it was observed that wild-type animals treated with paclitaxel (another microtubule-targeting chemotherapy drug) are more sensitive than their p38alpha KO littermates (FIG. 4). Measurement of mouse proprioceptor function/dysfunction indicates that sensory neuron-specific loss of p38 MARK preserves function in paclitaxel-treated mice

[0096] Raw neural traces during stretch in WT p38d^oxP/loxP ; black) and cKO (p38(f^KO-, red) afferents after vehicle are shown in FIG. 4A. FIG 4B is an example of an afferent that can entrain 1 :1 to sinusoidal vibration (small arrowhead) and one that cannot (large arrow). Afferent static sensitivity as measured by firing rate 3.5s into the hold phase of a 5% Lo stretch after VEH (open) or PTX (filled; Final Static Time or FST ; Lo = muscle length where maximum force of twitch contraction is generated). Points are single animals of the indicated genotype & treatment. FIG. 4D shows percent afferents that entrain to vibration as a function of frequency (100 pm peak-to-peak). Entrainment appears to fail at high frequency after PTX in p38a^loxP/loxP (black) but not p38a^{,:KO (red)}. Dashed lines VEH, solid lines PTX.

[0097] FIG. 5 shows the intraepidermal nerve fiber (IENF) density in p38aioxp/ioxp (A) and p38otcKo (B) mice treated with PTX. Nerve fibers labeled with PGP 9.5 (green), epidermis labeled with Ulex Europaeus Agglutinin I (red), and nuclei with DAPI (blue).

[0098] Taken together these data demonstrate the role of p38 MAPK activation has in mediating nerve toxicity by chemotherapeutic drugs.

[0099] The preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention is embodied by the appended claims.

Claims

WHAT IS CLAIMED IS:

1 . A method to reduce the incidence and/or severity of chemotherapy induced peripheral neuropathy (CIPN) to a patient undergoing treatment with a chemotherapeutic agent, the method comprising: administering an effective dose of a p38a MAP kinase inhibitor to reduce the incidence and/or severity of chemotherapy induced peripheral neuropathy (CIPN) associated with the chemotherapeutic agent.

2. The method of claim 1 , wherein the chemotherapeutic agent is targeted to microtubules.

3. The method of claim 2, wherein the chemotherapeutic agent comprises one or more of vinca alkaloids, such as vinblastine, vincristine, vinorelbine, vindesine and vinflunine, cryptophycins, halichondrins, eribulin, ixabepilone, cabazitaxel, enfortumab vedotin, trastuzumab, emtansine, tirbanibulin, estramustine, colchicine and combretastatins; paclitaxel, docetaxel, epothilones, and discodermolide.

4. The method of claim 2, wherein the chemotherapeutic agent comprises a vinca alkaloid.

5. The method of claim 4, wherein the vinca alkyloid is vincristine.

6. The method of claim 2, wherein the chemotherapy comprises a taxane.

7. The method of claim 6, wherein the taxane is paclitaxel.

8. The method of claim 1 , wherein the chemotherapeutic agent comprises administering a protease inhibitor.

9. The method of claim 8, wherein the protease inhibitor is bortezomib.

10. The method of any of claims 1 -9, wherein the the activity of the chemotherapeutic agent is substantially maintained.

1 1 . The method of any of claims 1 -10, wherein the p38a MAP kinase inhibitor is coformulated with the chemotherapeutic agent.

12. The method of any of claims 1 -8, wherein the p38cc MAP kinase inhibitor is separately formulated with the chemotherapeutic agent.

13. The method of any of claims 1 -10, wherein the chemotherapeutic drug and p38a MARK inhibitor are administered at the same time.

14. The method of any of claims 1 -10, wherein the chemotherapeutic drug and p38a MAPK inhibitor are administered at different times.

15. The method of any of claims 1 -14, wherein the p38oc MAPK inhibitor is adenosine triphosphate (ATP)-competitive and binds to the hinge region in p38 MAPK.

16. The method of any of claims 1 -14, wherein the p38oc MAPK inhibitor does not compete with ATP for the adenosine binding pocket but evoke a conformational reorganization of p38 MAPK that prevents ATP binding.

17. A therapeutic composition for use in the methods of any of claims 1-16.