WO2025230951A1

WO2025230951A1 - Method of treating adenoid cystic carcinoma

Info

Publication number: WO2025230951A1
Application number: PCT/US2025/026763
Authority: WO
Inventors: Ross CAGAN; Marshall Posner; Arghyashree ROYCHOWDHURYSINA
Original assignee: University of Glasgow; Icahn School of Medicine at Mount Sinai
Current assignee: University of Glasgow; Icahn School of Medicine at Mount Sinai
Priority date: 2024-04-29
Filing date: 2025-04-29
Publication date: 2025-11-06
Anticipated expiration: 2026-10-29

Abstract

Provided is a method for treating adenoid cystic carcinoma, including administering a janus kinase inhibitor to a subject diagnosed with or suspected of having adenoid cystic carcinoma. Also provided is a method for treating adenoid cystic carcinoma, including detecting or having detected a level of phosphorylation of signal transducer and activator of transcription (STAT) in a tumor sample from a subject having or suspected of having adenoid cystic carcinoma, and administering a janus kinase (JAK) inhibitor to the subject if the level of STAT phosphorylation is above a threshold level.

Description

METHOD OF TREATING ADENOID CYSTIC CARCINOMA CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit of priority from U.S. Provisional Patent Application No.63/639,861, filed April 29, 2024, the entire contents of which are incorporated herein by reference. GOVERNMENT RIGHTS STATEMENT [0002] This invention was made with government support under DE029444 awarded by the National Institute of Health. The government has certain rights in the invention. BACKGROUND [0003] Adenoid Cystic Carcinoma (ACC) is the second most common of the major salivary glands (Coca-Pelaz et al., 2015), impacting ~200,000 patients worldwide. It effects primarily the minor salivary glands and tends to metastasize extensively upon secondary recurrence. Currently no treatments are approved for ACC, which has a long-term poor prognosis with survival rates of 5, 10 and 20 years of 68%, 52% and 28% respectively (Romani et al., 2023) [0004] The majority of ACC tumors are characterized by an increase in activity of MYB, a transcriptional regulator with a broad range of targets. Typically, alterations in MYB involve overexpression, truncation or, most commonly, a fusion with NFIB due to a t(6;9) translocation, all of which result in loss of its C-terminal regulatory domain and acquisition of oncogenic properties (Persson et al., 2009; Andersson and Stenman, 2016). In addition to MYB, ACC tumors typically exhibit a complex array of additional mutations. For example, ~25% share co-activation of NOTCH1, a factor associated with aggressive metastatic behavior. Despite increasing molecular insights, no targeted therapies are currently approved for ACC patients. Effective, durable treatment remains an unmet clinical need. [0005] Despite increasing molecular insights however, no treatments are currently approved for ACC subjects, which remains an unmet clinical need. No effective systemic therapies exist for ACC given its resistance to standard cytotoxic chemotherapy. The rarity of ACC and lack of preclinical models have hampered efforts to identify actionable molecular targets. [0006] The present disclosure is directed to overcoming these and other deficiencies in the art. SUMMARY [0007] Provided is a method for treating adenoid cystic carcinoma, comprising administering a tofacitinib to a subject diagnosed with or suspected of having adenoid cystic carcinoma. The administering may include daily administering from about 5 mg to about 20 mg of the tofacitinib to the subject. The administering may include daily administering about 10 mg of the tofacitinib to the subject. The method may not further include administering a histone deacetylase (HDAC) inhibitor, administering a β-adrenergic receptor antagonist, or administering an HDAC inhibitor and a β-adrenergic receptor antagonist to the subject. The HDAC inhibitor may be vorinostat, the β-adrenergic receptor antagonist may be pindolol, or both. [0008] Also provided is a method for treating adenoid cystic carcinoma, comprising administering a janus kinase (JAK) inhibitor to a subject diagnosed with or suspected of having adenoid cystic carcinoma. The JAK inhibitor may be selected from tofacitinib, delgocitinib, peficitinib, abrocitinib, baricitinib, upadacitinib, filgotinib, a pharmaceutically, a pharmaceutically acceptable salt of any of the foregoing, or a combination of any two or more of the foregoing. The JAK inhibitor may be tofacitinib or a pharmaceutically acceptable salt thereof. The administering may include daily administering from about 5 mg to about 20 mg of the JAK inhibitor to the subject. The administering may include daily administering about 10 mg of the JAK inhibitor to the subject. The method may not further include administering a histone deacetylase (HDAC) inhibitor, administering a β-adrenergic receptor antagonist, or administering an HDAC inhibitor and a β-adrenergic receptor antagonist to the subject. The HDAC inhibitor may be vorinostat, the β-adrenergic receptor antagonist may be pindolol, or both. [0009] Also provided is a method for treating adenoid cystic carcinoma, comprising detecting or having detected a level of phosphorylation of signal transducer and activator of transcription (STAT) in a tumor sample from a subject having or suspected of having adenoid cystic carcinoma, and administering a janus kinase (JAK) inhibitor to the subject if the level of STAT phosphorylation is above a threshold level. The STAT may be STAT3. The threshold may be an H-score of about 150. The JAK inhibitor may be selected from tofacitinib, delgocitinib, peficitinib, abrocitinib, baricitinib, upadacitinib, filgotinib, a pharmaceutically acceptable salt of any of the foregoing, or any combination of two or more of the foregoing. The JAK inhibitor may be tofacitinib or a pharmaceutically acceptable salt thereof. The administering may include daily administering from about 5 mg to about 20 mg of the JAK inhibitor to the subject. The administering may include daily administering about 10 mg of the JAK inhibitor to the subject. The method may not further include administering a histone deacetylase (HDAC) inhibitor, administering a β-adrenergic receptor antagonist, or administering an HDAC inhibitor and a β-adrenergic receptor antagonist. The HDAC inhibitor may be vorinostat, the β-adrenergic receptor antagonist may be pindolol, or both. [0010] Also provided is a method for treating adenoid cystic carcinoma, comprising detecting or having detected a level of phosphorylation of signal transducer and activator of transcription (STAT) in a tumor sample from a subject having or suspected of having adenoid cystic carcinoma, and administering tofacitinib to the subject if the level of STAT phosphorylation is above a threshold level. The STAT may be STAT3. The threshold may be an H-score of about 150. The administering may include daily administering from about 5 mg to about 20 mg of the tofacitinib to the subject. The administering may include daily administering about 10 mg of the tofacitinib to the subject. The method may not further include administering a histone deacetylase (HDAC) inhibitor, administering a β-adrenergic receptor antagonist, or administering an HDAC inhibitor and a β-adrenergic receptor antagonist to the subject. The HDAC inhibitor may be vorinostat, the β-adrenergic receptor antagonist may be pindolol, or both. BRIEF DESCRIPTION OF THE DRAWINGS [0011] These and other features, aspects, and advantages of the present disclosure will become better understood when the following detailed description is read with reference to the accompanying drawings, wherein: [0012] FIG.1A shows a schematic workflow illustrating the experimental pipeline: subject-derived genomic data were used to construct multigenic Drosophila ACC avatar models; these were then used for in vivo drug screening followed by translational validation in subjects, in accordance with aspects of the present disclosure. [0013] FIG.1B shows a schematic of the multigenic expression cassette used to generate ACC avatar lines. Constructs incorporate UAS-driven expression modules for MYBΔC, MYB-NFIB, and additional gene targets, enabling conditional expression in epithelial tissues using GAL4 drivers. [0014] FIG.1C shows a summary of 12 personalized Drosophila ACC models constructed using subject-matched genomic profiles from TCGA, in accordance with aspects of the present disclosure. All models express the MYBΔC construct; additional alterations include combinations of oncogene overexpression and tumor suppressor knockdown using short hairpins. Each fly avatar corresponds to an individual ACC subject and integrates 2–10 genetic alterations. ACC1 and the MYB-NFIB line serve as controls. [0015] FIG.1D shows quantitation of relative wing area for 765>ACC12 (n ≥ 10 discs per genotype; p < 0.01, one-way ANOVA), in accordance with aspects of the present disclosure. [0016] FIG.1E shows representative wing imaginal disc images from larvae expressing the ACC12 transgene under control of the 765-GAL4 driver, showing increased disc size relative to controls, in accordance with aspects of the present disclosure. Treatment with a three-drug combination (tofacitinib 18 μM, vorinostat 0.1 μM, pindolol 10 μM) reduced disc overgrowth. [0017] FIG.1F shows viability screen across 12 ACC fly models (plus MYB-NFIB and MYBΔC controls) showing percent survival to adulthood upon treatment with the three- drug cocktail, in accordance with aspects of the present disclosure. The ACC12 model, which informed the original subject treatment, shows the strongest response. Other models display variable sensitivity, with several lines showing minimal or no rescue. Asterisks denote statistical significance (p < 0.05, p < 0.01, **p < 0.0001, ns = not significant, one-way ANOVA with Dunnett's post hoc test). [0018] FIG.2A shows ssurvival to adulthood across 14 Drosophila ACC avatar lines, each expressing MYBΔC or MYB-NFIB plus subject-specific genetic alterations, with and without tofacitinib treatment (18 μM), in accordance with aspects of the present disclosure. Tofacitinib significantly rescued viability in 8 of 12 subject-derived lines, including MYBΔC and MYB-NFIB controls. Asterisks indicate statistical significance compared to untreated control (p < 0.05, p < 0.01, **p < 0.0001, ns = not significant; one-way ANOVA with Dunnett’s post hoc test). [0019] FIG.2B shows viability rescue following treatment with delgocitinib (25 μM), a clinically approved JAK inhibitor, in accordance with aspects of the present disclosure. A similar pattern of rescue was observed, with 8/12 avatar lines exhibiting significant improvement in adult survival. [0020] FIG.2C shows Peficitinib (25 μM) also rescued a subset of ACC lines, overlapping with tofacitinib- and delgocitinib-responsive genotypes, in accordance with aspects of the present disclosure. These data support JAK pathway dependency across multiple ACC molecular subtypes. [0021] FIG.2D shows ggenetic reduction of JAK/STAT signaling components—via heterozygous RNAi knockdown of hopscotch (hop^Tum-1) or stat92E—rescued lethality in ACC12 and ACC1 (MYB-NFIB-only) models, phenocopying pharmacologic JAK inhibition, in accordance with aspects of the present disclosure. [0022] FIG.2E shows qquantification of wing disc size in 765>ACC12 larvae with and without genetic JAK/STAT pathway suppression in accordance with aspects of the present disclosure. Both hop and stat92E knockdown significantly reduced the overgrowth phenotype compared to controls, further supporting a JAK/STAT-mediated mechanism. [0023] FIG.2F shows rrepresentative images and quantification of wing disc area in MYBΔC-expressing larvae (control) showing disc hyperplasia that is rescued by genetic suppression of hop or stat92E, in accordance with aspects of the present disclosure. Bars represent mean ± SEM; p < 0.001 by one-way ANOVA. [0024] FIG.3A shows an overview of strategy to assess JAK inhibitors in Drosophila ACC models in accordance with aspects of the present disclosure. [0025] FIG 3B, upper panel, shows immunoblot analysis of pSTAT3 (Y705) and α- Tubulin in Drosophila larvae expressing ACC subject-specific constructs (ACC3–ACC8), compared to wild-type control, in accordance with aspects of the present disclosure. Elevated levels of pSTAT3 were observed in multiple lines, notably ACC4, ACC5, ACC6, ACC7, and ACC8, indicating constitutive JAK/STAT pathway activation in these genotypes. α-Tubulin serves as a loading control. Lower panel: Viability assay of selected ACC fly lines (ACC1, ACC4, ACC7, ACC8) treated with tofacitinib (18 μM). Lines exhibiting high baseline pSTAT3 (e.g., ACC4, ACC7, ACC8) showed significant rescue of adult survival, supporting the hypothesis that JAK/STAT pathway activation predicts tofacitinib sensitivity. [0026] FIG.3C, Left panel, shows quantification of pSTAT3 immunohistochemistry across 39 ACC subject samples using an H-score metric, in accordance with aspects of the present disclosure. Scores reflect intensity and distribution of pSTAT3 nuclear staining in tumor tissue cores. A subset of samples exhibit high pSTAT3 levels (H-score > 150), consistent with Drosophila model data. Right panel: Representative fluorescence in situ hybridization (FISH) image (schematic) indicating proposed correlation between MYB alterations (e.g., truncations or fusions) and elevated pSTAT3. Spatial heterogeneity in pSTAT3-positive tumor regions suggests intratumoral activation of JAK/STAT signaling. DETAILED DESCRIPTION [0027] As disclosed herein, JAK inhibitors may be an effective targeted therapy for a subset of ACC subjects with elevated JAK/STAT signaling. Using a personalized fly avatar model developed from an ACC subject’s tumor, a combination regimen including the JAK inhibitor tofacitinib was found to have anti-tumor efficacy. Further screening in additional fly avatars derived from databases of ACC subjects identified elevated JAK/STAT activity as a common vulnerability. Biomarker studies in subject tumor samples also revealed increased JAK/STAT activation in a proportion of cases. [0028] Adenoid cystic carcinoma (ACC) is a rare, malignant neoplasm arising predominantly in the secretory glands, with a high predilection for the salivary glands, particularly the minor salivary glands of the oral cavity. It is also known to occur in other exocrine glandular tissues, including but not limited to the lacrimal glands, tracheobronchial tree, breast, vulva, and skin appendages. [0029] ACC is histopathologically characterized by a biphasic population of epithelial and myoepithelial cells, which are typically arranged in distinctive growth patterns, including cribriform (the hallmark "Swiss-cheese" architecture), tubular, and solid configurations. The cribriform pattern is most frequently observed and diagnostically significant, defined by pseudocystic spaces filled with basophilic mucopolysaccharide or hyaline-like material. The solid variant is associated with a more aggressive clinical course and poorer prognosis. [0030] Clinically, ACC is noted for its deceptively indolent growth rate, often presenting as a painless, slow-growing mass. However, despite its slow progression, ACC exhibits a distinctively aggressive biological behavior, characterized by a high incidence of perineural invasion, frequent local recurrence, and a marked propensity for late-onset distant metastases. The most common sites of distant dissemination are the lungs, followed by bone, liver, and brain. [0031] Perineural invasion is a defining feature of ACC and contributes to its locally invasive phenotype, complicating surgical resection and often leading to incomplete excision and subsequent local relapse. The tumor's neurotropic behavior is facilitated by specific molecular interactions, including the upregulation of nerve growth factor (NGF), neural cell adhesion molecules (NCAMs), and various matrix metalloproteinases (MMPs). [0032] At the molecular level, ACC is frequently associated with chromosomal translocations involving the MYB or MYBL1 genes, most notably the t(6;9)(q22–23;p23–24) translocation, which results in the MYB-NFIB fusion gene. This genetic alteration leads to constitutive activation of the MYB transcription factor, driving oncogenic processes such as cell proliferation, survival, and angiogenesis. The detection of MYB or MYBL1 rearrangements via fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) can serve as a diagnostic adjunct in confirming ACC. [0033] Current therapeutic modalities include surgical resection with wide negative margins, often followed by adjuvant radiation therapy. Chemotherapeutic approaches have demonstrated limited efficacy, with ongoing research directed toward targeted therapies, including inhibitors of MYB signaling, angiogenesis, and epigenetic modulators. [0034] Due to the high risk of late recurrence and distant metastasis, long-term follow-up is essential. Prognostic indicators include histological subtype, tumor size and location, margin status, and presence of perineural or vascular invasion. [0035] As used herein, the term “treatment” or “treating” refers to any act of administering or applying a therapy with the purpose of preventing, delaying the onset of, reducing the severity of, ameliorating, suppressing, managing, or curing a disease, disorder, or medical condition. This term encompasses both prophylactic and therapeutic interventions. Prophylactic treatment refers to actions taken to prevent or reduce the likelihood of the development or recurrence of a disease in a subject at risk, while therapeutic treatment refers to efforts aimed at alleviating or mitigating symptoms, clinical signs, or pathological features after the disease has manifested. Treatment also includes palliative care, which focuses on reducing the severity or progression of symptoms to improve quality of life, and interventions aimed at managing the disease to control or slow its progression. Furthermore, treatment encompasses efforts that extend the lifespan or delay disease-related mortality in subjects affected by or predisposed to a condition. [0036] As used herein, the term “therapeutically effective amount” refers to the quantity of an agent, compound, composition, or intervention that, when administered to a subject, is sufficient to achieve a desired therapeutic effect, including but not limited to the prevention, delay, mitigation, reduction, or elimination of one or more symptoms or manifestations of a disease, disorder, or medical condition. A therapeutically effective amount may also include an amount that achieves a beneficial clinical outcome such as improvement in disease severity, prevention of disease progression, enhanced quality of life, or extension of survival. The precise amount will vary depending on a variety of factors including the nature of the condition being treated, the mode of administration, the specific agent or composition used, the age, weight, sex, and medical condition of the subject, and other clinical variables. In some embodiments, a therapeutically effective amount may be an amount sufficient to achieve a measurable biological response or pharmacological effect, which may or may not correspond to complete disease resolution. The term also encompasses prophylactically effective amounts where the goal is to prevent or reduce the risk of developing a disease or condition in a subject at risk. [0037] The terms “subject” or “subject in need thereof” are used interchangeably herein. These terms refer to a subject who has been diagnosed with the underlying disorder to be treated. The subject may currently be experiencing symptoms associated with the disorder or may have experienced symptoms in the past. Additionally, a “subject in need thereof” may be a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological systems of a disease, even though a diagnosis of this disease may not have been made. [0038] The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present disclosure are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present disclosure include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present disclosure include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms. Included in the present disclosure is a pharmaceutically acceptable salt of a JAK inhibitor as disclosed herein, and a pharmaceutical composition including a JAK inhibitor as disclosed herein, or a pharmaceutically acceptable salt thereof, optionally including one or more pharmaceutically acceptable excipient. [0039] A pharmaceutical composition including a JAK inhibitor or pharmaceutically acceptable salt thereof as disclosed herein includes, as a non-limiting example, such compound in a lyophilized or dry form. Formulations for administration to a subject include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of a recipient or intended purpose of the administration. A formulation may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. A method may include a step of bringing into association a JAK inhibitor or a pharmaceutically acceptable salt thereof (“active ingredient”) with a carrier which constitutes one or more accessory ingredients. In general, formulations may be prepared by uniformly and intimately bringing into association an active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. [0040] Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of an active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A compound may also be presented as a bolus, electuary or paste. For oral or other administration, a compound may be suspended in a solution, or dissolved in a solvent, such as alcohol, DMSO, water, saline, or other solvent, which may be further diluted or dissolved in another solution or solvent, and may or may contain a carrier or other excipient in some examples. [0041] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. 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 sustained, delayed or controlled release of the active ingredient therein. [0042] Formulations for parenteral or other administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render a formulation isotonic with the blood of the intended recipient. Formulations for parenteral or other administration also may include aqueous and non- aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0043] For the purpose of the present disclosure, a “pure” or “substantially pure” enantiomer is intended to mean that the enantiomer is at least 95% of the configuration shown and 5% or less of other enantiomers. Similarly, a “pure” or “substantially pure” diastereomer is intended to mean that the diastereomer is at least 95% of the relative configuration shown and 5% or less of other diastereomers. [0044] The pharmaceutical compositions disclosed herein may include one or more pharmaceutically acceptable excipients, including, but not limited to, one or more binders, bulking agents, buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, diluents, disintegrants, viscosity enhancing or reducing agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, taste-masking agents, perfuming agents, flavoring agents, diluents, polishing agents, polymer matrix systems, plasticizers and other known additives to provide an elegant presentation of the drug or aid in the manufacturing of a medicament or pharmaceutical product including a composition of the present disclosure. Non-limiting examples of carriers and excipients well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. [0045] As used herein, the term "about" refers to a range of values encompassing from 10% less than a stated numerical value to 10% greater than the stated numerical value. For example, "about 100 mg" would encompass a range from 90 mg to 110 mg. [0046] Janus kinase (JAK) inhibitors represent a class of small-molecule therapeutics that modulate intracellular signal transduction pathways associated with cytokine and growth factor receptors. The JAK family of non-receptor tyrosine kinases, which includes JAK1, JAK2, JAK3, and TYK2, plays a critical role in mediating the signal transduction of numerous pro-inflammatory and hematopoietic cytokines via the JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway. [0047] STAT proteins ("Signal Transducers and Activators of Transcription") are a family of cytoplasmic transcription factors that play a central role in relaying signals from cell surface receptors to the nucleus in response to cytokines and growth factors. In humans, there are seven STAT family members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. [0048] Upon cytokine or growth factor binding to its respective cell surface receptor, receptor-associated JAKs become activated through trans-phosphorylation. Activated JAKs subsequently phosphorylate tyrosine residues on the receptor, providing docking sites for STAT proteins. STATs are then phosphorylated by JAKs, leading to their dimerization and nuclear translocation, where they act as transcription factors to regulate the expression of genes involved in cell proliferation, differentiation, survival, and immune regulation. [0049] Activation of the JAK-STAT pathway can be indirectly detected by detection of the presence of phosphorylated STAT protein, or phospho-STAT (p-STAT). p-STAT may be detected immunohistochemically, using an antibody that specifically binds to a phosphorylated STAT protein but non non-phosphorylated STAT. Antibodies may also distinguish between different non-phosphorylated or phosphorylated members of the STAT family, being specific for STAT1, STAT2, STAT3, STAT4, STAT5, or STAT6, or p-STAT1, p-STAT2, p-STAT3, p-STAT4, p-STAT5, or p-STAT6. Immunohistochemical detection p- STAT1, p-STAT2, p-STAT3, p-STAT4, p-STAT5, or p-STAT6 in a tumor sample may indicate activation of the JAK-STAT pathway in cells of the tumor. In an implementation disclosed herein, detection of p-STAT3, including immunohistochemically, in a tumor sample from a subject having or suspected of having ACC indicates administration of a JAK inhibitor to the subject may be an effective treatment of ACC for the subject. [0050] Aberrant activation of JAK-STAT signaling has been implicated in the pathogenesis of a wide array of diseases, including autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus), inflammatory diseases (e.g., ulcerative colitis, atopic dermatitis), and hematological malignancies (e.g., myelofibrosis, polycythemia vera, and certain leukemias). JAK inhibitors act by selectively or non-selectively inhibiting one or more JAK enzymes, thereby interrupting the pathological cytokine-driven signaling cascades. [0051] Several JAK inhibitors have received regulatory approval and are currently in clinical use. Referred to herein are some examples of JAK inhibitors approved for therapeutic use, some non-limiting examples of which include tofacitinib (3-[(3R,4R)-4-methyl-3- [methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile), delgocitinib (3-[(3S,4R)-3-methyl-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7- diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile), peficitinib (4-[[(1S,3R)-5-hydroxy-2- adamantyl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide), abrocitinib (N-[3-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]propane-1-sulfonamide), baricitinib (2-[1- ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile), upadacitinib ((3S,4R)-3-ethyl-4-(1,5,7,10-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),3,7,9,11- pentaen-12-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide), and filgotinib (N-[5-[4- [(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]cyclopropanecarboxamide). [0052] For every implementation of the subject matter disclosed herein of administration of one of the foregoing, or another, JAK inhibitor, administration may be of a therapeutically effective dose. Administration of a therapeutically effective dose may be twice daily or once daily, or less often such as every two days or every three days or every four days or every five days or every six days or every seven days or every eight days or every nine days or every ten days or every eleven days or every twelve days or every thirteen days or every fourteen days or every fifteen days or every sixteen days or every seventeen days or every eighteen days or every nineteen days or every twenty days or every twenty-one days or every twenty-two days or every twenty-three days or every twenty-four days or every twenty-five days or every twenty-six days or every twenty-seven days or every twenty-eight days or every twenty-nine days or every thirty days. In an implementation, administration is once daily. [0053] A therapeutically effective dose may be about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. In an implementation, the dose is 10 mg. [0054] Histone deacetylase (HDAC) inhibitors represent a class of epigenetic modulators that exert therapeutic effects by altering the acetylation status of histone and non- histone proteins. HDACs are enzymes that remove acetyl groups from lysine residues on histones, leading to chromatin condensation and transcriptional repression. By inhibiting HDAC activity, HDAC inhibitors promote a more relaxed chromatin structure, thereby facilitating transcriptional activation of genes involved in cell cycle arrest, apoptosis, and differentiation. [0055] In an implementation, whether administration of a JAK inhibitor would be expected to be an effective treatment for a subject may be determined by whether or not p- STAT expression in a tumor of the subject equals of exceeds a threshold level of activation, wherein a level of expression of p-STAT below the threshold indicates administration of a JAK inhibitor would not be expected to be a therapeutically effective treatment and expression at or above the threshold would be expected to be a therapeutically effective treatment. The p-STAT may be p-STAT3. [0056] Whether expression of the p-STAT is below, at, or above the threshold may be determined by immunohistochemical detection of the p-STAT in a tumor from the subject and determining a histochemical score (H-score). An H-score is a widely used semi- quantitative method for evaluating the level of protein expression in tissue samples analyzed by immunohistochemistry (IHC). It combines both the intensity of staining and the proportion of cells stained at each intensity into a single composite score, providing a more nuanced assessment of biomarker expression compared to purely qualitative assessments. In an H-score assessment, a tissue sample is first labeled with an antibody against the target protein (e.g., p-STAT3) then treated for detection of cells to which the antibody bound, wherein a higher signal detection in a cell indicates a higher amount of the p-STAT expressed in the cell. [0057] Intensity of signal exhibited by cells is then scored according to the following rubric: Cells A pathologist or trained analyst then evaluates the sample, assigning each cell (or field) an intensity score typically categorized as: 0 = no staining of the cell, 1 = weak staining of the cell, 2 = moderate staining of the cell, and 3 = strong staining of the cell. The percentage of cells staining at each intensity level is also determined. An H-score is then calculated as: [0058] H-score = (% of cells with intensity 1×1) + (% of cells with intensity 2×2) + (% of cells with intensity 3×3). [0001] Thus, an H-score can range from 0 (no staining in any cells) to a maximum of 300 (100% of cells showing strong, 3+ intensity staining). For example, if 20% of the cells stain at intensity 1, 50% at intensity 2, and 10% at intensity 3, the H-score would be calculated as: (20×1)+(50×2)+(10×3)=20+100+30=150. In an implementation, a threshold H- score, below which administration of a JAK inhibitor may not be predicted to be a therapeutically effective and at or above which administration of a JAK inhibitor may be predicted to be therapeutically effective, may be about 50, or about 75, or about 100, or about 125, or about 150, or about 175, or about 200, or about 225. In an implementation, the threshold is an H-score of about 150. [0002] In the context of adenoid cystic carcinoma (ACC), HDAC inhibitors have emerged as a therapeutic approach due to their ability to target the epigenetic dysregulation that contributes to the pathogenesis and progression of this malignancy. ACC is frequently associated with aberrant gene expression profiles driven in part by the MYB-NFIB fusion oncogene, which alters transcriptional programs and promotes oncogenesis. HDAC inhibitors have demonstrated the capacity to modulate MYB target gene expression, disrupt tumor- promoting signaling pathways, and induce tumor cell differentiation and apoptosis. [0003] Preclinical studies have shown that treatment with HDAC inhibitors can reduce cell proliferation, inhibit tumor growth, and sensitize ACC cells to other forms of therapy, including chemotherapy and radiation. HDAC inhibition also has the potential to impair the invasive and neurotropic behavior of ACC, thereby limiting perineural invasion— a hallmark of this disease. In therapeutic use, a therapeutically effective amount of an HDAC inhibitor may be administered to a subject diagnosed with ACC to achieve clinical benefits such as tumor regression, stabilization of disease progression, mitigation of symptoms, or extension of survival. The specific dosage, frequency, and route of administration may vary depending on the compound's pharmacological properties, patient characteristics, and treatment regimen. Accordingly, HDAC inhibitors offer an epigenetic strategy for treating ACC, addressing both the underlying transcriptional dysregulation and the phenotypic aggressiveness of this rare but challenging malignancy. [0004] Disadvantageously, however, HDAC inhibitors are associated with a broad range of adverse effects due to their non-specific modulation of gene expression in both malignant and normal cells. These side effects can vary depending on the specific HDAC inhibitor used, the dosage and duration of treatment, as well as patient-specific factors. One of the most significant categories of toxicity includes hematologic effects, such as thrombocytopenia, neutropenia, and anemia. These cytopenias may necessitate dose reductions or treatment interruptions. In addition, gastrointestinal side effects are frequently observed and include nausea, vomiting, diarrhea, constipation, and anorexia. These symptoms can impact patient nutrition and overall tolerance of therapy. Fatigue and generalized weakness are among the most commonly reported adverse effects and can significantly impair a patient's quality of life. Cardiac toxicities also pose serious risks and include QT interval prolongation, arrhythmias, and changes in heart rate such as bradycardia or tachycardia. These cardiac events are sometimes exacerbated by associated electrolyte disturbances, such as hypokalemia and hypomagnesemia, and may require electrocardiographic monitoring throughout treatment. [0005] Liver toxicity is another concern, with patients frequently exhibiting elevated liver enzymes or hyperbilirubinemia. In severe cases, hepatic dysfunction may occur, necessitating regular liver function monitoring. HDAC inhibitors can also suppress the immune system, increasing the risk of infections, including opportunistic infections and viral reactivation, such as hepatitis B virus. Though less common, pulmonary toxicities such as interstitial lung disease and pneumonitis have been reported and may be serious, particularly with prolonged exposure. Dermatologic side effects include rash, dry skin, and pruritus. In rare cases, severe cutaneous adverse reactions such as Stevens-Johnson Syndrome have been observed. Electrolyte imbalances are also a notable side effect, especially when combined with cardiac toxicity, and often require correction to prevent complications. Neurotoxic effects, while less frequently reported, can include headache, dizziness, and, in rare cases, more severe manifestations such as confusion or encephalopathy. [0006] Furthermore, when used in combination with other therapies, the toxicity profile of HDAC inhibitors can be amplified, necessitating close clinical monitoring. Clinical use of HDAC inhibitors for the treatment of ACC is therefore limited and not always tolerated. [0007] Beta-adrenergic receptors (β-ARs), including β1, β2, and β3 subtypes, are G protein-coupled receptors that mediate the physiological effects of catecholamines such as epinephrine and norepinephrine. These receptors are expressed in various normal tissues and have also been found to be overexpressed in multiple malignancies, including ACC. β-AR signaling may play a role in cancer progression by promoting angiogenesis, cell proliferation, invasion, metastasis, and resistance to apoptosis. [0008] Beta-adrenergic antagonists, commonly known as beta-blockers, are a class of drugs traditionally used to manage cardiovascular conditions such as hypertension, arrhythmias, and ischemic heart disease. In the context of oncology, beta-blockers have been investigated for their potential to inhibit tumor-promoting adrenergic signaling. Preclinical and limited clinical data indicate that beta-blockers, particularly non-selective agents such as propranolol, may inhibit tumor growth and reduce metastatic potential in ACC by interfering with β-AR-mediated pathways. [0009] The therapeutic use of beta-adrenergic drugs in ACC may involve the administration of beta-blockers as monotherapy or in combination with other anti-neoplastic agents. Potential mechanisms of action include suppression of cyclic AMP (cAMP) signaling, inhibition of stress hormone-driven tumor progression, modulation of the tumor microenvironment, and enhancement of immune responses. [0010] While the repurposing of beta-blockers for cancer treatment presents a promising strategy, the administration of these agents is associated with well-characterized adverse effects. Negative effects may include bradycardia, hypotension, fatigue, dizziness, cold extremities, depression, and sexual dysfunction. In patients with reactive airway diseases such as asthma or chronic obstructive pulmonary disease (COPD), non-selective beta- blockers may precipitate bronchospasm. Furthermore, abrupt discontinuation of therapy can lead to rebound hypertension or angina. Careful patient selection and monitoring are essential to mitigate these risks. [0011] Clinical use of β-AR inhibitors for the treatment of ACC is therefore limited and not always tolerated. [0012] As used herein, the term “effective amount” means an amount of a cyclized polypeptide or pharmaceutically acceptable salt thereof as a pharmaceutical agent that may elicit a biological or medical response of a cell, tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. The term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a compound of Formula I, as well as salts, solvates, and physiological functional derivatives thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition. [0013] Also provided herein is a pharmaceutical composition including a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients thereof. The excipient(s) must be “acceptable” in the sense of being compatible with any other ingredients of the formulation and not deleterious to the recipient thereof. [0014] [0015] We administered a personalized treatment to a subject with advanced ACC. Utilizing fly genetics, we constructed a ‘personalized fly avatar’ to mimic the subject’s tumor genomic profile. Drug screening identified Tofacitinib, a JAK inhibitor, as a primary hit against ACC. We subsequently developed 12 personalized ACC ‘avatar’ models based on publicly-available genomic data from 12 ACC subjects. We then tested Tofacitinib and other JAK inhibitors across the 12 ACC fly lines. Lethality was rescued in 8/12 tested avatar lines, including oncogenic MYBΔC alone. Genetic reduction of Drosophila JAK/STAT pathway activity also rescued lethality, further supporting a role for JAK activity in MYB-driven tumors. We found strong correlation between sensitivity to Tofacitinib and elevated pSTAT3. [0016] Our results indicate that JAK is a therapeutic target for a broad set of ACC subjects and markers of JAK/STAT activity may provide a clinical biomarker. Of note, multiple JAK inhibitors are approved for non-cancer use and are well-tolerated, further highlighting the their therapeutic potential for treating ACC. [0017] Our study leverages cross-species avatar models of ACC to functionally identify druggable targets and screen for personalized therapeutic combinations. We report the first evidence that JAK inhibitors may provide clinical benefit for ACC subjects with heightened JAK/STAT pathway activity. EXAMPLES [0059] The following examples are intended to illustrate particular embodiments of the present disclosure, but are by no means intended to limit the scope thereof. [0060] A cross-species fly avatar was created for an ACC subject by integrating whole exome sequencing from the subject's tumor biopsy. The avatar recapitulated the mutational profile of the subject's cancer. High-throughput drug screening was performed using the avatar to test a library of FDA-approved compounds. A novel three-drug combination including the JAK inhibitor tofacitinib was identified. The drug combination was administered to the subject under a compassionate use protocol and showed significant anti-tumor activity. Additional fly avatars were generated from databases of ACC subjects to model a wider range of tumors. Many of these avatars also exhibited increased JAK/STAT signaling. Assays of JAK inhibitors in the avatars revealed a correlation between sensitivity to JAK inhibition and elevated JAK/STAT activity. Analysis of tumor tissue microarrays from 39 ACC subjects found a subset with increased JAK/STAT activation, further supporting JAK as a therapeutic target. Spatial transcriptomics may be applied to map intratumoral heterogeneity in JAK/STAT signaling in subject samples. [0061] Twelve ‘personalized fly avatar’ transgenic ACC lines were designed to model the genomic complexity of 12 ACC subjects. Tofacitinib and other JAK inhibitors rescued transgene-mediated lethality in 8/12 tested avatar lines, including a line expressing oncogenic MYBΔC alone. Genetic reduction of Drosophila JAK/STAT pathway activity also rescued lethality, further supporting a role for JAK activity in MYB-driven tumors. Disclosed herein is a strong correlation between sensitivity to tofacitinib and elevated pSTAT3. As disclosed herein, JAK may represent a therapeutic target for a broad set of ACC subjects and markers of JAK/STAT activity may provide a clinical biomarker. Multiple JAK inhibitors are approved for non-cancer use and are well-tolerated, further highlighting their therapeutic potential for treating ACC in accordance with aspects of the present disclosure. [0062] EXAMPLE 1: METHODS [0063] Fly Genetics and Construction of ACC Avatar Lines [0064] Drosophila melanogaster transgenic models were generated using a previously described multigenic vector system enabling co-expression of multiple oncogenes and tumor suppressor knockdowns under UAS control (Bangi et al., 2019; Bangi et al., 2021). ACC avatar lines were designed to reflect the genomic landscape of 12 individual ACC patients based on publicly available exome datasets. All lines include a core MYB-NFIB fusion transgene, amplified from clinical ACC specimens and cloned into a UAS-driven expression cassette. Additional genetic elements—overexpressed oncogenes and RNAi-based knockdowns of tumor suppressors—were incorporated to model patient-specific mutations. Constructs were introduced into the attP2 landing site via phiC31 integrase-mediated transgenesis. Transgene expression was driven in epithelial tissues using the 765-GAL4 or ptc-GAL4 drivers, enabling spatially restricted expression in the larval wing imaginal disc. Expression levels of introduced transgenes were confirmed by qPCR. [0065] Drug Treatments in Drosophila [0066] Drug screening was performed by administering compounds in standard fly food at concentrations of 50 µM unless otherwise stated. Tofacitinib, vorinostat, and pindolol were administered individually or in combination. Additional JAK inhibitors (delgocitinib, peficitinib) were evaluated at equimolar concentrations. For each genotype, approximately 100 embryos were collected and allowed to develop on drug-containing media at 25°C. Survival to adulthood was recorded as a primary readout of drug efficacy. Each assay was performed in biological triplicate, and results were analyzed using one-way ANOVA with post hoc correction. [0067] Genetic Epistasis and Dominant Modifier Analysis [0068] To assess the contribution of JAK/STAT signaling to ACC-associated lethality, genetic rescue experiments were performed using heterozygous loss-of-function alleles of hopscotch (hop^Tum-1) and stat92E. These alleles were introduced into the ptc>ACC1 and ptc>ACC12 genetic backgrounds via standard crosses. Progeny were scored for survival to adulthood and developmental phenotypes. Wing discs were dissected from wandering third instar larvae, fixed in 4% paraformaldehyde, and stained for size and morphology quantification using ImageJ. [0069] Immunohistochemistry on Human ACC Tissues [0070] Tissue microarrays (TMAs) were obtained from AMSBIO and comprised 39 ACC patient samples. Immunohistochemical staining for phosphorylated STAT3 (pSTAT3 Y705) was performed using a rabbit monoclonal antibody (Cell Signaling Technology) on 5 µm sections. Antigen retrieval was conducted in citrate buffer (pH 6.0), followed by incubation with the primary antibody at 1:100 dilution. Detection was achieved with HRP- conjugated secondary antibodies and DAB chromogen. Staining intensity and distribution were scored by a pathologist blinded to sample identity. Scoring categories included negative, heterogeneous, and uniformly positive nuclear pSTAT3 staining. [0071] Statistical Analysis [0072] Quantitative data are presented as mean ± SEM. Statistical comparisons between multiple groups were conducted using one-way ANOVA with Tukey’s post hoc test. For binary comparisons, two-tailed Student’s t-test was used. A p-value < 0.05 was considered statistically significant. Correlation between fly survival and pSTAT3 levels in human samples was assessed using Spearman’s rank correlation coefficient. All analyses were conducted using GraphPad Prism (v9.0) and R (v4.2.0). [0073] Cloning of MYB-NFIB and Construction of Multigenic Vectors [0074] The MYB-NFIB fusion transcript was amplified via RT-PCR from ACC patient-derived cDNA provided by Prof. Posner, using primers flanking the canonical breakpoint at exon 15 of MYB and exon 9 of NFIB. The PCR product was sequence-verified and cloned into a modified pUASTattB multigenic vector backbone containing multiple Gateway recombination sites. Additional oncogenic transgenes and short hairpin constructs were introduced by Gateway recombination using entry clones sourced from the Drosophila Genomics Resource Center (DGRC) or constructed in-house. RNAi sequences targeting tumor suppressor genes were validated using BLAST and synthesized as inverted repeats under UAS control. All constructs were integrated at the attP2 docking site on chromosome 3L via φC31-mediated transformation (BestGene Inc.). [0075] Quantitative PCR Validation of Transgene Expression [0076] Expression of UAS-driven constructs was validated using qPCR on total RNA extracted from dissected third instar larval tissues (typically wing discs). RNA was isolated using the RNeasy Mini Kit (Qiagen), followed by cDNA synthesis with SuperScript IV (Invitrogen). qPCR was performed using SYBR Green Master Mix (Applied Biosystems) on a QuantStudio 6 Flex Real-Time PCR System. Transcript levels were normalized to the rp49 reference gene. Primer pairs were optimized for efficiency and specificity; melt curve analysis confirmed single amplicons. [0077] Drosophila Husbandry and Drug Administration [0078] Flies were raised on standard cornmeal–molasses medium at 25°C under a 12 h light/dark cycle. For drug assays, compounds were dissolved in DMSO and added to cooled fly food to a final concentration of 50 µM. Tofacitinib, delgocitinib, and peficitinib were obtained from Selleck Chemicals; vorinostat and pindolol were sourced from Sigma-Aldrich. Controls were prepared with vehicle (0.1% DMSO) only. Embryos were collected on grape juice agar plates, washed in PBS, and transferred to vials containing drug-infused media. Survival to eclosion was scored after 14 days. [0079] Immunostaining of Wing Discs and Imaging [0080] Wing imaginal discs were dissected from wandering third instar larvae in cold PBS, fixed in 4% paraformaldehyde for 25 min, and permeabilized in PBS with 0.3% Triton X-100. Primary antibodies used included rabbit anti-pSTAT92E (1:200, Cell Signaling Technology) and mouse anti-MYC (1:200, DSHB). Alexa Fluor–conjugated secondary antibodies (Thermo Fisher) were used at 1:500. Discs were mounted in VECTASHIELD with DAPI (Vector Laboratories) and imaged on a Zeiss LSM 880 confocal microscope using a Plan-Apochromat 40×/1.3 oil DIC objective. Disc area was quantified using ImageJ (NIH), and integrated density was used as a readout of pathway activation. [0081] Immunohistochemistry Quantification and Scoring [0082] For TMAs, slides were deparaffinized, rehydrated through graded alcohols, and subjected to antigen retrieval in citrate buffer (pH 6.0) using a pressure cooker. Endogenous peroxidase activity was quenched with 3% hydrogen peroxide. After blocking in 5% goat serum, slides were incubated overnight at 4°C with anti-pSTAT3Y705 (1:100; CST #9145). Signal was visualized with DAB and hematoxylin counterstaining. TMAs were scanned using an Aperio ScanScope XT and scored independently by two investigators. Scoring scale: 0 (no staining), 1+ (heterogeneous/low), 2+ (moderate), 3+ (strong diffuse nuclear). Discordant cases were re-evaluated jointly. [0083] Statistical and Computational Analyses [0084] For analysis of rescue phenotypes, survival percentages were normalized to control genotypes and analyzed using one-way ANOVA with Dunnett’s post hoc correction. For correlation studies, pSTAT3 staining levels were binned by intensity and compared with drug sensitivity scores using Spearman's correlation. Heatmaps and clustering of drug responses were generated using the ComplexHeatmap package in R. For pathway enrichment analyses, we utilized DAVID and GSEA with the Molecular Signatures Database (MSigDB). Visualization of omics-pathway overlaps was performed using Cytoscape (v3.9.1). [0085] EXAMPLE 2: MODELLING ADENOID CYSTIC CARCINOMA (ACC) IN FLIES FOR DRUG ASSAYS [0086] Data from the TCGA patient database was used to establish a set of 11 personalized fly avatar ACC models (abbreviated ACC2-ACC12), each containing a transgene that includes oncogenic human MYB-NFIB plus additional targeted patient-specific genes. In addition, ‘core’ fly lines expressing human MYB-NFIB alone (ACC1) or MYB^ΔC alone, 14 lines in total were established (FIG.1). [0087] To model the MYB-NFIB fusion, primers were designed to amplify the fusion product from ACC patient DNA and subsequently cloned it in a multigenic plasmid vector. Each patient specific line contains 2-10 genetic alterations that were tailored into a multigenic vector platform combining overexpression constructs (oncogenes) and short hairpins (tumor suppressors FIGs.1A-1C; Bangi et al., 2019, Bangi et al., 2021). The constructs were fused behind a GAL4-inducible UAS promoter to permit targeted expression, and expression was validated by qPCR. [0088] Because drosophila does not contain a clear analogue to the human salivary gland, 765-GAL4 driver construct was used to express transgenes throughout the developing wing disc, a relatively naïve epithelium commonly used for oncogenic studies. For example, expressing the construct modelling patient ACC12 throughout the wing disc (abbreviated 765>ACC12) led to an increase in wing disc size (FIGs 1D, 1E). [0089] EXAMPLE 3: TESTING DRUGS TO VALIDATE THE ROLE OF JAK INHIBITORS FOR ACC [0090] In a previous study that included treatment of an ACC patient (Bangi et al., 2019), a cocktail of the JAK (Janus Kinase) inhibitor tofacitinib plus vorinostat (histone deacetylase inhibitor, used as an anti-cancer agent) plus pindolol (beta blocker used in heart disease) was identified as partially rescuing 765>ACC12. The patient exhibited a partial response to this cocktail for 11 months. [0091] As surprisingly determined and disclosed herein, JAK inhibitor alone vs. the three-drug cocktail (JAK inhibitor plus HDAC inhibitor plus β-AR antagonist) advantageously is an effective treatment for ACC without the disadvantageous side-effects of HDAC inhibitor and β-AR inhibitor administration. Feeding the three-drug combination tofacitinib-vorinostat-pindolol to 12 of our avatar transgenic models only showed strong rescue of the ACC12 model—the original model that identified the combination—with four additional models showing significantly lower levels of rescue to viable adults (FIG.1F). This bespoke drug combination, optimized for the ACC12 patient, as disclosed herein, may therefore not be useful for a broader ACC patient population. [0092] Given that tofacitinib emerged as the initial hit for the ACC12 model, next assessed was whether it was broadly useful in the library of Drosophila avatar lines disclosed herein. Very surprisingly, more lines were rescued to viability by tofacitinib alone than by the three-drug combination (FIG.2A): 8/12 ACC models were significantly rescued. Rescue included the transgenic line containing MYB-NFIB alone (ACC1), suggesting that tofacitinib was effective against the ‘core’ MYB transformation activity. The reduced rescue rate of the three-drug cocktail suggests that, for most ACC lines, including vorinostat plus pindolol led to additional toxicity without significant tumor rescue. [0093] The JAK signaling pathway controls multiple cellular functions, in particular immune response. Clinically relevant JAK inhibitors are well-tolerated and are effective in autoimmune diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease (Shawky et al., 2022). To further assess the potential of JAK inhibitors as a mode of treatment for ACC, two additional JAK inhibitors were tested, delgocitinib and peficitinib that are approved for the treatment of atopic dermatitis and rheumatoid arthritis (Markham et al., 2019, Dhillon, S, 2020). Mirroring tofacitinib findings, both JAK inhibitors significantly rescued 8/12 Drosophila ACC models (FIGs.2B, 2C). Together, this provides further evidence that the ACC rescue by these three drugs is through reducing JAK activity. [0094] To further determine whether the JAK-STAT pathway mediates lethality in our ACC avatar models, genetic heterozygosity (‘dominant genetic rescue’) was used to subtly reduce activity of key JAK-STAT components including Drosophila orthologs of JAK (765>ACC; hop^Tum-1-/+) and STAT (765>ACC; stat92E^-/+). Removing one functional copy of either hop or stat92E activity in ACC12 or ACC1 lines (FIG.2D) led to partial rescue of both fly lines to adulthood as well as a reduction in larval wing disc size towards wild type (FIGs. 2E, 2F).765>ACC1 expresses MYB-NFIB alone, and we conclude that oncogenic MYB activity leads to elevated JAK/STAT pathway activity in our models. Reducing this activity by classical genetic means or by drug administration was sufficient to reduce the impact of oncogenic MYB in our avatar lines, leading to improved animal survival. [0095] EXAMPLE 4: CORRELATION BETWEEN TOFACITINIB SENSITIVITY AND EXPRESSION OF PHOSPHORYLATED STAT AS A POTENTIAL BIOMARKER [0096] Regarding JAK inhibitors, the presence of both responders and non-responders as disclosed herein (FIG.3A) raised the question as to whether elevated phosphorylated- STAT, a measure of pathway activity, could predict tofacitinib sensitivity. Using an antibody to p-STAT3 that recognizes Drosophila pSTAT92E. Relative to control animals, p-STAT levels were strongly elevated in 765>ACC larvae that had responded to tofacitinib in the absence of drug (FIG.3B). This indicates that JAK-STAT pathway activity is strongly elevated specifically in those flies that are sensitive to JAK inhibition. The flies that were less sensitive to tofacitinib showed lower levels of p-STAT (FIG.3B). [0097] These findings are consistent elevated p-STAT serving as a biomarker for a patient’s sensitivity to tofacitinib. [0098] EXAMPLE 5: A SUBSET OF PATIENT TUMORS EXHIBIT ELEVATED PHOSPHORYLATED STAT3 [0099] To explore the relevance of Drosophila data to mammalian ACC JAK-STAT signatures, obtained high-quality 1.5 mm cores were obtained from 39 ACC patients; these patient samples were embedded as tissue microarrays (TMAs; sourced from AmsBio) and sectioned.78 ACC section cores obtained from these 39 patients were probed immunohistochemically using an anti-pSTAT3 antibody. Positive controls included breast cancer samples, while negative controls consisted of samples with no primary antibody. [0100] Elevated pSTAT3 staining was detected in 23 out of 39 patient samples, indicating the presence of heightened JAK/STAT signaling in a subset of ACC patients. (FIGs.3C, 3D). Elevated p-STAT, such as p-STAT3 (e.g., H-score at or above about 150) and MYB status in human ACC patients indicates therapeutic effectiveness of JAK inhibitory administration. [0101] EXAMPLE 6: DISCUSSION [0102] Drosophila avatars designed to model the genetic landscape of ACC patients, demonstrated the therapeutic effectiveness of JAK inhibitors as an effective monotherapy. JAK inhibitors have an extensive clinical record for inflammation-based disease and represent an attractive therapeutic lead. [0103] Drosophila avatars proved useful. Incorporating key genetic aberrations from ACC patients into fly models recapitulated a significant portion of the genetic diversity of individual patient’s disease and tested the efficacy of JAK inhibitors in a system that is both versatile and cost-effective. This approach not only supported the role of the JAK/STAT pathway in ACC pathogenesis but also further highlights the complexity of precision medicine in which treatment is tailored based on the genetic profile of an individual's tumor. For example, a three drug cocktail that was effective in the ACC12 avatar—and in the matched patient—surprisingly failed to show consistent activity across other avatar models and, in several lines, showed less efficacy than tofacitinib alone. Further, not all MYB-NFIB models were sensitive to JAK inhibitors, suggesting that additional mutations can alter the connection between oncogenic MYB and JAK pathway activity. [0104] Genetic and drug studies indicate that activating MYB is sufficient to activate JAK/STAT pathway signaling which, in turn, is a key component of MYB-mediated transformation; importantly, JAK/STAT pathway dependence was observed in avatar line ACC1, which contains oncogenic MYB-NFIB alone. This data was further supported by a patient TMA study, which found elevated pSTAT3 in a significant proportion of patients, though not all. Elevated pSTAT3 thus serves as a biomarker for patients likely to exhibit sensitivity to JAK inhibitor therapy. [0105] Disclosed herein is evidence for the therapeutic potential of administering a JAK inhibitor as am onotherapy for ACC, supported by preclinical models, patient sample data, and a recently treated patient. The importance of the JAK/STAT pathway in ACC pathogenesis and opens a new avenue for targeted therapy is disclosed herein. [0106] Although some non-limiting examples have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the present disclosure and these are therefore considered to be within the scope of the present disclosure as defined in the claims that follow. [0107] It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail herein (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are contemplated as being part of the inventive subject matter disclosed herein and may be used to achieve the benefits and advantages described herein.

Claims

WHAT IS CLAIMED IS: 1. A method for treating adenoid cystic carcinoma, comprising administering a tofacitinib to a subject diagnosed with or suspected of having adenoid cystic carcinoma.

2. The method of claim 1, wherein the administering comprises daily administering from about 5 mg to about 20 mg of the tofacitinib to the subject.

3. The method of claim 2, wherein the administering comprises daily administering about 10 mg of the tofacitinib to the subject.

4. The method any one of claim 1, wherein the method does not further comprise administering a histone deacetylase (HDAC) inhibitor, administering a β-adrenergic receptor antagonist, or administering an HDAC inhibitor and a β-adrenergic receptor antagonist to the subject.

5. The method of claim 4, wherein the HDAC inhibitor is vorinostat, the β-adrenergic receptor antagonist is pindolol, or both.

6. A method for treating adenoid cystic carcinoma, comprising administering a janus kinase (JAK) inhibitor to a subject diagnosed with or suspected of having adenoid cystic carcinoma.

7. The method of claim 6, wherein the JAK inhibitor is selected from tofacitinib, delgocitinib, peficitinib, abrocitinib, baricitinib, upadacitinib, filgotinib, a pharmaceutically acceptable salt of any of the foregoing, or a combination of any two or more of the foregoing.

8. The method of claim 6 or 7, wherein the JAK inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof.

9. The method of any one of claim 6 to 8, wherein the administering comprises daily administering from about 5 mg to about 20 mg of the JAK inhibitor to the subject.

10. The method of any one of claims 6 to 9, wherein the administering comprises daily administering about 10 mg of the JAK inhibitor to the subject.

11. The method any one of claims 6 to 10, wherein the method does not further comprise administering a histone deacetylase (HDAC) inhibitor, administering a β- adrenergic receptor antagonist, or administering an HDAC inhibitor and a β-adrenergic receptor antagonist to the subject.

12. The method of claim 11, wherein the HDAC inhibitor is vorinostat, the β-adrenergic receptor antagonist is pindolol, or both.

13. A method for treating adenoid cystic carcinoma, comprising detecting or having detected a level of phosphorylation of signal transducer and activator of transcription (STAT) in a tumor sample from a subject having or suspected of having adenoid cystic carcinoma, and administering a janus kinase (JAK) inhibitor to the subject if the level of STAT phosphorylation is above a threshold level.

14. The method of claim 13, wherein the STAT is STAT3.

15. The method of claim 13 or 14, wherein the threshold is an H-score of about 150.

16. The method any one of claims 13 to 15, wherein the JAK inhibitor is selected from tofacitinib, delgocitinib, peficitinib, abrocitinib, baricitinib, upadacitinib, filgotinib, a pharmaceutically acceptable salt of any of the foregoing, or any combination of two or more of the foregoing.

17. The method any one of claims 13 to 16, wherein the JAK inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof.

18. The method of any one of claims 13 to 17, wherein the administering comprises daily administering from about 5 mg to about 20 mg of the JAK inhibitor to the subject.

19. The method of any one of claims 13 to 18, wherein the administering comprises daily administering about 10 mg of the JAK inhibitor to the subject.

20. The method any one of claims 13 to 19, wherein the method does not further comprise administering a histone deacetylase (HDAC) inhibitor, administering a β- adrenergic receptor antagonist, or administering an HDAC inhibitor and a β-adrenergic receptor antagonist

21. The method of claim 20, wherein the HDAC inhibitor is vorinostat, the β-adrenergic receptor antagonist is pindolol, or both.

22. A method for treating adenoid cystic carcinoma, comprising detecting or having detected a level of phosphorylation of signal transducer and activator of transcription (STAT) in a tumor sample from a subject having or suspected of having adenoid cystic carcinoma, and administering tofacitinib to the subject if the level of STAT phosphorylation is above a threshold level.

23. The method of claim 22, wherein the STAT is STAT3.

24. The method of claim 22 or 23, wherein the threshold is an H-score of about 150.

25. The method of any one of claims 22 to 24, wherein the administering comprises daily administering from about 5 mg to about 20 mg of the tofacitinib to the subject.

26. The method of claim 25, wherein the administering comprises daily administering about 10 mg of the tofacitinib to the subject.

27. The method of claim 22, wherein the method does not further comprise administering a histone deacetylase (HDAC) inhibitor, administering a β-adrenergic receptor antagonist, or administering an HDAC inhibitor and a β-adrenergic receptor antagonist to the subject.

28. The method of claim 27, wherein the HDAC inhibitor is vorinostat, the β-adrenergic receptor antagonist is pindolol, or both.