WO2023060227A1 - Inhibiteurs de tead et utilisations associées - Google Patents

Inhibiteurs de tead et utilisations associées Download PDF

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Publication number
WO2023060227A1
WO2023060227A1 PCT/US2022/077747 US2022077747W WO2023060227A1 WO 2023060227 A1 WO2023060227 A1 WO 2023060227A1 US 2022077747 W US2022077747 W US 2022077747W WO 2023060227 A1 WO2023060227 A1 WO 2023060227A1
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cancer
patient
yap1
taz
tumor
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PCT/US2022/077747
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English (en)
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Marta Sanchez-Martin
Xiaoyan Michelle ZHANG
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Ikena Oncology, Inc.
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Publication of WO2023060227A1 publication Critical patent/WO2023060227A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4703—Regulators; Modulating activity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to uses of TEAD inhibitors for treating cancer patients, including, for example, cancer patients who are YAP1 and/or TAZ nuclear positive, and cancer patients who have genetic alterations in Hippo pathway genes.
  • Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with TEAD transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers.
  • YAP1 and/or TAZ nuclear localization are indicative of patient responsiveness to treatment with a TEAD inhibitor.
  • NF2, LATS1/2, YAP1, TAZ, MST1/2, and BAP1 are indicative of patient responsiveness to treatment with a TEAD inhibitor.
  • YAP 1 and/or TAZ nuclear positive patients and patients having genetic alterations in Hippo pathway genes are higher in mesothelioma (MESO), gall bladder/cholangiocarcinoma (CHOL), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinomas (HNSCC), esophageal carcinoma (ESCA), and renal cell carcinoma (KIRC).
  • MEO mesothelioma
  • CLC non-small cell lung cancer
  • HNSCC head and neck squamous cell carcinomas
  • ESCA esophageal carcinoma
  • KIRC renal cell carcinoma
  • methods for determining or predicting efficacy of treatments using TEAD inhibitors and/or selecting a patient for application or administration of a treatment comprising a TEAD inhibitor, such as Compound A comprise, in part, methods of identifying patients having YAP1 and/or TAZ nuclear positivity and/or genetic alterations in Hippo pathway genes, and methods for treating patients having YAP1 and/or TAZ nuclear positivity and/or genetic alterations in Hippo pathway genes using TEAD inhibitors, such as Compound A.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient who is YAP1 and/or TAZ nuclear positive, comprising administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • a TEAD inhibitor for example, as described herein.
  • the patient is determined as being YAP1 and/or TAZ nuclear positive, for example, using a method as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient is YAP1 and/or TAZ nuclear positive, for example, using an IHC staining method as described herein.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient who has a genetic alteration in one or more Hippo pathway genes, comprising administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • a proliferative disorder such as cancer
  • the patient is determined as having a genetic alteration in one or more Hippo pathway genes, for example, using a method as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient has a genetic alteration in one or more Hippo pathway genes, for example, using any of the methods as described herein, for example, NGS (including, for example, WES, WTS, WGS or targeted sequencing), Sanger Sequencing, array CGH, FISH, amplicon sequencing, and SNP arrays.
  • NGS including, for example, WES, WTS, WGS or targeted sequencing
  • Sanger Sequencing sequencing, array CGH, FISH, amplicon sequencing, and SNP arrays.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, comprising immunohistochemistry (IHC) staining a tumor tissue of a patient, and selecting a patient who is YAP 1 and/or TAZ nuclear staining positive for administration of a therapeutically effective amount of a TEAD inhibitor.
  • IHC immunohistochemistry
  • the present invention provides a method of treating cancer, comprising selecting a patient who is YAP1 and/or TAZ nuclear positive, and administering to the patient a therapeutically effective amount of a TEAD inhibitor.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient, comprising selecting a patient who is YAP1 and/or TAZ nuclear positive, for example, using a method as described herein, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient is YAP1 and/or TAZ nuclear positive, for example, using an IHC staining method as described herein.
  • a Hippo pathway gene is selected from NF2, LATS1/2, YAP1, TAZ, MST1/2, and BAP1.
  • the present invention provides a method for identifying or selecting a cancer patient who has a genetic alteration in Hippo pathway genes, comprising measuring or determining whether a tumor sample from the patient has a genetic alteration in Hippo pathway genes, for example, using a method as described herein, and selecting a patient who has a genetic alteration in Hippo pathway genes.
  • the present invention provides a method of treating cancer, comprising selecting a patient who has a genetic alteration in Hippo pathway genes, and administering to the patient a therapeutically effective amount of a TEAD inhibitor.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient, comprising selecting a patient who has a genetic alteration in Hippo pathway genes, for example, using a method as described herein, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient has a genetic alteration in Hippo pathway genes, for example, using any of the methods as described herein, for example, NGS (including, for example, WES, WTS, WGS or targeted sequencing), Sanger Sequencing, array CGH, FISH, amplicon sequencing, and SNP arrays.
  • NGS and/or Sanger sequencing are used for measuring or determining gene mutations.
  • NGS, FISH, amplicon sequencing and/or SNP arrays are used for measuring or determining gene fusions.
  • CGH arrays, FISH, and/or NGS are used for measuring or determining gene copy number alterations.
  • a cancer is selected from those as described herein.
  • a TEAD inhibitor is selected from those as described herein.
  • a TEAD inhibitor is Compound A, or a pharmaceutically acceptable salt thereof.
  • FIG. 1 depicts alterations in Hippo pathway genes, including, for example, NF2, YAP1, TAZ, LATS1/2, MST1/2, and B API.
  • YAP1 and/or TAZ nuclear localization and/or genetic alteration in Hippo pathway genes can be used as a predictive biomarker for identifying and selecting cancer patients who can receive clinical benefit or be responsive to treatment with a TEAD inhibitor, such as Compound A.
  • immunohistochemistry staining can identify cancer patients who are YAP1 and/or TAZ nuclear positive.
  • Various tumor tissues have been analyzed using immunohistochemistry (IHC) staining. See, for example, the IHC staining data of meningioma, sarcoma, mesothelioma, and NSCLC, as described herein.
  • IHC staining data of meningioma, sarcoma, mesothelioma, and NSCLC, as described herein.
  • cancer patients who are YAP1 and/or TAZ nuclear positive may be more likely to benefit from a TEAD inhibitor treatment.
  • YAP1 and/or TAZ nuclear positive patients varies significantly across different types of cancer. For example, based on IHC staining, there are a higher percentage of meningioma, sarcoma, and mesothelioma patients who are YAP1 and/or TAZ nuclear positive than other cancer types. Accordingly, for certain cancer types (for example, meningioma, sarcoma, and mesothelioma), a preselection of YAP1 and/or TAZ nuclear positive patients could significantly enhance the effectiveness of a TEAD inhibitor treatment.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient who is YAP1 and/or TAZ nuclear positive, comprising administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • a TEAD inhibitor for example, as described herein.
  • the patient is determined as being YAP1 and/or TAZ nuclear positive, for example, using a method as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient is YAP1 and/or TAZ nuclear positive, for example, using an IHC staining method as described herein.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient who has a genetic alteration in one or more Hippo pathway genes, comprising administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • a proliferative disorder such as cancer
  • the patient is determined as having a genetic alteration in one or more Hippo pathway genes, for example, using a method as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient has a genetic alteration in one or more Hippo pathway genes, for example, using any of the methods as described herein, for example, NGS (including, for example, WES, WTS, WGS or targeted sequencing), Sanger Sequencing, array CGH, FISH, amplicon sequencing, and SNP arrays.
  • the one or more Hippo pathway genes are selected from NF2, YAP1, TAZ, LATS 1/2, MST 1/2, and BAP1.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient is YAP1 and/or TAZ nuclear positive, for example, using an IHC staining method as described herein.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient, comprising selecting a patient who has a genetic alteration in one or more Hippo pathway genes, for example, using a method as described herein, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient has a genetic alteration in one or more Hippo pathway genes, for example, using any of the methods as described herein, for example, NGS (including, for example, WES, WTS, WGS or targeted sequencing), array CGH, Sanger Sequencing, FISH, amplicon sequencing, and SNP arrays.
  • the one or more Hippo pathway genes are selected from NF2, YAP1, TAZ, LATS 1/2, MST 1/2, and BAP1.
  • the present invention provides a method for IHC staining a tumor tissue of a patient, comprising staining a tumor tissue section using a YAP1 or TAZ monoclonal antibody.
  • the present invention provides a method for identifying or selecting a cancer patient, comprising using an IHC staining method as described herein.
  • the present invention provides a method for treating cancer, comprising selecting a cancer patient using an IHC staining method, as described herein, and administering a therapeutically effective amount of a TEAD inhibitor as described herein.
  • the present invention provides a method for identifying or selecting a cancer patient who has a genetic alteration in one or more Hippo pathway genes, comprising measuring or determining whether a tumor sample from the patient has a genetic alteration in Hippo pathway genes, for example, using a method as described herein, and selecting a patient who has a genetic alteration in one or more Hippo pathway genes.
  • the present invention provides a method for treating cancer, comprising selecting a cancer patient who has a genetic alteration in one or more Hippo pathway genes, for example, using a method as described herein, and administering a therapeutically effective amount of a TEAD inhibitor as described herein.
  • the one or more Hippo pathway genes are selected from NF2, YAP1, TAZ, LATS 1/2, MST 1/2, and B API.
  • the present invention provides a method for treating a cancer patient who is YAP1 and/or TAZ nuclear positive, and has a genetic alteration in one or more Hippo pathway genes, using the methods as described herein.
  • the present invention provides a method for treating a cancer patient who is YAP1 and/or TAZ nuclear positive, and who has a genetic alteration in one or more Hippo pathway genes, comprising administering a therapeutically effective amount of a TEAD inhibitor as described herein.
  • the one or more Hippo pathway genes are selected from NF2, YAP1, TAZ, LATS 1/2, MST 1/2, and BAP 1.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, and has a genetic alteration in one or more Hippo pathway genes, using the methods as described herein.
  • the present invention provides a method for treating cancer, comprising selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, and who has a genetic alteration in one or more Hippo pathway genes, for example, using the methods as described herein, and administering a therapeutically effective amount of a TEAD inhibitor as described herein.
  • the present invention provides a method for treating a cancer patient who is YAP1 and/or TAZ nuclear positive, and who has a genetic alteration in one or more Hippo pathway genes, comprising administering a therapeutically effective amount of a TEAD inhibitor as described herein.
  • the one or more Hippo pathway genes are selected from NF2, YAP1, TAZ, LATS 1/2, MST 1/2, and BAPl.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, and has a genetic alteration in Hippo pathway gene NF2, using the methods as described herein.
  • the present invention provides a method for treating cancer, comprising selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, and who has a genetic alteration in Hippo pathway gene NF2, for example, using the methods as described herein, and administering a therapeutically effective amount of a TEAD inhibitor as described herein.
  • the present invention provides a method for treating a cancer patient who is YAP1 and/or TAZ nuclear positive, and who has a genetic alteration in Hippo pathway gene NF2, comprising administering a therapeutically effective amount of a TEAD inhibitor as described herein.
  • inhibitor or “TEAD inhibitor” or “TEAD antagonist” are defined as a compound that binds to and/or inhibits TEAD with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner.
  • the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • an inhibitor has an IC50 and/or binding constant of less than about 100 pM, less than about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • a TEAL) inhibitor is a compound or a TEAD binding moiety as described in Pobbati et al., “Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy,” Structure 2015, 23, 2076-2086; Gibault et al., “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem. 2018, 61, 5057-5072; Bum-Erdene et al., “Small-Molecule Covalent Modification of conserveed Cysteine Leads to Allosteric Inhibition of the TEAD* Yap Protein-Protein Interaction,” Cell Chemical Biology 2019, 26, 1-12; Holden et.
  • Compound A refers to an TEAD inhibitor, N-methyl-3-(l- methyl-lH-imidazol-4-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzenesulfonamide, of formula: some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is in crystal form.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci ⁇ alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • the terms “about” or “approximately” have the meaning of within 20% of a given value or range. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.
  • an increase is used interchangeably and encompass any measurable increase in a biological function and/or biological activity and/or a concentration and/or amount, such as, for example, an increase in YAP1 and/or TAZ nuclear positivity.
  • an increase can be by at least about 10%, about 15%, about
  • the terms “increased concentration,” or “increased levels” or “increased amounts” of a substance (e.g., nuclear YAP1 and/or TAZ) in a sample, such as a tumor biopsy, refers to an increase in the amount of the substance of about 5%, about 10%, about 15%, about
  • control sample or control samples such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control, as determined by techniques known in the art.
  • a subject can also be determined to have an “increased concentration” or “increased amount” of a substance if the concentration of the substance is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more relative to the mean (average) or median amount of the substance in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples.
  • concentration of the substance is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more relative to the mean (average) or median amount of the substance in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples.
  • control or baseline levels can be previously determined, or measured prior to the measurement in the sample, or can be obtained from a database of such control samples. In other words, the control and subject samples do not have to be tested simultaneously.
  • “reduced concentration,” “decreased concentrations,” “decreased amounts,” “lowered levels,” or “reduced levels” refers to a decrease in concentration or a decrease in level by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% in a sample relative to a control.
  • a subject "in need of prevention,” “in need of treatment,” or “in need thereof,” refers to one, who by the judgment of an appropriate medical practitioner (e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non-human mammals), would reasonably benefit from a given treatment or therapy.
  • an appropriate medical practitioner e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non-human mammals
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the term “patient” refers to an animal, preferably a mammal, and, most preferably, a human.
  • a patient or subject "in need of prevention,” “in need of treatment,” or “in need thereof,” refers to one, who by the judgment of an appropriate medical practitioner (e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of nonhuman mammals), would reasonably benefit from a given treatment or therapy.
  • an appropriate medical practitioner e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of nonhuman mammals
  • a therapeutically effective amount of refers to the amount of a TEAD inhibitor (e.g., compound A, or a pharmaceutically acceptable salt thereof), which is effective to inhibit TEAD activity in a biological sample or in a patient.
  • a therapeutically effective amount of refers to the amount of a TEAD inhibitor (e.g., compound A, or a pharmaceutically acceptable salt thereof), which measurably displaces an endogenous ligand which binds to TEAD in the nucleus.
  • promote(s) cancer regression means that administering an effective amount of the drug, alone or in combination with one or more additional anti -neoplastic agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • effective and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety.
  • Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient.
  • Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
  • therapeutic efficacy or “responsiveness to treatment” or “therapeutic benefit” or “benefit from therapy” refer to an improvement in one or more of overall survival, progression-free survival, partial response, complete response, and overall response rate and can also include a reduction in cancer or tumor growth or size, a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. 5. Description of Exemplary Methods and Uses
  • the present invention provides methods of identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive and/or has genetic alteration in one or more Hippo pathway genes for treatment with a TEAD inhibitor.
  • the methods comprise identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive.
  • Such methods can comprise, for example, determining whether a patient is YAP1 and/or TAZ nuclear positive using available methods know in the art, such as, for example, IHC staining.
  • the methods comprise identifying or selecting a cancer patient who has genetic alteration in one or more Hippo pathway genes.
  • the method further comprises administering a TEAD inhibitor to the patient who is YAP1 and/or TAZ nuclear positive, such as Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering a TEAD inhibitor to the patient who has genetic alteration in one or more Hippo pathway genes, such as Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for IHC staining a tumor tissue of a patient, comprising staining a tumor tissue section using a YAP1 monoclonal antibody. In some embodiments, the present invention provides a method for IHC staining a tumor tissue of a patient, comprising staining a tumor tissue section using a TAZ monoclonal antibody.
  • a YAP1 monoclonal antibody is [EPR19812] (ab205270). In some embodiments, a YAP1 monoclonal antibody is YAP (D8H1X) XP® Rabbit mAb.
  • a YAP1 monoclonal antibody is YAP/TAZ (E9M8G) Rabbit mAb.
  • a YAP1 monoclonal antibody is [EP1674Y] (ab52771).
  • a YAP1 monoclonal antibody is [2F12] (ab56701).
  • a YAP1 monoclonal antibody is Anti-YAPl antibody (abl 14862).
  • a YAP1 monoclonal antibody is NB110-58358.
  • a TAZ monoclonal antibody is CSE9J5A.
  • a TAZ monoclonal antibody is [CL0371] (ab242313). In some embodiments, a TAZ monoclonal antibody is (ab224239). In some embodiments, a TAZ monoclonal antibody is (abl 10239). In some embodiments, a TAZ monoclonal antibody is (7H33L24) (Thermo Fisher). In some embodiments, a TAZ monoclonal antibody is 2b3 (Thermo Fisher). In some embodiments, a TAZ monoclonal antibody is Ifl 1 (Thermo Fisher). [0047] In some embodiments, a tumor tissue section is an about 4pm thick tissue section on a positively charged glass slide.
  • a tumor tissue section is about 2.0, 2.5, 3.0, 3.5, 4.5, 5.0, 5.5, or 6.0 pm thick on a positively-charged glass slide.
  • a tumor tissue section is stained at about pH 1.0, 1.5, 2.0, 2.5, 3.0, 3.5 or 4.0.
  • a tumor tissue section is stained at about pH 4.5, 5.0, 5.5, 6.0, 6.5, or 7.0.
  • a tumor tissue section is stained at about pH 7.5, 8.0, 8.5, or 9.0.
  • a tumor tissue section is stained at about pH 2.0.
  • a tumor tissue section is stained for about 40 minutes.
  • a tumor tissue section is stained for about 20, 25, 30, 35, 45, 50, 55, or 60 minutes.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, comprising IHC staining a tumor tissue of a patient, and selecting a patient who is YAP 1 and/or TAZ nuclear staining positive and administering a TEAD inhibitor to the patient, such as Compound A or a pharmaceutically acceptable salt thereof.
  • YAP1 and/or TAZ nuclear positive refers to that certain percentage of cells in a tumor biopsy core having a detectable amount of YAP1 and/or TAZ, respectively, in the nucleus.
  • YAP1 and/or TAZ nuclear positive refers to that about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% of cells in a tumor biopsy core have a detectable amount of YAP1 and/or TAZ, respectively, in the nucleus.
  • a detectable amount of YAP 1 and/or TAZ1 in the nucleus refers to detecting YAP1 and/or TAZ1 translocating from the cytoplasm to the nucleus in the absence of phosphorylation.
  • YAP1 and/or TAZ nuclear positive refers to that about 5% or more cells in a tumor biopsy core have a detectable amount of YAP1 and/or TAZ, respectively, in the nucleus.
  • YAP1 and/or TAZ nuclear positive refers to that about 20% or more of cells in a tumor biopsy core have a detectable amount of YAP 1 and/or TAZ, respectively, in the nucleus.
  • YAP1 and/or TAZ nuclear positive refers to that about 50% or more of cells in a tumor biopsy core have a detectable amount of YAP 1 and/or TAZ, respectively, in the nucleus.
  • a tumor biopsy core refers to a tumor region of the tumor biopsy core.
  • a tumor biopsy core refers to a tumor microenvironment (or stroma) region of the tumor biopsy core.
  • a tumor tissue region refers to a tumor biopsy core in a tissue microarray (TMA).
  • the present invention provides a method for identifying or selecting a cancer patient who has a genetic alteration in one or more Hippo pathway genes, comprising measuring one or more Hippo pathway gene copies in a sample from the patient, such as a tumor sample, and selecting a patient who has a genetic alteration in one or more Hippo pathway genes for treatment with a TEAD inhibitor.
  • the method further comprises administering a TEAD inhibitor, such as Compound A or a pharmaceutically acceptable salt thereof, to the patient who has a genetic alteration in one or more Hippo pathway genes.
  • the term “genetic alteration in one or more Hippo pathway genes” refers to that certain percentage of cells in a sample, such as a tumor sample, having a detectable amount of genetic alteration in one or more Hippo pathway genes.
  • a genetic alteration in a gene can refer, for example, to a loss-of-function mutation in the gene (including, for example, frameshifts, nonsense mutations and splicing mutations), a change in gene copy number (including, for example, copy gain, amplification, copy loss, or deletion), or a fusion of the gene with another gene, such as, for example, a TAZ-CAMTA1 fusion or YAP1- TFE3 fusion.
  • genetic alteration in Hippo pathway genes refers to that about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% of cells, such as tumor cells, in a sample have at least about three copies of genetically altered Hippo pathway genes, at least about four copies of genetically altered Hippo pathway genes, at least about five copies of genetically altered Hippo pathway genes, at least about six copies of genetically altered Hippo pathway genes, at least about seven copies of genetically altered Hippo pathway genes, at least about eight copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes,
  • genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about 15 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 40% tumor cells in a sample have at least about 4 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about four copies of genetically altered Hippo pathway genes. In some embodiments, a Hippo pathway gene is NF2. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is NF2 deficiency. In some embodiments, NF2 deficiency refers to NF2 loss of function mutations.
  • NF2 deficiency refers to NF2 copy losses or deletions. In some embodiments, NF2 deficiency refers to absent or very low NF2 mRNA expression.
  • a Hippo pathway gene is YAP1. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is YAP1 amplification. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is a YAP1 fusion, such as a YAP1-TFE3 fusion. In some embodiments, a Hippo pathway gene is TAZ. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is TAZ amplification.
  • the genetic alteration in the one or more Hippo pathway genes is a TAZ fusion, such as a TAZ-CAMTA1 fusion.
  • a Hippo pathway gene is LATS 1/2.
  • the genetic alteration in the one or more Hippo pathway genes is LATS 1/2 copy number loss or deletion.
  • a Hippo pathway gene is MST1/2.
  • a Hippo pathway gene is BAP1.
  • Methods and assays of measuring or determining genetic alteration in one or more Hippo pathway genes in a sample are known in the art and can be used with the methods described herein.
  • Such assays and methods include immunoassays, nextgeneration sequencing ((NGS), including, for example, WES, WTS, WGS or targeted sequencing), Sanger sequencing, array CGH, SNP arrays, amplicon sequencing, and fluorescent in situ hybridization (FISH).
  • NGS nextgeneration sequencing
  • FISH fluorescent in situ hybridization
  • Next Generation Sequence is used to detect genetic alterations in Hippo pathway genes.
  • Next Generation Sequencing encompasses DNA sequencing using targeted panels, Whole exome sequencing, Whole Transcriptome sequencing and whole genome sequencing are methods that allow determination of copy number variations (CNV) in genes of interest (Zhao, BMC bioinformatics 2012). Copy number alterations include deletions or amplifications of genes.
  • CNV copy number variations
  • To detect CNV DNA is isolated from the samples of interest, which can be fresh or FFPE tissue, such as biopsies and blood, among other tissues. The DNA is amplified and labeled to form libraries which are then run into NGS sequencers. The results from the sequencers are then analyzed using computational algorithms specifically designed to infer CNVs.
  • RNAscope is used to detect expression and localization of Hippo pathway genes.
  • RNAscope is a method that allows for in situ RNA analysis detection and quantification in formalin-fixed, paraffin-embedded tissues (Wand J Mol Diagn. 2012).
  • RNA ISH and particularly RNAscope can be utilized to quantify expression of a given gene in cells.
  • RNAscope can be utilized herein to assess mRNA expression of genetically altered Hippo pathway genes in cancer cell lines and immune cells from 10 tumor types in a tumor microarray (Pancreas, Colon, Kidney, Head & Neck, Melanoma, Prostate, Lung, Ovary, Bladder and Breast). Images are scanned and analyzed using computational software (HALO). This method is suitable to determine mRNA expression of genetically altered Hippo pathway genes in tumor cells and tumor microenvironment by H-SCORE.
  • HALO computational software
  • fluorescent in situ hybridization is used to detect genetic alterations in Hippo pathway genes, including, for example, to detect copy number alterations and fusion genes.
  • cells are obtained from a biological sample, such as an FFPE sample, and hybridized with a probe set specific for a Hippo pathway gene. Probe signals are captured and inverted DAPI images reviewed. Samples can be deemed positive for genetic alteration in a Hippo pathway gene if various criteria are met. For example, > 10% tumor cells > 15 copies of a genetically altered Hippo pathway gene, > 40% tumor cells > 4 copies of a genetically altered Hippo pathway gene, and/or > 10% tumor cells > 4 copies (cluster) of a genetically altered Hippo pathway gene.
  • an immunohistochemistry (IHC) staining assay is used to detect an amount of YAP 1 and/or TAZ in the nucleus.
  • an immunohistochemistry (IHC) staining assay is used to detect an amount of YAP 1 and/or TAZ in the nucleus, which are produced by genetically altered Hippo pathway genes YAP1 and/or TAZ, respectively.
  • IHC is a method that uses antibodies to check for certain antigens (markers), such as YAP1 and/or TAZ, in a sample of tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to the antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope.
  • an IHC staining assay is as described in Example 1 herein.
  • YAP1 nuclear positive refers to YAP1 nuclear staining positive in an IHC staining assay.
  • TAZ nuclear positive refers to TAZ nuclear staining positive in an IHC staining assay.
  • YAP1 and/or TAZ nuclear staining positive refers to that a detectable number of cells in a tumor biopsy core are staining positive in an IHC staining assay.
  • YAP1 and/or TAZ nuclear staining positive refers to that about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% of cells in a tumor biopsy core are staining positive in an IHC staining assay.
  • a tumor biopsy core refers to a tumor region of the tumor biopsy core.
  • a tumor biopsy core refers to a tumor microenvironment (or stroma) region of the tumor biopsy core.
  • a tumor tissue region refers to a tumor biopsy core in a tissue microarray (TMA).
  • an IHC staining assay comprises measuring staining intensity in a tumor biopsy core.
  • staining intensity is measured by the methods as described in Example 1 herein.
  • staining intensity is measured by visual scoring, for example, by manual scoring using conventional light microscopy.
  • staining intensity is measured by computational tissue analysis (CTA) scoring.
  • the staining intensity levels can be no staining (0), weak staining (1+), median staining (2+), or strong staining (3+).
  • staining positive refers to all staining intensity (including 1+, 2+, and 3+ intensities).
  • staining positive refers to pooled 2+ and 3+ staining intensity (including all 2+ and 3+ intensities). In some embodiments, staining intensity is measured in a tumor region of a tumor biopsy core. In some embodiments, staining intensity is measured in a tumor microenvironment (or stroma) region of a tumor biopsy core. [0060] As described herein, IHC staining has shown that the percentage of YAP1 and/or TAZ nuclear positive patients varies significantly across different types of cancer. Accordingly, selecting YAP1 and/or TAZ nuclear positive patients prior to a TEAD inhibitor treatment can be particularly beneficial for certain types of cancer.
  • the present invention provides a method of selecting a YAP1 and/or TAZ nuclear positive patient of a particular cancer type.
  • the particular cancer type is selected from mesothelioma (MESO), gall bladder/cholangiocarcinoma (CHOL), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinomas (HNSCC), esophageal carcinoma (ESC A), and renal cell carcinoma (KIRC).
  • MEO mesothelioma
  • CHOL gall bladder/cholangiocarcinoma
  • NSCLC non-small cell lung cancer
  • HNSCC head and neck squamous cell carcinomas
  • ESC A esophageal carcinoma
  • KIRC renal cell carcinoma
  • a method of selecting a YAP1 and/or TAZ nuclear positive patient is for selecting mesothelioma patients.
  • IHC staining shows that certain percent of mesothelioma is YAP1 and/or TAZ nuclear positive, as shown in Table 1 below.
  • IHC staining shows that about 46% of mesothelioma patients are YAP1 nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • IHC staining shows that about 19% of mesothelioma patients are TAZ nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • a method of selecting a YAP1 and/or TAZ nuclear positive patient is for selecting NSCLC patients.
  • IHC staining shows that certain percent of NSCLC is YAP1 and/or TAZ nuclear positive, as shown in Table 1 below.
  • IHC staining shows that about 25% of NSCLC patients are YAP1 nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • IHC staining shows that about 10% of NSCLC patients are TAZ nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • a method of selecting a YAP1 and/or TAZ nuclear positive patient is for selecting sarcoma patients, such as synovial sarcoma patients.
  • IHC staining shows that certain percent of sarcoma is YAP1 and/or TAZ nuclear positive, as shown in Table 1 below.
  • IHC staining shows that about 56% of sarcoma patients are YAP1 nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • IHC staining shows that about 11% of sarcoma patients are TAZ nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • a method of selecting a YAP1 and/or TAZ nuclear positive patient is for selecting meningioma patients.
  • IHC staining shows that certain percent of meningioma is YAP1 and/or TAZ nuclear positive, as shown in Table 1 below.
  • IHC staining shows that about 76% of meningioma patients are YAP1 nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • IHC staining shows that about 8% of meningioma patients are TAZ nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • a method of selecting a YAP1 and/or TAZ nuclear positive patient is for selecting gall bladder/cholangiocarcinoma patients.
  • IHC staining shows that certain percent of gall bladder/cholangiocarcinoma is YAP1 and/or TAZ nuclear positive, as shown in Table 1 below.
  • IHC staining shows that about 31% of gall bladder/cholangiocarcinoma patients are YAP1 nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • IHC staining shows that about 4% of gall bladder/cholangiocarcinoma patients are TAZ nuclear staining positive (at 2+ and 3+ intensities) in a tumor region of a tumor biopsy core.
  • the present invention provides a method of selecting a YAP1 and/or TAZ nuclear positive patient comprising selecting a cancer patient having an H-Score equal to or higher than the mean value of the cancer type.
  • the present invention provides a method of treating cancer in a patient, comprising selecting a patient who is YAP1 and/or TAZ nuclear positive, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, or a pharmaceutical composition thereof.
  • a cancer is selected from mesothelioma (MESO), gall bladder/cholangiocarcinoma (CHOL), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinomas (HNSCC), esophageal carcinoma (ESCA), and renal cell carcinoma (KIRC).
  • the present invention provides a method of treating cancer in a patient, comprising selecting a patient who is YAP1 and/or TAZ nuclear positive by an IHC staining assay, as described herein, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, as described herein, or a pharmaceutical composition thereof.
  • the present invention provides a method of treating cancer in a patient, comprising selecting a patient having about 5% or more cells that are YAP1 and/or TAZ nuclear staining positive at all intensity (including 1+, 2+, and 3+ staining intensity) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring in a tumor region of a tumor biopsy core, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, as described herein, or a pharmaceutical composition thereof.
  • the present invention provides a method of treating cancer in a patient, comprising selecting a patient having about 20% or more cells that are YAP1 and/or TAZ nuclear staining positive at all intensity or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring in a tumor region of a tumor biopsy core, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, as described herein, or a pharmaceutical composition thereof.
  • the present invention provides a method of treating cancer in a patient, comprising selecting a patient having about 50% or more cells that are YAP1 and/or TAZ nuclear staining positive at all intensity or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring in a tumor region of a tumor biopsy core, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, as described herein, or a pharmaceutical composition thereof.
  • a TEAD inhibitor is selected from the compounds as described in WO 2017/053706, WO 2017/111076, WO 2018/204532, WO 2018/235926, US 20190010136, WO 2019/040380, WO 2019/113236, WO 2019/222431, WO 2019/232216, WO 2020/051099, WO 2020/081572, WO 2020/097389, WO 2020/190774, or WO 2020/214734, the contents of each of which are herein incorporated by reference in their entireties.
  • the TEAD inhibitor is selected from those described in WO 2020/243415, the contents of which are herein incorporated by reference in their entirety.
  • the TEAD inhibitor is selected from those described in WO 2020/243423, the contents of which are herein incorporated by reference in their entirety. In certain embodiments, the TEAD inhibitor is selected from those described in U.S. Patent No. 11,274,082, the contents of which are herein incorporated by reference in their entirety. In certain embodiments, the TEAD inhibitor is selected from those described in WO 2022/120353, the contents of which are herein incorporated by reference in their entirety. In certain embodiments, the TEAD inhibitor is selected from those described in WO 2022/120354, the contents of which are herein incorporated by reference in their entirety. In certain embodiments, the TEAD inhibitor is a TEAD degrader. In certain embodiments, the TEAD degrader is selected from those described in WO 2022/120355, the contents of which are herein incorporated by reference in their entirety.
  • a TEAD inhibitor is Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating mesothelioma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 5% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating mesothelioma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 20% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating mesothelioma in a patient, comprising:
  • the present invention provides a method of treating NSCLC in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 5% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating NSCLC in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 20% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating NSCLC in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 50% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating HNSCC in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 5% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating HNSCC in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 20% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating HNSCC in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 50% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating gall bladder/cholangiocarcinoma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 5% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating gall bladder/cholangiocarcinoma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 20% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating gall bladder/cholangiocarcinoma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 50% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating esophageal carcinoma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 5% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating esophageal carcinoma in a patient, comprising: IHC staining a tumor tissue of a patient; selecting a patient having about 20% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating esophageal carcinoma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 50% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating renal cell carcinoma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 5% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating renal cell carcinoma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 20% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating renal cell carcinoma in a patient, comprising:
  • IHC staining a tumor tissue of a patient selecting a patient having about 50% or more cells in a tumor region of a tumor biopsy core which are YAP1 and/or TAZ nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring or manual scoring; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, comprising detecting and measuring YAP1 and/or TAZ in the nucleus of a tumor tissue of the patient using Next Generation Sequencing (NGS), and selecting a patient who is YAP1 and/or TAZ nuclear positive.
  • NGS Next Generation Sequencing
  • RNA sequencing is used to quantitatively measure gene expression of genes known to be targets of YAP1-TEAD and TAZ-TEAD transcriptional activity (e.g., CTGF or CYR61).
  • RNA is isolated from the samples of interest which can be fresh or FFPE tissue, such as biopsies and blood among other tissues.
  • the RNA is amplified and labeled to form libraries which are then run into NGS sequencers.
  • the results from the sequencers are analyzed using computational algorithms specifically designed to assess gene expression.
  • the results from the sequencers are analyzed using computational algorithms specifically designed to assess differential gene expression between two conditions.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, comprising detecting and measuring YAP1 and/or TAZ in the nucleus of a tumor tissue of the patient using Quantitative PCR, and selecting a patient who is YAP1 and/or TAZ nuclear positive.
  • quantitative PCR is used to quantify the expression of genes that are targets of YAP1-TEAD or TAZ-TEAD complexes.
  • RNA is extracted from tumor, blood and other tissues, for example, using a commercial kit.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, comprising detecting and measuring YAP1 and/or TAZ in the nucleus of a tumor tissue of the patient using Nanostring, and selecting a patient who is YAP1 and/or TAZ nuclear positive.
  • Nanostring allows measurement of gene signature expression changes in samples as a method alterative to RNAseq.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, comprising detecting and measuring YAP1 and/or TAZ in the nucleus of a tumor tissue of the patient using RNAscope, and selecting a patient who is YAP1 and/or TAZ nuclear positive.
  • RNAscope allows in situ RNA analysis detection and quantification in formalin-fixed, paraffin-embedded tissues (Wand J Mol Diagn. 2012).
  • RNA ISH, and particularly RNAscope is utilized to quantify expression of a given gene within specific cell types.
  • RNAscope allows quantification of transcripts (mRNA molecules) from genes known to be targets of YAP1-TEAD or TAZ-TEAD complexes.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, comprising detecting and measuring YAP1 and/or TAZ in the nucleus of a tumor tissue of the patient using Fluorescence microscopy, and selecting a patient who is YAP1 and/or TAZ nuclear positive.
  • fluorescence microscopy measures nuclear YAP1 and TAZ.
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, comprising detecting and measuring YAP1 and/or TAZ in the nucleus of a tumor tissue of the patient using Co Immunoprecipitation and LC/MS, and selecting a patient who is YAP1 and/or TAZ nuclear positive.
  • Co Immunoprecipitation and LC/MS measure the amount of YAP1 or TAZ bound to TEAD as a readout of activation status (they only form complex when active).
  • the present invention provides a method for identifying or selecting a cancer patient who is YAP1 and/or TAZ nuclear positive, comprising detecting and measuring YAP1 and/or TAZ in the nucleus of a tumor tissue of the patient using Co Immunoprecipitation and western blotting, and selecting a patient who is YAP1 and/or TAZ nuclear positive.
  • Co Immunoprecipitation and western blotting measure the amount of YAP 1 or TAZ bound to TEAD as a readout of activation status (they only form complex when active).
  • a method described herein comprises administering a pharmaceutical composition comprising a TEAD inhibitor, as described herein, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of a TEAD inhibitor in a composition is such that is effective to measurably bind to and/or inhibit TEAD in a biological sample or in a patient.
  • a TEAD inhibitor composition is formulated for oral administration to a patient.
  • compositions of this invention refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3 -butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food. [00110]
  • the amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient who is YAP1 and/or TAZ nuclear positive, comprising administering to the patient a therapeutically effective amount of a TEAL) inhibitor, for example, as described herein.
  • a TEAL TEAL
  • the patient is determined as being YAP1 and/or TAZ nuclear positive, for example, using a method as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient is YAP1 and/or TAZ nuclear positive, for example, using an IHC staining method as described herein.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient who has genetic alteration in one or more Hippo pathway genes, comprising administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • the patient is determined as having genetic alteration in one or more Hippo pathway genes, for example, using a method as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient has genetic alteration in one or more Hippo pathway genes, for example, using any of the methods as described herein, for example, NGS (including, for example, WES, WTS, WGS, or targeted sequencing), Sanger Sequencing, array CGH, FISH, amplicon sequencing, and SNP arrays.
  • NGS including, for example, WES, WTS, WGS, or targeted sequencing
  • Sanger Sequencing sequencing, array CGH, FISH, amplicon sequencing, and SNP arrays.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient, comprising selecting a patient who is YAP1 and/or TAZ nuclear positive, for example, using a method as described herein, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient is YAP1 and/or TAZ nuclear positive, for example, using an IHC staining method as described herein.
  • the present invention provides a method of treating a proliferative disorder, such as cancer, in a patient, comprising selecting a patient who has genetic alteration in one or more Hippo pathway genes, for example, using a method as described herein, and administering to the patient a therapeutically effective amount of a TEAD inhibitor, for example, as described herein.
  • a treatment method further comprises measuring or determining whether a tumor sample from the patient has genetic alteration in one or more Hippo pathway genes, for example, using any of the methods as described herein, for example, NGS (including WES, WTS, WGS or targeted sequencing), Sanger Sequencing, array CGH, FISH, amplicon sequencing, and SNP arrays.
  • a TEAD inhibitor is Compound A or a pharmaceutically acceptable salt thereof.
  • the cancer or proliferative disorder or tumor to be treated using the methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
  • a cancer to be treated using the methods described herein can be selected from mesothelioma, gall bladder/cholangiocarcinoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinomas (HNSCC), esophageal carcinoma, renal cell carcinoma, and clonal hematopoiesis.
  • the cancer is mesothelioma.
  • the cancer is gall bladder/cholangiocarcinoma.
  • the cancer is non-small cell lung cancer (NSCLC).
  • the cancer is head and neck squamous cell carcinomas (HNSCC).
  • the cancer is esophageal carcinoma.
  • the cancer is renal cell carcinoma.
  • the cancer is clonal hematopoiesis.
  • the cancer has a genetic alteration in one or more Hippo pathway genes.
  • the genetic alteration in one or more Hippo pathway genes is NF2 deficiency, i. e. , the cancer is an NF2-deficient cancer.
  • the genetic alteration in the one or more Hippo pathway genes is a YAP1 fusion, such as a YAP1-TFE3 fusion, z.e., the cancer is a YAP1 fusion cancer, such as a YAP1-TFE3 fusion.
  • the genetic alteration in the one or more Hippo pathway genes is TAZ amplification, z.e., the cancer has a TAZ amplification.
  • the genetic alteration in the one or more Hippo pathway genes is a TAZ fusion, such as a TAZ-CAMTA1 fusion, z.e., the cancer is a TAZ fusion cancer, such as a TAZ-CAMTA1 fusion.
  • the genetic alteration in the one or more Hippo pathway genes is YAP1 amplification, z.e., the cancer has a YAP1 amplification.
  • the genetic alteration in the one or more Hippo pathway genes is LATS 1/2 deletion or copy loss, z.e., the cancer has a LATS 1/2 deletion or copy loss.
  • the cancer shows high YAP1 nuclear expression and is from a patient who has acquired resistance to EGFR inhibitors. In some embodiments, the cancer shows high YAP1 nuclear expression and is from a patient who has acquired resistance to MEK1 inhibitors.
  • Cancer includes, in some embodiments, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcom
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma schwannoma
  • neurofibrosarcoma meningioma, melanoma
  • neuroblastoma
  • the cancer is acoustic neuroma, astrocytoma (e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • astrocytoma e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - G
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymph
  • the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/ stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma.
  • Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyos
  • the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma
  • HCC hepato
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer
  • the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments,
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis- 1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • MPNST peripheral nerve sheath tumors
  • the cancer is neurofibromatosis- 1 associated MPNST.
  • the cancer is Waldenstrom
  • the cancer is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Tumor, Astrocytoma, Brain and Spinal Cord Tumor, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Cancer, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer,
  • ALL Acute Lympho
  • the cancer is selected from bladder cancer, breast cancer (including TNBC), cervical cancer, colorectal cancer, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), esophageal adenocarcinoma, glioblastoma, head and neck cancer, leukemia (acute and chronic), low-grade glioma, lung cancer (including adenocarcinoma, non-small cell lung cancer, and squamous cell carcinoma), Hodgkin's lymphoma, non-Hodgkin lymphoma (NHL), melanoma, multiple myeloma (MM), ovarian cancer, pancreatic cancer, prostate cancer, renal cancer (including renal clear cell carcinoma and kidney papillary cell carcinoma), and stomach cancer.
  • CLL chronic lymphocytic leukemia
  • DLBCL diffuse large B-cell lymphoma
  • esophageal adenocarcinoma esophageal adenocar
  • the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular cancer, neuroblastoma, other solid tumors or other hematological cancers.
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • pancreatic cancer liver cancer, hepatocellular cancer, neuroblastoma, other solid tumors or other hematological cancers.
  • the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, or AML.
  • the present invention further features methods and compositions for the diagnosis, prognosis and treatment of viral-associated cancers, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV- I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus- associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • HCV human immunodeficiency virus
  • HPV human papilloma virus
  • HTLV-I human T-cell leukemia virus type I
  • the methods or uses described herein inhibit or reduce or arrest the growth or spread of a cancer or tumor. In some embodiments, the methods or uses described herein inhibit or reduce or arrest further growth of the cancer or tumor. In some embodiments, the methods or uses described herein reduce the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90% or at least 99% relative to the size of the cancer or tumor prior to treatment.
  • the size e.g., volume or mass
  • the methods or uses described herein reduce the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90% or at least 99% relative to the quantity of cancers or tumors prior to treatment.
  • the compounds and compositions, according to the methods of the present invention can be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer or tumor.
  • the exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like.
  • the compounds and compositions, according to the methods of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions is decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism depends upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient or “subject,” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intraci sternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated.
  • the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the following examples are provided for illustrative purposes only and are not to be construed as limiting this invention in any manner.
  • Compound A can be prepared by methods known to one of ordinary skill in the art, for example, as described in WO2018195397 and US20180327411, the contents of which are incorporated herein by reference in their entireties.
  • CTA computational tissue analysis
  • TME tumor microenvironment, or stroma region, which is a separate region from tumor region
  • TMA tissue microarray.
  • all TMAs are human tumor biopsies.
  • % cells positive per core the percentage of cells that are YAP1 and/or TAZ nuclear staining positive in a biopsy core
  • # of TME+ cores the number of cores that have >50% (or 20%, 5%) YAP1 and/or TAZ nuclear positive cells at all intensity in TME region
  • Tumor+ cores the number of cores that have >50% (or 20%, 5%) YAP1 and/or TAZ nuclear positive cells at all intensity in tumor region
  • # of total cores in the TMA how many cores in the TMA (tumor microarray)
  • % TME+ cores the percentage of cores that are >50% (or 20%, 5%) YAP1 and/or TAZ nuclear positive in TME region
  • % Tumor+ cores the percentage of cores that are >50% (or 20%, 5%) YAP1 and/or TAZ nuclear positive in tumor region
  • % 1+ Nucleus the percentage of positive cells with YAP1 and/or TAZ nuclear staining at 1+ intensity in one biopsy core
  • % 2+ Nucleus the percentage of positive cells with YAP1 and/or TAZ nuclear staining at 2+ intensity in one biopsy core
  • % 3+ Nucleus the percentage of positive cells with YAP1 and/or TAZ nuclear staining at 3+ intensity in one biopsy core
  • Example 1 IHC Staining Protocol: YAP1 Monoplex for Use in FFPE
  • FFPE Formalin-Fixed Paraffin Embedded
  • Staining conditions were pH 2.0 for 20 minutes and DAB for 10 minutes.
  • CSE9J5A was diluted in CST specific reagent, and not in Leica diluent reagent.
  • the Leica BPRD kit utilizes a goat anti rabbit polymer and a mouse anti -rabbit linker.
  • Anti -YAP 1 antibody was used at 1 :2000 to stain tumor samples, TMA cores and xenografts samples equivalent to a final concentration of 0.386 ug per slide; Anti-TAZ antibody was used at 1 :50 to stain samples; equivalent to a final concentration of 4.68 ug per slide. Isotype and concentration matched irrelevant antibody were used as a negative control. Each antibody run included two sections of normal lung tissue as positive control, as strong YAP1 or TAZ staining is observed in the lung epithelium.
  • IHC stained glass slides were interpreted by use of manual scorings The intensity of staining for nucleus was graded on 0-3 scale according to the following criteria: 0 (no staining observed), 1 (weak staining), 2 (moderate staining) and 3 (strong staining). The frequency of each staining intensity was determined, and the results were reported using % values and an H score according to the formula below:

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Abstract

La présente invention concerne des procédés de sélection d'un patient atteint d'un cancer qui est positif au YAP1 et/ou au TAZ nucléaire, ainsi que des méthodes de traitement du cancer chez un patient atteint d'un cancer positif au YAP1 et/ou au TAZ nucléaire et l'administration au patient d'un inhibiteur de TEAD.
PCT/US2022/077747 2021-10-07 2022-10-07 Inhibiteurs de tead et utilisations associées WO2023060227A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
US11925651B2 (en) 2019-05-31 2024-03-12 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
WO2024092116A1 (fr) 2022-10-26 2024-05-02 Ikena Oncology, Inc. Association d'inhibiteurs de tead et d'inhibiteurs d'egfr et utilisations associées
US12103915B2 (en) 2022-09-29 2024-10-01 Insilico Medicine Ip Limited TEAD inhibitors and methods of uses thereof

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