Methods and systems for patient selection and treatment

Abstract

Provided herein are methods and systems for treating patients with a TEAD inhibitor, selecting patients suitable for treatment, and measuring efficacy of treatment with same.

Description

WSGR Docket No. 47612-752.601METHODS AND SYSTEMS FOR PATIENT SELECTION AND TREATMENTCROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No. 63 / 724,091 filed on November 22, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Personalized medicine is a model that promises customization of healthcare with treatments selected for subgroups of patients. In this scenario, diagnostic testing is used to select optimal therapies based on a patient’ s genetics or other molecular or cellular assay. Cancer research has identified genetic types of cancer that appear the same in traditional pathology, raising the possibility of finding drugs that have not given good results applied to the general population but may be successful in a fraction of cases with a particular genetic profile. For example, Trastuzumab is a monoclonal antibody that inhibits the HER2 / neu receptor. This drug is only used in patients with over-expression of HER2 / neu.SUMMARY

[0003] In an aspect, provided herein are methods of treating a cancer in an individual in need thereof. In some embodiments, the method comprises administering a yes-associated protein (YAP)Ztranscriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a genetic alteration in a Hippo pathway gene. In some embodiments, the genetic alteration results in altered expression of the gene. In some embodiments, the genetic alteration is a loss of function alteration. In some embodiments, the loss of function alteration is in a gene selected from the group consisting of NF2, LATS1, LATS2, SAV1, STK3, SIK4, M0B1A, MOB1B, WWC1, FRMD6, TAOK1, TAOK2, and TAOK3. In some embodiments, the genetic alteration is a gain of function alteration. In some embodiments, the gain of function alteration is in a gene selected from the group consisting of YAP1, WWTR1 (TAZ), TEAD1, TEAD2, TEAD3, and TEAD4. In some embodiments, the gain of function alteration is a YAP / WWTR1 rearrangement. In some embodiments, the YAP / WWTR1 rearrangement is selected from the group consisting of YAP1-TFE3, WWTR1(TAZ)-CAMTA1, YAP1-MAMLD1, YAP1-FAM118B, YAP1-SS18, YAP1-MAML2, YAP1-NUTM1, YAP1-MAML2, YAP 1 -F AMI 18B, YAP1-PYGO1, YAP1-LMO1, YAP1-KMT2A, YAP1-SHM1, YAP1-CFAP300(YAP1-C110RF70), and YAP1-MRPL48. In some embodiments, the yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:WSGR Docket No. 47612-752.601Formula (I); wherein: R is Ci-Cefluoroalkyl; and R1is (a) Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl; (b) Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl; or (c) Ci- Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, - NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogen unsubstituted Ci-Cealkyl. In some embodiments, R1is Ci-Cealkyl substituted with -OH. In some embodiments, R1is Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2, or unsubstituted pyrazinyl. In some embodiments, R1is Ci-Cealkyl substituted with pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R is -CF3. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; R3is hydrogen or unsubstituted Ci-Cealkyl; and R is -CF3. In some embodiments, the compound is selected from the group consisting of:WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer breast cancer, melanoma, hepatocellular carcinoma, low grade glioma, glioblastoma, ependymoma, ST- ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the genetic alteration is detected by nextgeneration sequencing of genomic DNA or whole transcriptome RNA. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a tumor sample. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a cell-free nucleic acid sample. In some embodiments, alteration in expression of the gene is detected by next-generation sequencing of whole transcriptome RNA or a proteomic assay. In some embodiments, the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the proteomic assay is conducted on a tumor sample. In some embodiments, the genetic alteration is detected by a circulating RNA (cRNA)- digital droplet PCR (ddPCR) assay. In some embodiments, the cRNA is derived from a blood sample or a cell-free nucleic acid sample.

[0004] In another aspect, provided herein are methods of treating a cancer in an individual in need thereof comprising administering a yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a genetic alteration in a gene that leads to constitutive activation of YAP / TAZ-TEAD activity. In some embodiments, the genetic alteration results in altered expression of the gene. In some embodiments, the genetic alteration is a loss of function alteration. In some embodiments, the genetic alteration is in a gene selected from the group consisting of FAT1, FAT2, FAT3, FAT4, GNAQ, GNA11, CDH1, RHOA, BAP1, ZFTA-RELA(Cl lorf95-RELA), and CLDN18-ARHGAP. In some embodiments, the yes-associated protein (YAP)Ztranscriptional enhancer activator domain (TEAD) inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I);WSGR Docket No. 47612-752.601 wherein: R is Ci-Cefluoroalkyl; and R1is (a) Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl; (b) Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl; or (c) Ci- Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, - NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogen unsubstituted Ci-Cealkyl. In some embodiments, R1is Ci-Cealkyl substituted with -OH. In some embodiments, R1is Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2, or unsubstituted pyrazinyl. In some embodiments, R1is Ci-Cealkyl substituted with pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R is -CF3. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; R3is hydrogen or unsubstituted Ci-Cealkyl; and R is -CF3. In some embodiments, the compound is selected from the group consisting of:WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601acceptable salt or solvate thereof. In some embodiments, the compound is:pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer breast cancer, melanoma, hepatocellular carcinoma, low grade glioma, glioblastoma, ependymoma, ST- ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the genetic alteration is detected by nextgeneration sequencing of genomic DNA or whole transcriptome RNA. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a tumor sample. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a cell-free nucleic acid sample. In some embodiments,WSGR Docket No. 47612-752.601 alteration in expression of the gene is detected by next-generation sequencing of whole transcriptome RNA or a proteomic assay. In some embodiments, the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the proteomic assay is conducted on a tumor sample. In some embodiments, the genetic alteration is detected by a fusion circulating RNA (cRNA)- digital droplet PCR (ddPCR) assay. In some embodiments, the cRNA is derived from a tumor sample or a cell-free nucleic acid sample.

[0005] In another aspect, provided herein are methods of treating a cancer in an individual in need thereof comprising administering a yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a high probability of response to the TEAD inhibitor, wherein the high probability of response is determined by: (a) measuring a gene expression level for CRIM1, ANKRD1, GADD45B, WTIP, AXL, TOP2A, BIRC5, CTGF, AMOTL2, AJUBA, ITGB2, FJX1, FOSL1, ASAP1, CDC20, CENPF, CYR61, DDAH1, FGF2, SERPINE1, and TGFB2 in a sample from the individual; and (b) processing the gene expression levels using an algorithm trained using gene expression levels of samples that are responsive to the TEAD inhibitor and gene expression levels of samples that are not responsive to the TEAD inhibitor, thereby determining a probability of response to the TEAD inhibitor in the individual. In some embodiments, the algorithm is a random-forest based algorithm. In some embodiments, the algorithm was developed using TEAD inhibitor response data and bulk RNA-seq data. In some embodiments, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer breast cancer, melanoma, hepatocellular carcinoma, low grade glioma, glioblastoma, ependymoma, ST- ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, gene expression is measured by assaying levels of RNA or levels of protein. In some embodiments, the RNA or the protein are derived from a tumor sample. In some embodiments, the RNA is derived from a tumor sample or a cell-free nucleic acid sample. In some embodiments, assaying levels of RNA comprises next-generation sequencing of RNA or quantitative PCR. In some embodiments, the assaying levels of protein comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the yes- associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:WSGR Docket No. 47612-752.601Formula (I); wherein: R is Ci-Cefluoroalkyl; and R1is (a) Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl; (b) Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl; or (c) Ci- Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, - NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogen unsubstituted Ci-Cealkyl. In some embodiments, R1is Ci-Cealkyl substituted with -OH. In some embodiments, R1is Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2, or unsubstituted pyrazinyl. In some embodiments, R1is Ci-Cealkyl substituted with pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R is -CF3. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; R3is hydrogen or unsubstituted Ci-Cealkyl; and R is -CF3. In some embodiments, the compound is selected from the group consisting of:WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601acceptable salt or solvate thereof. In some embodiments, the compound is:pharmaceutically acceptable salt or solvate thereof.

[0006] In another aspect, provided herein are methods of measuring a response to a yes-associated protein(YAP) / transcriptional enhancer activator domain (TEAD) inhibitor comprising: (a) administering an individual with cancer the TEAD inhibitor; (b) measuring a gene expression level of a pharmacodynamics gene; and correlating the gene expression level of the pharmacodynamics gene to the response to the TEAD inhibitor. In some embodiments, the pharmacodynamics gene is selected from the group consisting of AJUBA, AM0TL2, ANKRD1, ANKRD2, AREG, AXL, BIRC5, BUB1, CCDC80, CCN1 (aka, CYR61), CCN2 (aka, CTGF), CCND1, CD274, CDC20, CRIM1, FASN, FGF2, FJX1, FLT3, FOSL1, F0XM1, GADD45B, HK2, IL21R, IL6, ITGA11, LATS2, MYCN, NF2, NT5E, NUAK2, PLK1, PTPN14, SCD,SLC2A1, SLC2A14, SLC7A5, SOD2, VEGFA, and WTIP. In some embodiments, the cancer is selectedWSGR Docket No. 47612-752.601 from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer breast cancer, melanoma, hepatocellular carcinoma, low grade glioma, glioblastoma, ependymoma, ST-ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the gene expression level comprises RNA expression. In some embodiments, RNA is isolated from a tumor sample, a blood sample, a serum sample, or a plasma sample. In some embodiments, RNA is cell-free RNA or whole transcriptome RNA. In some embodiments, the gene expression comprises protein expression. In some embodiments, protein is isolated from a tumor sample or a blood sample. In some embodiments, the protein is in a formalin-fixed paraffin embedded sample. In some embodiments, the gene expression is measured using a quantitative RNA assay or a quantitative protein assay. In some embodiments, the quantitative RNA assay comprises a nanostring assay, next-generation sequencing, or quantitative RT-PCR. In some embodiments, the quantitative protein assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the yes-associated protein (YAP ( / transcriptional enhancer activator domain (TEAD) inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein: R is Ci-Cefluoroalkyl; and R1is (a) Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl; (b) Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl; or (c) Ci- Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, - NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogen unsubstituted Ci-Cealkyl. In some embodiments, R1is Ci-Cealkyl substituted with -OH. In some embodiments, R1is Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2, or unsubstituted pyrazinyl. In some embodiments, R1is Ci-Cealkyl substituted with pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R is -CF3. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; R3is hydrogen or unsubstituted Ci-Cealkyl; and R is -CF3. In some embodiments, the compound is selected from the group consisting of:WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is:pharmaceutically acceptable salt or solvate thereof.

[0007] In another aspect, provided herein are kits for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a) reagents for identifying a genetic alteration in a Hippo pathway gene; and (b) instructions for identifying the individual suitable for treatment with the TEAD inhibitor based on the genetic alteration in the Hippo pathway gene.

[0008] In another aspect, provided herein are kits for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a) reagents for identifying a genetic alteration in a gene that leads to constitutive activation of the YAP / TAZ-TEAD transcriptional activity; and (b) instructions for identifying the individual suitable for treatment with the TEAD inhibitor based on the genetic alteration in that gene that leads to constitutive activation of the YAP / TAZ-TEAD transcriptional activity.

[0009] In another aspect, provided herein are kits for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a) reagents for measuring a gene expression level for CRIM1, ANKRD1,GADD45B, WTIP, AXL, TOP2A, BIRC5, CTGF, AM0TL2, AJUBA, ITGB2, FJX1, FOSL1, AS API, CDC20, CENPF, CYR61, DDAH1, FGF2, SERPINE1, and TGFB2 in a sample from the individual; (b) an algorithm for processing the gene expression levels using an algorithm trained using gene expression levels of samples that are responsive to the TEAD inhibitor and gene expression levels of samples that are not responsive to the TEAD inhibitor; and (c) instructions for identifying the individual suitable for treatment with the TEAD inhibitor based on the genetic alteration in the gene.

[0010] In another aspect, provided herein are kits for measuring a response to a TEAD inhibitor comprising: (a) reagents for measuring a gene expression level of a pharmacodynamics gene; and (b) instructions for correlating the gene expression level of the pharmacodynamics gene to the response to the TEAD inhibitor.

[0011] In another aspect, provided herein are systems for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a) a computer configured to receive a user request to perform a detection of a genetic alteration in a Hippo pathway gene in a sample from the individual; (b) an assay unit that (i) performs an assay to detect the genetic alteration in the Hippo pathway gene; and (ii) computer processes results of the assay to determine whether the individual has the genetic alteration in the HippoWSGR Docket No. 47612-752.601 pathway gene; and (c) a report generator that sends a report to a recipient, wherein the report contains results indicating suitability of the individual for treatment with the TEAD inhibitor.

[0012] In another aspect, provided herein are systems for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a) a computer configured to receive a user request to perform a detection of a genetic alteration in a gene that leads to constitutive activation of the YAP / TAZ-TEAD transcriptional activity in a sample from the individual; (b) an assay unit that (i) performs an assay to detect the genetic alteration that leads to constitutive activation of the YAP / TAZ-TEAD transcriptional activity; and (ii) computer processes results of the assay to determine whether the individual has the genetic alteration that leads to constitutive activation of the YAP / TAZ-TEAD transcriptional activity; and (c) a report generator that sends a report to a recipient, wherein the report contains results indicating suitability of the individual for treatment with the TEAD inhibitor.

[0013] In another aspect, provided herein are systems for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a) a computer configured to receive a user request to perform a measurement of a gene expression level for a set of genes comprising CRIM1, ANKRD1, GADD45B, WTIP, AXL, TOP2A, BIRC5, CTGF, AM0TL2, AJUBA, ITGB2, FJX1, FOSL1, AS API, CDC20, CENPF, CYR61, DDAH1, FGF2, SERPINE1, and TGFB2 in a sample from the individual; (b) an assay unit that (i) performs an assay to detect the gene expression level of the set of genes; and (ii) computer processes results of the assay relative gene expression levels of the set of genes; and (c) a report generator that sends a report to a recipient, wherein the report contains results indicating suitability of the individual for treatment with the TEAD inhibitor.

[0014] In another aspect, provided herein are systems for measuring a response to a TEAD inhibitor of an individual administered with the TEAD inhibitor comprising: (a) a computer configured to receive a user request to perform a detection of a gene expression level of a pharmacodynamics gene in a sample from the individual; (b) an assay unit that (i) performs an assay to detect the gene expression level of the pharmacodynamics gene; and (ii) computer processes results of the assay to correlate the expression level of the pharmacodynamics gene with a response to the TEAD inhibitor; and (c) a report generator that sends a report to a recipient, wherein the report contains results indicating whether the individual is responding to the TEAD inhibitor.INCORPORATION BY REFERENCE

[0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] An understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:WSGR Docket No. 47612-752.601

[0017] FIG. 1 shows a computer system that is programmed or otherwise configured to implement methods provided herein.

[0018] FIG. 2 shows validation of Random-Forest based Algorithm prediction model with in vivo study. This data demonstrates that VT3989 shows monotherapy activity in an HCC PDX model.DETAILED DESCRIPTION

[0019] Provided herein are biomarkers, systems, methods and kits that have potential to improve clinical outcome in patients treated with yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitors.Biomarkers for yes- associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor treatment

[0020] Provided herein are biomarkers for determining which patients benefit from treatment with a yes- associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor. In some embodiments, use of such inhibitors improves treatment outcomes for patients since, in some cases, patients lacking the biomarker(s) will be given a treatment better suited to their cancer. In other cases, patients having the biomarker(s) will be given the TEAD inhibitor with better confidence that the treatment will show clinical efficacy. In some embodiments, the biomarker is a genetic alteration. In some embodiments, the biomarker is a gene expression alteration.

[0021] Additionally provided herein are methods of treating a cancer in an individual in need thereof comprising administering a yes-associated protein (YAP)Ztranscriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a genetic alteration in one or more biomarkers provided herein. In some embodiments, the biomarker is a Hippo pathway core gene. In some embodiments, the biomarker is a gene that regulates the YAP / TAZ-TEAD transcriptional activity. In some embodiments, the biomarker is a YAP / TAZ-TEAD activated gene.

[0022] Additionally provided herein are methods of treating cancer in an individual in need thereof comprising administering a TEAD inhibitor to the individual when the individual has a predictive gene signature identified by measuring expression of a plurality of genes described in Table 3.

[0023] Further provided herein are methods of determining efficacy of a TEAD inhibitor by measuring expression of pharmacodynamic gene described in Table 4.

[0024] In various embodiments of methods provided herein, one or more genetic alterations are identified in an individual with cancer. In some embodiments, the one or more genetic alterations are identified in nucleic acids isolated from a sample from the subject. In some embodiments, the nucleic acids are deoxyribonucleic acid (DNA). In some embodiments, the nucleic acids are ribonucleic acid (RNA). In some embodiments, the nucleic acids are DNA and RNA. In some embodiments, the nucleic acids are cell- free nucleic acids. In some embodiments, the DNA is genomic DNA. In some embodiments, the RNA is a transcriptome. In some embodiments, the one or more genetic alterations are identified in protein or peptides isolated from a sample from the subject. In some embodiments, the genetic alteration is identifiedWSGR Docket No. 47612-752.601 by sequencing nucleic acids. In some embodiments, sequencing includes without limitation, sequencing systems manufactured by Illumina (sequencing systems such as HiSeq® and MiSeq®), Life Technologies (Ion Torrent®, SOLiD®, etc.), Roche’s 454 Life Sciences systems, Pacific Biosciences systems, Oxford Nanopore Technologies, nanoball sequencing, sequencing by hybridization, polymerized colony (POLONY) sequencing, nanogrid rolling circle sequencing (ROLONY), etc. In some embodiments, sequencing comprises use of HiSeq® and MiSeq® systems to produce reads of about or more than about 50, 75, 100, 125, 150, 175, 200, 250, 300, or more nucleotides in length. In some embodiments, sequencing comprises a sequencing by synthesis process, where individual nucleotides are identified iteratively, as they are added to the growing primer extension product. Pyrosequencing is an example of a sequence by synthesis process that identifies the incorporation of a nucleotide by assaying the resulting synthesis mixture for the presence of by-products of the sequencing reaction, namely pyrophosphate. In some embodiments, the nucleic acids in the sample can be sequenced by ligation. This method typically uses a DNA ligase enzyme to identify the target sequence, for example, as used in the polony method and in the SOLiD technology (Applied Biosystems, now Invitrogen).

[0025] In various embodiments of methods provided herein, gene expression is measured using any suitable gene expression assay. In some embodiments, the gene expression assay comprises a quantitative analysis of RNA. In some embodiments, the gene expression assay comprises a quantitative analysis of protein. In some embodiments, the gene expression assay comprises one or more of a microarray, quantitative PCR, quantitative RT-PCR, RNA sequencing, nanostring, immunofluorescence, enzyme-linked immunosorbent assay, immunohistochemistry, Western blot, or other suitable method.

[0026] In various embodiments of methods provided herein, one or more genetic alterations or gene expression alterations are identified in a sample isolated from an individual with cancer. In some embodiments, the sample is a tissue sample (e.g., tumor, lung, brain, bone, bone marrow, stomach, intestine, colon, pancreas, ovary, testes, uterus, cervix). In some embodiments, the tissue sample is a formalin fixed paraffin embedded (FFPE) sample. In some embodiments, the sample is a bodily fluid (e.g., blood, urine, serum, plasma, lymph, saliva, buccal swab, vaginal secretions, anal secretions, perspiration, semen). Hippo Pathway Core Gene Biomarkers

[0027] In an aspect, provided herein are methods of treating a cancer in an individual in need thereof. In some embodiments, the method comprises administering a yes-associated protein (YAP)Ztranscriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a genetic alteration in a Hippo pathway gene. In some embodiments, the genetic alteration is in a gene described in Table 1. Nonlimiting examples of types of genetic alterations include single nucleotide polymorphisms (SNP), deletion / insertion polymorphisms (DIP), missense mutations, nonsense mutations, frame shift deletions, frame shift insertions, in frame deletions, splice site alterations, copy number variants (CNV), short tandem repeats (STR), restriction fragment length polymorphisms (RFLP), simple sequence repeats (SSR), variable number of tandem repeats (VNTR), randomly amplified polymorphic DNA (RAPD), amplified fragment length polymorphisms (AFLP), inter-retrotransposon amplified polymorphisms (IRAP), long and shortWSGR Docket No. 47612-752.601 interspersed elements (LINE / SINE), long tandem repeats (LTR), mobile elements, retrotransposon microsatellite amplified polymorphisms, retrotransposon-based insertion polymorphisms, sequence specific amplified polymorphism, and heritable epigenetic modification (for example, DNA methylation). In some embodiments, these variations result in a change to the protein coding sequence of the gene. In some embodiments, these variations result in a change in expression of the gene. In some embodiments, these variations result in a splicing change in the gene. In some embodiments, these variations result in a fusion of the regulatory sequences of one gene to the protein coding sequence of another gene.

[0028] In some embodiments, the genetic alteration results in altered expression of the gene. In some embodiments, altered expression of the gene comprises an increase in expression of the gene. In some embodiments, altered expression comprises a decrease in expression of the gene. In some embodiments, altered expression occurs when there is a mutation in a regulatory sequence of the gene. In some embodiments, altered expression occurs when there is a mutation that causes an epigenetic change in the gene (e.g., methylation). In some embodiments, altered expression occurs when there is a transposition of the coding sequence of one gene to the regulatory sequence of another gene. In some embodiments, altered expression occurs when there is a mutation that causes an RNA splicing change in the sequence of the gene.

[0029] In some embodiments, the genetic alteration is a loss of function alteration. In some embodiment^ a loss of function alteration is a genetic alteration that causes a non-functional protein to be made from the gene. In some embodiments, a loss of function alteration is a genetic alteration that causes insufficient amounts of the gene to be expressed. In some embodiments, the loss of function alteration is in a gene selected from the group consisting of NF2, LATS1, LATS2, SAV1, STK3, SIK4, M0B1A, MOB1B, WWC1, FRMD6, TAOK1, TAOK2, and TAOK3.

[0030] In some embodiments, the genetic alteration is a gain of function alteration. In some embodiments, the gain of function alteration is an alteration in a regulatory region of coding sequence of the gene that causes the encoded protein to be constitutively active. In some embodiments, the gain of function mutation causes an increase in expression of the gene. In some embodiments, the gain of function alteration is in a gene selected from the group consisting ofYAPl, WWTR1 (TAZ), TEAD1, TEAD2, TEAD3, and TEAD4. In some embodiments, the gain of function alteration is a YAP / WWTR1 rearrangement. In some embodiments, the YAP / WWTR.1 rearrangement is selected from the group consisting of YAP1 -TFE3, WWTR1(TAZ)-CAMTA1, YAP I -MAMLD I . YAP 1 -F AMI 18B, YAP1-SS18, YAP I -MAML2. YAP1- NUTM1, YAP1-MAML2, YAP1-FAM118B, YAP1-PYGO1, YAP1-LMO1, YAP1-KMT2A, YAP1- STIMI, YAP1-CFAP300(YAP1-C110RF70), and YAP1-MRPL48.

[0031] In various embodiments of methods herein the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, head and neck cancer, bladder cancer, esophageal cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, sarcoma, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, glioblastoma, and squamous cell carcinoma.WSGR Docket No. 47612-752.601In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0032] In various aspects of method provided herein, genetic alterations are detected using any suitable method where nucleic acids or proteins from a cancer are analyzed. In some embodiments, the genetic alteration is detected by next-generation sequencing of genomic DNA or whole transcriptome RNA. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a tumor sample. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a cell -free nucleic acid sample. In some embodiments, the genetic alteration is detected by a fusion circulating RNA (cRNA)- digital droplet PCR (ddPCR) assay. In some embodiments, the cRNA is derived from a blood or a cell-free nucleic acid sample.

[0033] In various embodiments of methods provided herein, the genetic alteration is an alteration in expression of the gene. In some embodiments, alteration in expression of the gene is detected by nextgeneration sequencing of whole transcriptome RNA or a proteomic assay. In some embodiments, the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the proteomic assay is conducted on a tumor sample.YAP / TAZ-TEAD Activity Biomarkers

[0034] In an aspect, provided herein are methods of treating a cancer in an individual in need thereof comprising administering a yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a genetic alteration or genetic rearrangement that leads to the activation of the YAP / TAZ-TEAD transcriptional activity. In some embodiments, the genetic alteration is in a gene described in Table 2. In some embodiments, the genetic alteration is a gene rearrangement shown in Table 2. Non-limiting examples of types of genetic alterations include single nucleotide polymorphisms (SNP), deletion / insertion polymorphisms (DIP), missense mutations, nonsense mutations, frame shift deletions, frame shift insertions, in frame deletions, splice site alterations, copy number variants (CNV), short tandem repeats (STR), restriction fragment length polymorphisms (RFLP), simple sequence repeats (SSR), variable number of tandem repeats (VNTR), randomly amplified polymorphic DNA (RAPD), amplified fragment length polymorphisms (AFLP), inter -retrotransposon amplified polymorphisms (IRAP), long and short interspersed elements (LINE / SINE), long tandem repeats (LTR), mobile elements,WSGR Docket No. 47612-752.601 retrotransposon microsatellite amplified polymorphisms, retrotransposon-based insertion polymorphisms, sequence specific amplified polymorphism, and heritable epigenetic modification (for example, DNA methylation). In some embodiments, these variations result in a change to the protein coding sequence of the gene. In some embodiments, these variations result in a change in expression of the gene. In some embodiments, these variations result in a splicing change in the gene. In some embodiments, these variations result in a fusion of the regulatory sequences of one gene to the protein coding sequence of another gene. In some embodiments, these variations result in a fusion of the protein coding sequence of one gene to the protein coding sequence of another gene.

[0035] In some embodiments, the genetic alteration results in altered expression of the gene. In some embodiments, altered expression of the gene comprises an increase in expression of the gene. In some embodiments, altered expression comprises a decrease in expression of the gene. In some embodiments, altered expression occurs when there is a mutation in a regulatory sequence of the gene. In some embodiments, altered expression occurs when there is a mutation that causes an epigenetic change in the gene (e.g., methylation). In some embodiments, altered expression occurs when there is a transposition of the coding sequence of one gene to the regulatory sequence of another gene. In some embodiments, altered expression occurs when there is a mutation that causes an RNA splicing change in the sequence of the gene.

[0036] In some embodiments, the genetic alteration is a loss of function alteration. In some embodiment^ a loss of function alteration is a genetic alteration that causes a non-functional protein to be made from the gene. In some embodiments, a loss of function alteration is a genetic alteration that causes insufficient amounts of the gene to be expressed. In some embodiments, the genetic alteration is in a gene described in Table 2. In some embodiments, the genetic alteration is in a gene selected from the group consisting of FAT1, FAT2, FAT3, FAT4, GNAQ, GNA11, CDH1, RHOA, BAP1, ZFTA-RELA(Cl lorf95-RELA), and CLDN18-ARHGAP.

[0037] In various embodiments of methods herein the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, head and neck cancer, bladder cancer, esophageal cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, sarcoma, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, glioblastoma, and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0038] In various aspects of method provided herein, genetic alterations are detected using any suitable method where nucleic acids or proteins from a cancer are analyzed. In some embodiments, the genetic alteration is detected by next-generation sequencing of genomic DNA or whole transcriptome RNA. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a tumor sample. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a cell -free nucleic acid sample. In some embodiments, the genetic alteration is detected by a fusion circulating RNA (cRNA)-WSGR Docket No. 47612-752.601 digital droplet PCR (ddPCR) assay. In some embodiments, the cRNA is derived from a blood or a cell-free nucleic acid sample.

[0039] In various embodiments of methods provided herein, the genetic alteration is an alteration in expression of the gene. In some embodiments, alteration in expression of the gene is detected by nextgeneration sequencing of whole transcriptome RNA or a proteomic assay. In some embodiments, the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the proteomic assay is conducted on a tumor sample.Predictive Gene Signature Biomarkers

[0040] In an aspect, provided herein are methods of treating a cancer in an individual in need thereof comprising administering a yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a high probability of response to the TEAD inhibitor. In some embodiments, the high probability of response is determined by measuring gene expression levels for CRIM1, ANKRD1, GADD45B, WTIP, AXL, TOP2A, BIRC5, CTGF, AMOTL2, AJUBA, ITGB2, FJX1, FOSL1, ASAP1, CDC20, CENPF, CYR61, DDAH1, FGF2, SERPINE1, and TGFB2 in a sample from the individual. In some embodiments, the method comprises processing the gene expression levels using an algorithm trained using gene expression levels of samples that are responsive to the TEAD inhibitor and gene expression levels of samples that are not responsive to the TEAD inhibitor. In some embodiments, the algorithm is a random-forest based algorithm. In some embodiments the algorithm was developed using TEAD inhibitor response data and bulk RNA-seq data.

[0041] In various aspects of methods provided herein, in some embodiments, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, head and neck cancer, bladder cancer, esophageal cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, low grade glioma, glioblastoma, ependymoma, ST-ependymoma, liposarcoma, soft- tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0042] In various aspects of methods provided herein, gene expression is measured by assaying levels of RNA or levels of protein. In some embodiments, the RNA or the protein are derived from a tumor sample. In some embodiments, the RNA is derived from a tumor sample or a cell-free nucleic acid sample. In someWSGR Docket No. 47612-752.601 embodiments, assaying levels of RNA comprises next-generation sequencing of RNA or quantitative PCR. In some embodiments, assaying levels of protein comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.Pharmacodynamic Biomarkers

[0043] In another aspect, provided herein are methods of measuring a response to a yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor. In some embodiments, methods comprise administering an individual with cancer the TEAD inhibitor. In some embodiments, the method comprises measuring gene expression level of a pharmacodynamics gene. In some embodiments, the method comprises correlating the gene expression level of the pharmacodynamics gene to the response to the TEAD inhibitor. In some embodiments, the pharmacodynamics gene is selected from the group consisting of AJUBA, AMOTL2, ANKRD1, ANKRD2, AREG, AXL, BIRC5, BUB1, CCDC80, CCN1 (aka, CYR61), CCN2 (aka, CTGF), CCND1, CD274, CDC20, CRIM1, FASN, FGF2, FJX1, FLT3, FOSL1, FOXM1, GADD45B, HK2, IL21R, IL6, ITGA11, LATS2, MYCN, NF2, NT5E, NUAK2, PLK1, PTPN14, SCD, SLC2A1, SLC2A14, SLC7A5, SOD2, VEGFA, and WTIP.

[0044] In various aspects of methods provided herein, in some embodiments, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, head and neck cancer, bladder cancer, esophageal cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, low grade glioma, glioblastoma, ependymoma, ST- ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0045] In various aspects of methods provided herein, in some embodiments, the gene expression level comprises RNA expression. In some embodiments, RNA is isolated from a tumor sample, a blood sample, a serum sample, or a plasma sample. In some embodiments, RNA is cell-free RNA or whole transcriptome RNA. In some embodiments, the gene expression comprises protein expression. In some embodiments, protein is isolated from a tumor sample or a blood sample. In some embodiments, protein is in a formalin- fixed paraffin embedded sample.WSGR Docket No. 47612-752.601

[0046] In various aspects of methods provided herein, in some embodiments, the gene expression is measured using a quantitative RNA assay or a quantitative protein assay. In some embodiments, the quantitative RNA assay comprises a nanostring assay, next generation sequencing or quantitative RT-PCR. In some embodiments, the quantitative protein assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.Systems

[0047] In an aspect, provided herein are systems for identifying an individual suitable for treatment with a TEAD inhibitor. In some embodiments, systems comprise: (a) a computer configured to receive a user request to perform a detection of a genetic alteration in a Hippo pathway gene in a sample from the individual. In some embodiments, systems comprise an assay unit that (i) performs an assay to detect the genetic alteration in the Hippo pathway gene; and (ii) computer processes results of the assay to determine whether the individual has the genetic alteration in the Hippo pathway gene. In some embodiments, systems comprise a report generator that sends a report to a recipient, wherein the report contains results indicating suitability of the individual for treatment with the TEAD inhibitor. In some embodiments, the genetic alteration is in a gene described in Table 1. Non-limiting examples of types of genetic alterations include single nucleotide polymorphisms (SNP), deletion / insertion polymorphisms (DIP), missense mutations, nonsense mutations, frame shift deletions, frame shift insertions, in frame deletions, splice site alterations, copy number variants (CNV), short tandem repeats (STR), restriction fragment length polymorphisms (RFLP), simple sequence repeats (SSR), variable number of tandem repeats (VNTR), randomly amplified polymorphic DNA (RAPD), amplified fragment length polymorphisms (AFLP), inter-retrotransposon amplified polymorphisms (IRAP), long and short interspersed elements (LINE / SINE), long tandem repeats (LTR), mobile elements, retrotransposon microsatellite amplified polymorphisms, retrotransposon-based insertion polymorphisms, sequence specific amplified polymorphism, and heritable epigenetic modification (for example, DNA methylation). In some embodiments, these variations result in a change to the protein coding sequence of the gene. In some embodiments, these variations result in a change in expression of the gene. In some embodiments, these variations result in a splicing change in the gene. In some embodiments, these variations result in a fusion of the regulatory sequences of one gene to the protein coding sequence ofWSGR Docket No. 47612-752.601 another gene. In some embodiments, these variations result in a fusion of the protein coding sequence of one gene to the protein coding sequence of another gene.

[0048] In some embodiments, the genetic alteration results in altered expression of the gene. In some embodiments, altered expression of the gene comprises an increase in expression of the gene. In some embodiments, altered expression comprises a decrease in expression of the gene. In some embodiments, altered expression occurs when there is a mutation in a regulatory sequence of the gene. In some embodiments, altered expression occurs when there is a mutation that causes an epigenetic change in the gene (e.g., methylation). In some embodiments, altered expression occurs when there is a transposition of the coding sequence of one gene to the regulatory sequence of another gene. In some embodiments, altered expression occurs when there is a mutation that causes an RNA splicing change in the sequence of the gene.

[0049] In some embodiments, the genetic alteration is a loss of function alteration. In some embodiment^ a loss of function alteration is a genetic alteration that causes a non-functional protein to be made from the gene. In some embodiments, a loss of function alteration is a genetic alteration that causes insufficient amounts of the gene to be expressed. In some embodiments, the loss of function alteration is in a gene selected from the group consisting of NF2, LATS1, LATS2, SAV1, STK3, SIK4, M0B1A, MOB1B, WWC1, FRMD6, TAOK1, TAOK2, and TAOK3.

[0050] In some embodiments, the genetic alteration is a gain of function alteration. In some embodiments, the gain of function alteration is an alteration in a regulatory region of coding sequence of the gene that causes the encoded protein to be constitutively active. In some embodiments, the gain of function mutation causes an increase in expression of the gene. In some embodiments, the gain of function alteration is in a gene selected from the group consisting ofYAPl, WWTR1 (TAZ), TEAD1, TEAD2, TEAD3, and TEAD4. In some embodiments, the gain of function alteration is a YAP / WWTR1 rearrangement. In some embodiments, the YAP / WWTR1 rearrangement is selected from the group consisting of YAP1 -TFE3, WWTR1(TAZ)-CAMTA1, YAP I -MAMLD I . YAP 1 -F AMI 18B, YAP1-SS18, YAP I -MAML2. YAP1- NUTM1, YAP1-MAML2, YAP1-FAM118B, YAP1-PYGO1, YAP1-LMO1, YAP1-KMT2A, YAP1- STIMI, YAP1-CFAP300(YAP1-C110RF70), and YAP1-MRPL48.

[0051] In various embodiments of systems herein the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, head and neck cancer, bladder cancer, esophageal cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, sarcoma, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, glioblastoma, and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0052] In various aspects of systems provided herein, genetic alterations are detected using any suitable method where nucleic acids or proteins from a cancer are analyzed. In some embodiments, the genetic alteration is detected by next-generation sequencing of genomic DNA or whole transcriptome RNA. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a tumor sample. InWSGR Docket No. 47612-752.601 some embodiments, the genomic DNA or whole transcriptome RNA are derived from a cell -free nucleic acid sample. In some embodiments, the genetic alteration is detected by a fusion circulating RNA (cRNA)- digital droplet PCR (ddPCR) assay. In some embodiments, the cRNA is derived from a blood sample or a cell-free nucleic acid sample.

[0053] In various embodiments of systems provided herein, the genetic alteration is an alteration in expression of the gene. In some embodiments, alteration in expression of the gene is detected by nextgeneration sequencing of whole transcriptome RNA or a proteomic assay. In some embodiments, the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the proteomic assay is conducted on a tumor sample.

[0054] In another aspect, provided herein are systems for identifying an individual suitable for treatment with a TEAD inhibitor. In some embodiments, systems comprise a computer configured to receive a user request to perform a detection of a genetic alteration in a gene that results in the activation of the YAP / TAZ- TEAD activity in a sample from the individual. In some embodiments, systems comprise an assay unit that (i) performs an assay to detect the genetic alteration in the gene that regulates the YAP / TAZ-TEAD activity; and (ii) computer processes results of the assay to determine whether the individual has the genetic alteration in the gene that regulates the YAP / TAZ-TEAD activity. In some embodiments, systems comprise a report generator that sends a report to a recipient, wherein the report contains results indicating suitability of the individual for treatment with the TEAD inhibitor. Non-limiting examples of types of genetic alterations include single nucleotide polymorphisms (SNP), deletion / insertion polymorphisms (DIP), missense mutations, nonsense mutations, frame shift deletions, frame shift insertions, in frame deletions, splice site alterations, copy number variants (CNV), short tandem repeats (STR), restriction fragment length polymorphisms (RFLP), simple sequence repeats (SSR), variable number of tandem repeats (VNTR), randomly amplified polymorphic DNA (RAPD), amplified fragment length polymorphisms (AFLP), inter - retrotransposon amplified polymorphisms (IRAP), long and short interspersed elements (LINE / SINE), long tandem repeats (LTR), mobile elements, retrotransposon microsatellite amplified polymorphisms, retrotransposon-based insertion polymorphisms, sequence specific amplified polymorphism, and heritable epigenetic modification (for example, DNA methylation). In some embodiments, these variations result in a change to the protein coding sequence of the gene. In some embodiments, these variations result in a change in expression of the gene. In some embodiments, these variations result in a splicing change in the gene. In some embodiments, these variations result in a fusion of the regulatory sequences of one gene to the protein coding sequence of another gene.

[0055] In some embodiments, the genetic alteration results in altered expression of the gene. In some embodiments, altered expression of the gene comprises an increase in expression of the gene. In some embodiments, altered expression comprises a decrease in expression of the gene. In some embodiments, altered expression occurs when there is a mutation in a regulatory sequence of the gene. In some embodiments, altered expression occurs when there is a mutation that causes an epigenetic change in the gene (e.g., methylation). In some embodiments, altered expression occurs when there is a transposition ofWSGR Docket No. 47612-752.601 the coding sequence of one gene to the regulatory sequence of another gene. In some embodiments, altered expression occurs when there is a mutation that causes an RNA splicing change in the sequence of the gene.

[0056] In some embodiments, the genetic alteration is a loss of function alteration. In some embodiment^ a loss of function alteration is a genetic alteration that causes a non-functional protein to be made from the gene. In some embodiments, a loss of function alteration is a genetic alteration that causes insufficient amounts of the gene to be expressed. In some embodiments, the genetic alteration is in a gene described in Table 2. In some embodiments, the genetic alteration is in a gene selected from the group consisting of FAT1, FAT2, FAT3, FAT4, GNAQ, GNA11, CDH1, RHOA, BAP1, ZFTA-RELA(Cl lorf95-RELA), and CLDN18-ARHGAP.

[0057] In various embodiments of systems herein the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, head and neck cancer, bladder cancer, esophageal cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, sarcoma, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, glioblastoma, and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0058] In various aspects of systems provided herein, genetic alterations are detected using any suitable method where nucleic acids or proteins from a cancer are analyzed. In some embodiments, the genetic alteration is detected by next-generation sequencing of genomic DNA or whole transcriptome RNA. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a tumor sample. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a cell -free nucleic acid sample. In some embodiments, the genetic alteration is detected by a fusion circulating RNA (cRNA)- digital droplet PCR (ddPCR) assay. In some embodiments, the cRNA is derived from a blood sample or a cell-free nucleic acid sample.

[0059] In various embodiments of systems provided herein, the genetic alteration is an alteration in expression of the gene. In some embodiments, alteration in expression of the gene is detected by nextgeneration sequencing of whole transcriptome RNA or a proteomic assay. In some embodiments, the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the proteomic assay is conducted on a tumor sample.

[0060] In another aspect, provided herein are systems for identifying an individual suitable for treatment with a TEAD inhibitor comprising: a computer configured to receive a user request to perform a measurement of gene expression levels for a set of genes comprising CRIM1, ANKRD1, GADD45B, WTIP, AXL, TOP2A, BIRC5, CTGF, AMOTL2, AJUBA, ITGB2, FJX1, FOSL1, AS API, CDC20, CENPF, CYR61, DDAH1, FGF2, SERPINE1, and TGFB2 in a sample from the individual; an assay unit that performs an assay to detect the gene expression level of the set of genes; and computer processes results of the assay relative gene expression levels of the set of genes; and a report generator that sends a report to a recipient, wherein the report contains results indicating suitability of the individual for treatment with theWSGR Docket No. 47612-752.601TEAD inhibitor. In some embodiments, the method comprises processing the gene expression levels using an algorithm trained using gene expression levels of samples that are responsive to the TEAD inhibitor and gene expression levels of samples that are not responsive to the TEAD inhibitor. In some embodiments, the algorithm is a random-forest based algorithm. In some embodiments the algorithm was developed using TEAD inhibitor response data and bulk RNA-seq data.

[0061] In various aspects of systems provided herein, in some embodiments, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, esophageal cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, low grade glioma, glioblastoma, ependymoma, ST-ependymoma, liposarcoma, soft- tissue sarcomas, well-and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0062] In various aspects of systems provided herein, gene expression is measured by assaying levels of RNA or levels of protein. In some embodiments, the RNA or the protein are derived from a tumor sample. In some embodiments, the RNA is derived from a tumor sample or a cell-free nucleic acid sample. In some embodiments, assaying levels of RNA comprises next-generation sequencing of RNA or quantitative PCR. In some embodiments, assaying levels of protein comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.

[0063] In another aspect provided herein are systems for measuring a response to a TEAD inhibitor of an individual administered with the TEAD inhibitor comprising: a computer configured to receive a user request to perform a detection of gene expression level of a pharmacodynamics gene in a sample from the individual; an assay unit that performs an assay to detect the gene expression level of the pharmacodynamics gene; and computer processes results of the assay to correlate the expression level of the pharmacodynamics gene with a response to the TEAD inhibitor; and a report generator that sends a report to a recipient, wherein the report contains results indicating whether the individual is responding to the TEAD inhibitor. In some embodiments, the pharmacodynamics gene is selected from the group consisting of AJUBA, AMOTL2, ANKRD1, ANKRD2, AREG, AXL, BIRC5, BUB1, CCDC80, CCN1 (aka, CYR61), CCN2 (aka, CTGF), CCND1, CD274, CDC20, CRIM1, FASN, FGF2, FJX1, FLT3, FOSL1, FOXM1, GADD45B, HK2, IL21R, IL6, ITGA11, LATS2, MYCN, NF2, NT5E, NUAK2, PLK1, PTPN14, SCD, SLC2A1, SLC2A14, SLC7A5, SOD2, VEGFA, and WTIP.

[0064] In various aspects of systems provided herein, in some embodiments, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, head and neck cancer, bladder cancer, esophageal cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, epithelioid hemangioendothelioma, osteosarcoma, spindleWSGR Docket No. 47612-752.601 cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, low grade glioma, glioblastoma, ependymoma, ST- ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0065] In various aspects of systems provided herein, in some embodiments, the gene expression level comprises RNA expression. In some embodiments, RNA is isolated from a tumor sample, a blood sample, a serum sample, or a plasma sample. In some embodiments, RNA is cell-free RNA or whole transcriptome RNA. In some embodiments, the gene expression comprises protein expression. In some embodiments, protein is isolated from a tumor sample or a blood sample. In some embodiments, protein is in a formalin- fixed paraffin embedded sample.

[0066] In various aspects of systems provided herein, in some embodiments, the gene expression is measured using a quantitative RNA assay or a quantitative protein assay. In some embodiments, the quantitative RNA assay comprises a nanostring assay, next generation sequencing or quantitative RT-PCR. In some embodiments, the quantitative protein assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.

[0067] In various aspects, systems or computer systems are provided that are programmed to implement methods of the disclosure. FIG. 1 shows a computer system 101 that is programmed or otherwise configured to identify an individual suitable for treatment with a TEAD inhibitor. In some embodiments, the computer system 101 regulates various aspects of performing methods of identifying individuals suitable for treatment with a TEAD inhibitor provided in the present disclosure, such as, for example, receiving a user request to perform a detection of a genetic alteration, an assay unit to perform an assay to detect the genetic alteration, and a report generator for sending the results. In some embodiments, the computer system 101 is an electronic device of a user or a computer system that is remotely located with respect to the electronic device. In some embodiments, the electronic device is a mobile electronic device.

[0068] In aspects, the computer system 101 includes a central processing unit (CPU, also “processor” and “computer processor” herein) 105, which, in some embodiments, is a single core or multi core processor, or a plurality of processors for parallel processing. The computer system 101 also includes memory or memory location 110 (e.g., random- access memory, read-only memory, flash memory), electronic storage unit 115 (e.g., hard disk), communication interface 120 (e.g., network adapter) for communicating with one or more other systems, and peripheral devices 125, such as cache, other memory, data storage and / or electronic display adapters. The memory 110, storage unit 115, interface 120 and peripheral devices 125 are in communication with the CPU 105 through a communication bus (solid lines), such as a motherboard. In some embodiments, the storage unit 115 is a data storage unit (or data repository) for storing data. In some embodiments, the computer system 101 is operatively coupled to a computer network (“network”) 130 with the aid of the communication interface 120. In some embodiments, the network 130 is the Internet, an internet and / or extranet, or an intranet and / or extranet that is in communication with the Internet. The network 130 in some cases is a telecommunication and / or dataWSGR Docket No. 47612-752.601 network. In some embodiments the network 130 includes one or more computer servers, which enable distributed computing, such as cloud computing. In some embodiments, the network 130, in some cases with the aid of the computer system 101, implements a peer-to-peer network, which enables devices coupled to the computer system 101 to behave as a client or a server.

[0069] In some embodiments, the CPU 105 executes a sequence of machine-readable instructions, which are embodied in a program or software. In some embodiments, the instructions are stored in a memory location, such as the memory 110. In some embodiments, the instructions are directed to the CPU 105, which subsequently programs or otherwise configure the CPU 105 to implement methods of the present disclosure. Examples of operations performed by the CPU 105 include, but are not limited to fetch, decode, execute, and writeback.

[0070] In some embodiments, the CPU 105 is part of a circuit, such as an integrated circuit. In some embodiments, one or more other components of the system 101 are included in the circuit. In some cases, the circuit is an application specific integrated circuit (ASIC).

[0071] In some embodiments, the storage unit 115 stores files, such as drivers, libraries and saved programs. In some embodiments, the storage unit 115 stores user data, e.g., user preferences and user programs. The computer system 101 in some cases includes one or more additional data storage units that are external to the computer system 101, such as located on a remote server that is in communication with the computer system 101 through an intranet or the Internet.

[0072] In some embodiments, the computer system 101 communicates with one or more remote computer systems through the network 130. For instance, in some embodiments, the computer system 101 communicates with a remote computer system of a user (e.g., a medical provider wanting to know whether an individual will benefit from treatment with a TEAD inhibitor). Examples of remote computer systems include personal computers (e.g., portable PC), slate or tablet PC’s (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones, Smart phones (e.g., Apple® iPhone, Android-enabled device, Blackberry®), or personal digital assistants. In some embodiments, the user accesses the computer system 101 via the network 130.

[0073] In some embodiments, methods as described herein are implemented by way of machine (e.g., computer processor) executable code stored on an electronic storage location of the computer system 101, such as, for example, on the memory 110 or electronic storage unit 115. In some embodiments, the machine executable or machine readable code is provided in the form of software. During use, in some embodiment^ the code is executed by the processor 105. In some cases, the code is retrieved from the storage unit 115 and stored on the memory 110 for ready access by the processor 105. In some situations, the electronic storage unit 115 is precluded, and machine- executable instructions are stored on memory 110.

[0074] In some embodiments, the code is pre-compiled and configured for use with a machine having a processer adapted to execute the code, or is compiled during runtime. In some embodiments, the code is supplied in a programming language that is selected to enable the code to execute in a pre-compiled or as- compiled fashion.WSGR Docket No. 47612-752.601

[0075] Aspects of the systems and methods provided herein, such as the computer system 101, are, in some embodiments, embodied in programming. Various aspects of the technology, in some embodiments, are thought of as “products” or “articles of manufacture” typically in the form of machine (or processor) executable code and / or associated data that is carried on or embodied in a type of machine readable medium. In some embodiments, machine-executable code is stored on an electronic storage unit, such as memory (e.g., read-only memory, random- access memory, flash memory) or a hard disk. In some embodiments, “storage” type media includes any or all of the tangible memory of the computers, processors or the like, or associated modules thereof, such as various semiconductor memories, tape drives, disk drives and the like, which provide non-transitory storage at any time for the software programming. In some embodiments, all or portions of the software at times are communicated through the Internet or various other telecommunication networks. Such communications, for example, enable loading of the software from one computer or processor into another, for example, from a management server or host computer into the computer platform of an application server. Thus, another type of media that, in some embodiments, bears the software elements includes optical, electrical and electromagnetic waves, such as used across physical interfaces between local devices, through wired and optical landline networks and over various air-links. In some embodiments, the physical elements that carry such waves, such as wired or wireless links, optical links or the like, also are considered as media bearing the software. As used herein, unless restricted to non- transitory, tangible “storage” media, terms such as computer or machine “readable medium” refer to any medium that participates in providing instructions to a processor for execution.

[0076] Hence, in some embodiments, a machine readable medium, such as computer-executable code, takes many forms, including but not limited to, a tangible storage medium, a carrier wave medium or physical transmission medium. In some embodiments, non-volatile storage media include, for example, optical or magnetic disks, such as any of the storage devices in any computer(s) or the like, such as are used to implement the databases, etc. shown in the drawings. Volatile storage media include dynamic memory, such as main memory of such a computer platform. Tangible transmission media include coaxial cables; copper wire and fiber optics, including the wires that comprise a bus within a computer system. In some embodiments carrier-wave transmission media takes the form of electric or electromagnetic signals, or acoustic or light waves such as those generated during radio frequency (RF) and infrared (IR) data communications. Common forms of computer-readable media therefore include for example: a floppy disk, a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD or DVD-ROM, any other optical medium, punch cards paper tape, any other physical storage medium with patterns of holes, a RAM, a ROM, a PROM and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave transporting data or instructions, cables or links transporting such a carrier wave, or any other medium from which, in some embodiments a computer reads programming code and / or data. In some embodiments, many of these forms of computer readable media are involved in carrying one or more sequences of one or more instructions to a processor for execution.WSGR Docket No. 47612-752.601

[0077] In some embodiments, the computer system 101 includes or is in communication with an electronic display 135 that comprises a user interface (UI) 140 for providing, for example, a report indicating whether an individual will benefit from treatment with a TE AD inhibitor. Examples of UI’ s include, without limitation, a graphical user interface (GUI) and web-based user interface.

[0078] In some embodiments, methods and systems of the present disclosure are implemented by way of one or more algorithms. An algorithm can be implemented by way of software upon execution by the central processing unit 105. In some embodiments, the algorithm can, for example, process data to determine whether an individual will benefit from treatment with a TEAD inhibitor.Kits

[0079] In an aspect, provided herein are kits for identifying an individual suitable for treatment with a TEAD inhibitor comprising. In some embodiments, the kits comprise reagents for identifying a genetic alteration in a Hippo pathway gene. In some embodiments, the kits comprise instructions for identifying the individual suitable for treatment with the TEAD inhibitor based on the genetic alteration in the Hippo pathway gene. In some embodiments, the genetic alteration is in a gene described in Table 1. Non-limiting examples of types of genetic alterations include single nucleotide polymorphisms (SNP), deletion / insertion polymorphisms (DIP), missense mutations, nonsense mutations, frame shift deletions, frame shift insertions, in frame deletions, splice site alterations, copy number variants (CNV), short tandem repeats (STR), restriction fragment length polymorphisms (RFLP), simple sequence repeats (SSR), variable number of tandem repeats (VNTR), randomly amplified polymorphic DNA (RAPD), amplified fragment length polymorphisms (AFLP), inter -retrotransposon amplified polymorphisms (IRAP), long and short interspersed elements (LINE / SINE), long tandem repeats (LTR), mobile elements, retrotransposon microsatellite amplified polymorphisms, retrotransposon-based insertion polymorphisms, sequence specific amplified polymorphism, and heritable epigenetic modification (for example, DNA methylation). In some embodiments, these variations result in a change to the protein coding sequence of the gene. In some embodiments, these variations result in a change in expression of the gene. In some embodiments, these variations result in a splicing change in the gene. In some embodiments, these variations result in a fusion of the regulatory sequences of one gene to the protein coding sequence of another gene.

[0080] In some embodiments, the genetic alteration results in altered expression of the gene. In some embodiments, altered expression of the gene comprises an increase in expression of the gene. In some embodiments, altered expression comprises a decrease in expression of the gene. In some embodiments, altered expression occurs when there is a mutation in a regulatory sequence of the gene. In some embodiments, altered expression occurs when there is a mutation that causes an epigenetic change in the gene (e.g., methylation). In some embodiments, altered expression occurs when there is a transposition of the coding sequence of one gene to the regulatory sequence of another gene. In some embodiments, altered expression occurs when there is a mutation that causes an RNA splicing change in the sequence of the gene.WSGR Docket No. 47612-752.601

[0081] In some embodiments, the genetic alteration is a loss of function alteration. In some embodiment^ a loss of function alteration is a genetic alteration that causes a non-functional protein to be made from the gene. In some embodiments, a loss of function alteration is a genetic alteration that causes insufficient amounts of the gene to be expressed. In some embodiments, the loss of function alteration is in a gene selected from the group consisting of NF2, LATS1, LATS2, SAV1, STK3, SIK4, M0B1A, MOB1B, WWC1, FRMD6, TAOK1, TAOK2, and TAOK3.

[0082] In some embodiments, the genetic alteration is a gain of function alteration. In some embodiments, the gain of function alteration is an alteration in a regulatory region of coding sequence of the gene that causes the encoded protein to be constitutively active. In some embodiments, the gain of function mutation causes an increase in expression of the gene. In some embodiments, the gain of function alteration is in a gene selected from the group consisting ofYAPl, WWTR1 (TAZ), TEAD1, TEAD2, TEAD3, and TEAD4. In some embodiments, the gain of function alteration is a YAP / WWTR1 rearrangement. In some embodiments, the YAP / WWTR.1 rearrangement is selected from the group consisting of YAP1 -TFE3, WWTR1(TAZ)-CAMTA1, YAP I -MAMLD I . YAP 1 -F AMI 18B, YAP1-SS18, YAP I -MAML2. YAP1- NUTM1, YAP1-MAML2, YAP1-FAM118B, YAP1-PYGO1, YAP1-LMO1, YAP1-KMT2A, YAP1- STIMI, YAP1-CFAP300(YAP1-C110RF70), and YAP1-MRPL48.

[0083] In various embodiments of kits provided herein the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, head and neck cancer, bladder cancer, esophageal cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, sarcoma, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, glioblastoma, and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0084] In various aspects of kits provided herein, genetic alterations are detected using any suitable method where nucleic acids or proteins from a cancer are analyzed. In some embodiments, the genetic alteration is detected by next-generation sequencing of genomic DNA or whole transcriptome RNA. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a tumor sample. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a cell -free nucleic acid sample. In some embodiments, the genetic alteration is detected by a fusion circulating RNA (cRNA)- digital droplet PCR (ddPCR) assay. In some embodiments, the cRNA is derived from a blood sample or a cell-free nucleic acid sample.

[0085] In various embodiments of kits provided herein, the genetic alteration is an alteration in expression of the gene. In some embodiments, alteration in expression of the gene is detected by next-generation sequencing of whole transcriptome RNA or a proteomic assay. In some embodiments, the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the proteomic assay is conducted on a tumor sample.WSGR Docket No. 47612-752.601

[0086] In another aspect, provided herein are kits for identifying an individual suitable for treatment with a TEAD inhibitor. In some embodiments, the kits comprise reagents for identifying a genetic alteration in a YAP / TAZ-TEAD activity activator gene. In some embodiments, the kits comprise instructions for identifying the individual suitable for treatment with the TEAD inhibitor based on the genetic alteration in the YAP / TAZ-TEAD activity activator gene. In some embodiments, the genetic alteration is in a gene described in Table 2. Non-limiting examples of types of genetic alterations include single nucleotide polymorphisms (SNP), deletion / insertion polymorphisms (DIP), missense mutations, nonsense mutations, frame shift deletions, frame shift insertions, in frame deletions, splice site alterations, copy number variants (CNV), short tandem repeats (STR), restriction fragment length polymorphisms (RFLP), simple sequence repeats (SSR), variable number of tandem repeats (VNTR), randomly amplified polymorphic DNA (RAPD), amplified fragment length polymorphisms (AFLP), inter -retrotransposon amplified polymorphisms (IRAP), long and short interspersed elements (LINE / SINE), long tandem repeats (LTR), mobile elements, retrotransposon microsatellite amplified polymorphisms, retrotransposon-based insertion polymorphisms, sequence specific amplified polymorphism, and heritable epigenetic modification (for example, DNA methylation). In some embodiments, these variations result in a change to the protein coding sequence of the gene. In some embodiments, these variations result in a change in expression of the gene. In some embodiments, these variations result in a splicing change in the gene. In some embodiments, these variations result in a fusion of the regulatory sequences of one gene to the protein coding sequence of another gene.

[0087] In some embodiments, the genetic alteration results in altered expression of the gene. In some embodiments, altered expression of the gene comprises an increase in expression of the gene. In some embodiments, altered expression comprises a decrease in expression of the gene. In some embodiments, altered expression occurs when there is a mutation in a regulatory sequence of the gene. In some embodiments, altered expression occurs when there is a mutation that causes an epigenetic change in the gene (e.g., methylation). In some embodiments, altered expression occurs when there is a transposition of the coding sequence of one gene to the regulatory sequence of another gene. In some embodiments, altered expression occurs when there is a mutation that causes an RNA splicing change in the sequence of the gene.

[0088] In some embodiments, the genetic alteration is a loss of function alteration. In some embodiment^ a loss of function alteration is a genetic alteration that causes a non-functional protein to be made from the gene. In some embodiments, a loss of function alteration is a genetic alteration that causes insufficient amounts of the gene to be expressed. In some embodiments, the genetic alteration is in a gene described in Table 2. In some embodiments, the genetic alteration is in a gene selected from the group consisting of FAT1, FAT2, FAT3, FAT4, GNAQ, GNA11, CDH1, RHOA, BAP1, ZFTA-RELA(Cl lorf95-RELA), and CLDN18-ARHGAP.

[0089] In various embodiments of kits provided herein the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, head and neck cancer, bladder cancer, esophageal cancer, melanoma, hepatocellularWSGR Docket No. 47612-752.601 carcinoma, renal cell carcinoma, sarcoma, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, glioblastoma, and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0090] In various aspects of kits provided herein, genetic alterations are detected using any suitable method where nucleic acids or proteins from a cancer are analyzed. In some embodiments, the genetic alteration is detected by next-generation sequencing of genomic DNA or whole transcriptome RNA. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a tumor sample. In some embodiments, the genomic DNA or whole transcriptome RNA are derived from a cell -free nucleic acid sample. In some embodiments, the genetic alteration is detected by a fusion circulating RNA (cRNA)- digital droplet PCR (ddPCR) assay. In some embodiments, the cRNA is derived from a blood sample or a cell-free nucleic acid sample.

[0091] In various embodiments of kits provided herein, the genetic alteration is an alteration in expression of the gene. In some embodiments, alteration in expression of the gene is detected by next-generation sequencing of whole transcriptome RNA or a proteomic assay. In some embodiments, the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence. In some embodiments, the proteomic assay is conducted on a tumor sample.

[0092] In another aspect, provided herein are kits for identifying an individual suitable for treatment with a TEAD inhibitor. In some embodiments, kits comprise reagents for measuring a gene expression level for CRIM1, ANKRD1, GADD45B, WTIP, AXL, TOP2A, BIRC5, CTGF, AMOTL2, AJUBA, ITGB2, FJX1, FOSL1, ASAP1, CDC20, CENPF, CYR61, DDAH1, FGF2, SERPINE1, and TGFB2 in a sample from the individual. In some embodiments, kits include an algorithm for processing the gene expression levels using an algorithm trained using gene expression levels of samples that are responsive to the TEAD inhibitor and gene expression levels of samples that are not responsive to the TEAD inhibitor. In some embodiments, kits comprise instructions for identifying the individual suitable for treatment with the TEAD inhibitor based on the genetic alteration in the gene. In some embodiments, the algorithm is trained using gene expression levels of samples that are responsive to the TEAD inhibitor and gene expression levels of samples that are not responsive to the TEAD inhibitor. In some embodiments, the algorithm is a random-forest based algorithm. In some embodiments the algorithm was developed using TEAD inhibitor response data and bulk RNA-seq data.

[0093] In various aspects of kits provided herein, in some embodiments, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, head and neck cancer, bladder cancer, esophageal cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, sarcoma, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, glioblastoma, low grade glioma, glioblastoma, ependymoma, ST-ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiatedWSGR Docket No. 47612-752.601 liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0094] In various aspects of kits provided herein, gene expression is measured by assaying levels of RNA or levels of protein. In some embodiments, the RNA or the protein are derived from a tumor sample. In some embodiments, the RNA is derived from a tumor sample or a cell -free nucleic acid sample. In some embodiments, assaying levels of RNA comprises next-generation sequencing of RNA or quantitative PCR. In some embodiments, assaying levels of protein comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.

[0095] In another aspect, provided herein are kits for measuring a response to a TEAD inhibitor comprising reagents for measuring a gene expression level of a pharmacodynamics gene and instructions for correlating the gene expression level of the pharmacodynamics gene to the response to the TEAD inhibitor. In some embodiments, the pharmacodynamics gene is selected from the group consisting of AJUBA, AMOTL2, ANKRD1, ANKRD2, AREG, AXL, BIRC5, BUB1, CCDC80, CCN1 (aka, CYR61), CCN2 (aka, CTGF), CCND1, CD274, CDC20, CRIM1, FASN, FGF2, FJX1, FLT3, FOSL1, FOXM1, GADD45B, HK2, IL21R, IL6, ITGA11, LATS2, MYCN, NF2, NT5E, NUAK2, PLK1, PTPN14, SCD, SLC2A1, SLC2A14, SLC7A5, SOD2, VEGFA, and WTIP.

[0096] In various aspects of methods provided herein, in some embodiments, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer breast cancer, bladder cancer, esophageal cancer, epithelioid hemangioendothelioma, osteosarcoma, spindle cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, melanoma, hepatocellular carcinoma, renal cell carcinoma, low grade glioma, glioblastoma, ependymoma, ST-ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[0097] In various aspects of kits provided herein, in some embodiments, the gene expression level comprises RNA expression. In some embodiments, RNA is isolated from a tumor sample, a blood sample, a serum sample, or a plasma sample. In some embodiments, RNA is cell-free RNA or whole transcriptome RNA. In some embodiments, the gene expression comprises protein expression. In some embodiments, protein is isolated from a tumor sample or a blood sample. In some embodiments, protein is in a formalin- fixed paraffin embedded sample.

[0098] In various aspects of kits provided herein, in some embodiments, the gene expression is measured using a quantitative RNA assay or a quantitative protein assay. In some embodiments, the quantitative RNA assay comprises a nanostring assay, next generation sequencing or quantitative RT-PCR. In some embodiments, the quantitative protein assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.WSGR Docket No. 47612-752.601The Hippo Signaling Network

[0099] The Hippo signaling network (also known as the Salvador / W arts / Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTR1). The Hippo kinase cascade phosphorylates and inhibits YAP / TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP / TAZ control. In an un-phosphorylated / de-phosphorylated state, YAP, also known as YAP1 or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors to upregulate genes that promote proliferation and migration and inhibit apoptosis. In some instances, unregulated upregulation of these genes involved in proliferation, migration, and anti -apoptosis leads to development of cancer. In some instances, overexpression of YAP / TAZ is associated with cancer.

[0100] Additional core members of the Hippo signaling pathway comprise the serine / threonine kinases MST1 / 2 (homologues of Hippo / Hpo in Drosophila), Latsl / 2 (homologues of Warts / Wts), and their adaptor proteins Savl (homologue of Salvador / Sav) and Mob (MOBKL1 A and MOBKL1B; homologues of Mats), respectively. In general, MST1 / 2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl / 2 kinase. Latsl / 2 is also activated by the scaffold protein Mob. The activated Latsl / 2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP / TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.

[0101] In some instances, Latsl / 2 phosphorylates YAP at the [HXRXXS] consensus motifs. YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Latsl / 2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Latsl / 2 phosphorylates YAP at all five of the consensus motifs. In some instances, Latsl / 2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[0102] Additional phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK15 / e in the degradation motif, which then signals for interaction with the f>- TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.

[0103] In some instances, Latsl / 2 phosphorylates TAZ at the [HXRXXS] consensus motifs. TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residues. In some instances, Latsl / 2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Latsl / 2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Latsl / 2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results inWSGR Docket No. 47612-752.601 cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[0104] In some embodiments, phosphorylated YAP / TAZ accumulates in the cytoplasm, and undergoes SCFP-T CP-modiated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g., Cdc4), Skpl, abridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme. In some cases, the F- box family comprises more than 40 members, in which exemplary members include F-box / WD repeatcontaining protein 1A (FBXW1A, TrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S- phase kinase- associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g., SCFpTrCP1) interacts with an El ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP / TAZ substrate. Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. In some embodiments, the ubiquitinated YAP / TAZ further undergoes the degradation process through the 26S proteasome.

[0105] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.YAP / TAZ Interaction with TEAD

[0106] In some embodiments, un-phosphorylated and / or dephosphorylated YAP / TAZ accumulates in the nucleus. Within the nucleus, YAP / TAZ interacts with the TEAD family of transcription factors (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) to activate genes involved in anti -apoptosis and proliferation, such as for example CTFG, Cyr61, and FGF1.

[0107] In some embodiments, the compounds disclosed herein modulate the interaction between YAP / TAZ and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP / TAZ and TEAD.YAP / TAZ regulation mediated by G-proteins / GPCRs

[0108] In some embodiments, the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins (Fig. 2). G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs. In some instances, there are two classes of G proteins: monomeric small GTPases and heterotrimeric G protein complexes. In some instances, the latter class of complexes comprise of alpha (Ga), beta (Gp), and gamma (G7) subunits. In someWSGR Docket No. 47612-752.601 cases, there are several classes of Gasubunits: Gq / na, Gu / uo, Gi / Oa (G inhibitory, G other), and Gsa (G stimulatory).

[0109] In some instances, Gia (G inhibitory), Goa (G other), Gq / na, and G / na coupled GPCRs activate YAP / TAZ and promote nuclear translocation. In other instances, Gsa (G stimulatory) coupled GPCRs suppress YAP / TAZ activity, leading to YAP / TAZ degradation.[OOllOJIn some cases, Gia (G inhibitory), Goa (G other), Gq / na, and G / na coupled GPCRs activate YAP / TAZ through repression of Latsl / 2 activities. In contrast, Gsa, in some embodiments, induces Latsl / 2 activity, thereby promoting YAP / TAZ degradation.GqFamily

[0111] Gqa (also known as Gq / n protein), participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca2+) release from intracellular storage through the activation of phospholipase C (PLC). The activated PLC hydrolyzes phosphatidylinositol 4,5 -bisphosphate (PIP2) to diacyl glycerol (DAG) and IP3. In some instances, IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca2+channel. In some cases, the binding triggers the opening of the Ca2+channel, and thereby increases the release of Ca2+into the cytoplasm.

[0112] In some embodiments, the GPCRs that interact with Gqa include, but are not limited to, 5- hydroxytryptamine receptor (5-HT receptor) types 5-HT2 and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine Hl receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M3, and Ms; and trace amine- associated receptor 1.

[0113] In some instances, there are several types of Gqa: Gq, Gq / n, Gq / 14, and Gq / is. The Gqprotein is encoded by GNAQ. Gq / n is encoded by GNA11. Gq / i4 is encoded by GNA14. Gq / is is encoded by GNA15.

[0114] In some instances, mutations or modifications of the Gqa genes have been associated with cancer. Indeed, studies have shown that mutations in Gqa promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and / or GNA11.

[0115] In some instances, mutations or modifications of the Gqa genes have been associated with congenital diseases. In some instances, mutations of Gqa have been observed in congenital diseases such as Port-Wine Stain and / or Sturge-Weber Syndrome. In some instances, about 92% of Port-Wine stain cases harbors a mutation in GNAQ. In some instances, about 88% of Sturge-Weber Syndrome harbors a mutation in GNAQ. G12 / 13 Family

[0116] G / na modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g. Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.WSGR Docket No. 47612-752.601

[0117] In some embodiments, the GPCRs that interact with Gwna include, but are not limited to, purinergic receptors (e.g. P2Yi, P2Y2, P2Y4, P2Ye); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)-1, P AR- 2] ; thromboxane (TXA2); sphingosine 1- phosphate (e.g. SIP2, SIP3, SlP4 and SIPs); lysophosphati die acid (e.g. LPAi, LPA2, LPA3); angiotensin II (ATI); serotonin (5-HT2Cand 5-HT4); somatostatin (ssts); endothelin (ETA and ETB); cholecystokinin (CCKi); Via vasopressin receptors; Ds dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; Ai adenosine receptors; on adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium- sensing receptors; KSHV-ORF74 chemokine receptors; NKi tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors.

[0118] In some instances, G12 / 13O S further subdivided into G and G13 types which are encoded by GNA12 and GNA13, respectively.Gi / o Family

[0119] G / oa (G inhibitory, G other) (also known as Gi / Go or Gi protein) suppresses the production of 3’,5’- cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.

[0120] In some embodiments, the GPCRs that interact with Gia include, but are not limited to, 5- hydroxytryptamine receptor (5-HT receptor) types 5-HTi and 5-HTs; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as Ai and A3; adrenergic receptors such as a2A, a2B, and 02c; apelin receptors; calcium- sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GABAB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8); histamine receptors such as H3 and H4 receptors; melatonin receptors such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and melatonin receptor type 3 (MT3); niacin receptors such as NIACR1 and NIACR2; opioid receptors such as 5, K, p, and nociceptin receptors; prostaglandin receptors such as prostaglandin E receptor 1 (EPi), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors sstl, sst2, sst3, sst4, and sst5; and trace amine-associated receptor 8.

[0121] In some instances, there are several types of Gia: Gal, Gia2, Ga3, Gia4, Goa, Gt, Ggust, and Gz. Gal is encoded by GNAI1. Ga2 is encoded by GNAI2. Ga3 is encoded by GNAI3. Goa. the ao subunit, is encoded by GNAO1. Gtis encoded by GNAT1 and GNAT2. Ggust is encoded by GNAT3. Gzis encoded by GNAZ.GsFamily

[0122] Gsa (also known as G stimulatory, Gsalpha subunit, or Gsprotein) activates the cAMP -dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3’, 5’ - cyclic AMP (cAMP) and pyrophosphate. In some embodiments, the GPCRs that interact with Gsa include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HTe, and 5-HT?;WSGR Docket No. 47612-752.601 adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and A2t>; arginine vasopressin receptor 2 (AVPR2); -adrenergic receptors Pi, 2, and 3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor Di-like family receptors such as Di and Ds; follicle-stimulating hormone receptor (FSH-receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H2 receptor; luteinizing hormone / choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D2 and I2; secretin receptor; thyrotropin receptor; trace amine-associated receptor 1; and box jellyfish opsin.

[0123] In some instances, there are two types of Gsa: Gsand Goir. Gsis encoded by GNAS. Goifis encoded by GNAL.Additional Regulators of the Hippo signaling network

[0124] In some embodiments, the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some instances, the Crumbs complex comprises transmembrane CRB proteins which assemble multi -protein complexes that function in cell polarity. In some instances, CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components. In some instances, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.

[0125] In some instances, the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1.

[0126] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity. In some embodiments, E-cad- associated protein a-catenin regulates YAP through sequestering YAP / 14-3-3 complexes in the cytoplasm. In other instances, Ajuba protein family members interact with Latsl / 2 kinase activity, thereby preventing inactivation of YAP / TAZ.

[0127] In some embodiments, additional proteins that interact with YAP / TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1 / 2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1 / 2.

[0128] In some embodiments, the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivator (TAZ / YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivatorWSGR Docket No. 47612-752.601(TAZ / YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivator (TAZ / Y AP).

[0129] In some embodiments, the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G- protein and / or its coupled GPCR. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of the Gqa family proteins such as Gq, Gq / n, Gq / i4, and Gq / is; the G12 / 1301 family of proteins such as G12 and G13; or the Gia family of proteins such as GiOtl, Ga2, Ga3, Ga4, Goa, Gt, Ggust, and Gz. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq / n. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq / . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq / 15. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of GiO.I . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of GiO.2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gi0t3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of GiO.4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Goa. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gz.

[0130] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Savl. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TEAD.

[0131] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g., 26S proteasome).

[0132] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42.

[0133] Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.WSGR Docket No. 47612-752.601

[0134] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a ubiquitinspecific protease. USP47 is a member of the ubiquitin-specific protease (USP / UBP) superfamily of cysteine proteases. In some embodiments, the compounds disclosed herein are inhibitors of USP47.Compounds

[0135] Disclosed herein are yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein:R is Ci-Cefluoroalkyl; andR1is(a) Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl;(b) Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl; or(c) Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl.

[0136] In some embodiments, R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogai. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; and R3is unsubstituted Ci-Cealkyl. In some embodiments, R1is Ci-Cealkyl substituted with -OR3; and R3is -CH3.

[0137] In some embodiments, R1is Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl. In some embodiments, R1is Ci-Cealkyl substituted with unsubstituted pyridinyl. In some embodiments, R1is Ci- Cealkyl substituted with pyridinyl substituted with -NH2 or -N(CH3)2. In some embodiments, R1is Ci- Cealkyl substituted with pyridinyl substituted with -NH2. In some embodiments, R1is Ci-Cealkyl substituted with pyridinyl substituted with -N(CH3)2. In some embodiments, R1is Ci-Cealkyl substituted with unsubstituted pyrazinyl.

[0138] In some embodiments, R1is Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci-WSGR Docket No. 47612-752.601Cealkyl substituted with 1 or 2 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, - N(CH3)2, and pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with 2 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci -Cealkyl substituted with 2 substituents each independently selected from -OH, -OCH3, -NH2, and pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with OH, and -NH2. In some embodiments, R1is Ci-Cealkyl substituted with 2 -OH. In some embodiments, R1is Ci-Cealkyl substituted with -OH and pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with 1 substituent selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci-Cealkyl substituted with -OH. In some embodiments, R1is Ci -Cealkyl substituted with -OCH3. In some embodiments, R1is Ci -Cealkyl substituted with -NH2. In some embodiments, R1is Ci-Cealkyl substituted with -NHCH3. In some embodiments, R1is Ci -Cealkyl substituted with -N(CH3)2. In some embodiments, R1is Ci -Cealkyl substituted with pyridinyl.

[0139] In some embodiments, R is -CF3.Methods of Sequencing

[0140] According to some embodiments of methods, systems, and kits provided herein, polynucleotides (or amplification products thereof, which may have optionally been enriched) are subjected to a sequencing reaction to generate sequencing reads. Sequencing depth is chosen based on what is needed for the sample being sequenced. In some cases, sequencing is low depth or fewer reads or reads per molecule, used interchangeably herein. In some cases, sequencing is high depth or more reads or reads per molecule, used interchangeably herein. Sequencing reads produced by such methods may be used in accordance with other methods disclosed herein. A variety of sequencing methodologies are available, particularly high- throughput sequencing methodologies. Examples include, without limitation, sequencing systems manufactured by Illumina (sequencing systems such as HiSeq® and MiSeq®), Life Technologies (Ion Torrent®, SOLiD®, etc.), Roche’s 454 Life Sciences systems, Pacific Biosciences systems, Oxford Nanopore Technologies, nanoball sequencing, sequencing by hybridization, polymerized colony (POLONY) sequencing, nanogrid rolling circle sequencing (ROLONY), etc. In some embodiments, sequencing comprises use of HiSeq® and MiSeq® systems to produce reads of about or more than about 50, 75, 100, 125, 150, 175, 200, 250, 300, or more nucleotides in length. In some embodiments, sequencing comprises a sequencing by synthesis process, where individual nucleotides are identified iteratively, as they are added to the growing primer extension product. Pyrosequencing is an example of a sequence by synthesis process that identifies the incorporation of a nucleotide by assaying the resulting synthesis mixture for the presence of by-products of the sequencing reaction, namely pyrophosphate. In particular, a primer / template / polymerase complex is contacted with a single type of nucleotide. If that nucleotide is incorporated, the polymerization reaction cleaves the nucleoside triphosphate between the a and f> phosphates of the triphosphate chain, releasing pyrophosphate. The presence of released pyrophosphate is then identified using a chemiluminescent enzyme reporter system that converts the pyrophosphate, with AMP, into ATP, then measures ATP using a luciferase enzyme to produce measurable light signals. WhereWSGR Docket No. 47612-752.601 light is detected, the base is Incorporated, where no light is detected, the base is not incorporated. Following appropriate washing steps, the various bases are cyclically contacted with the complex to sequentially identify subsequent bases in the template sequence. See, e.g., U. S. Pat. No. 6,210,891.

[0141] In related sequencing processes, the primer / template / polymerase complex is immobilized upon a substrate and the complex is contacted with labeled nucleotides. The immobilization of the complex may be through the primer sequence, the template sequence and / or the polymerase enzyme, and may be covalent or noncovalent. For example, immobilization of the complex can be via a linkage between the polymerase or the primer and the substrate surface. In alternate configurations, the nucleotides are provided with and without removable terminator groups. Upon incorporation, the label is coupled with the complex and is thus detectable. In the case of terminator bearing nucleotides, all four different nucleotides, bearing individually identifiable labels, are contacted with the complex. Incorporation of the labeled nucleotide arrests extension, by virtue of the presence of the terminator, and adds the label to the complex, allowing identification of the incorporated nucleotide. The label and terminator are then removed from the incorporated nucleotide, and following appropriate washing steps, the process is repeated. In the case of non -terminated nucleotides, a single type of labeled nucleotide is added to the complex to determine whether it will be incorporated, as with pyrosequencing. Following removal of the label group on the nucleotide and appropriate washing steps, the various different nucleotides are cycled through the reaction mixture in the same process. See, e.g, U.S. Pat. No. 6,833,246, incorporated herein by reference in its entirety for all purposes. For example, the Illumina Genome Analyzer System is based on technology described in WO 98 / 44151, wherein DNA molecules are bound to a sequencing platform (flow cell) via an anchor probe binding site (otherwise referred to as a flow cell binding site) and amplified in situ on a glass slide. A solid surface on which DNA molecules are amplified typically comprise a plurality of first and second bound oligonucleotides, the first complementary to a sequence near or at one end of a target polynucleotide and the second complementary to a sequence near or at the other end of a target polynucleotide. This arrangement permits bridge amplification, such as described in US20140121116. The DNA molecules are then annealed to a sequencing primer and sequenced in parallel base-by-base using a reversible terminator approach. Hybridization of a sequencing primer may be preceded by cleavage of one strand of a double-stranded bridge polynucleotide at a cleavage site in one of the bound oligonucleotides anchoring the bridge, thus leaving one single strand not bound to the solid substrate that may be removed by denaturing, and the other strand bound and available for hybridization to a sequencing primer. Typically, the Illumina Genome Analyzer System utilizes flow-cells with 8 channels, generating sequencing reads of 18 to 36 bases in length, generating >1.3 Gbp of high quality data per run (see www.illumina.com).

[0142] In yet a further sequence by synthesis process, the incorporation of differently labeled nucleotides is observed in real time as template dependent synthesis is carried out. An individual immobilized primer / template / polymerase complex may be observed as fluorescently labeled nucleotides are incorporated, permitting real time identification of each added base as it is added. In this process, label groups may be attached to a portion of the nucleotide that is cleaved during incorporation. For example, by attaching theWSGR Docket No. 47612-752.601 label group to a portion of the phosphate chain removed during incorporation, i.e., a ,y, or other terminal phosphate group on a nucleoside polyphosphate, the label is not incorporated into the nascent strand, and instead, natural DNA is produced. Observation of individual molecules may involve the optical confinement of the complex within a very small illumination volume. By optically confining the complex, a monitored region may be created, in which randomly diffusing nucleotides may be present for a very short period of time, while incorporated nucleotides may be retained within the observation volume for longer as they are being incorporated. This may result in a characteristic signal associated with the incorporation event, which is also characterized by a signal profile that is characteristic of the base being added. Interacting label components, such as fluorescent resonant energy transfer (FRET) dye pairs, may be provided with the polymerase or other portion of the complex and the incorporating nucleotide, such that the incorporation event puts the labeling components in interactive proximity, and a characteristic signal results, that is again, also characteristic of the base being incorporated (See, e.g., U.S. Pat. Nos. 6,917,726, 7,033,764, 7,052,847, 7,056,676, 7,170,050, 7,361,466, and 7,416,844; and US 20070134128, each of which is entirely incorporated herein by reference).

[0143] In some embodiments, the nucleic acids in the sample can be sequenced by ligation. This method typically uses a DNA ligase enzyme to identify the target sequence, for example, as used in the polony method and in the SOLiD technology (Applied Biosystems, now Invitrogen). In general, a pool of all possible oligonucleotides of a fixed length is provided, labeled according to the sequenced position. Oligonucleotides are annealed and ligated; the preferential ligation by DNA ligase for matching sequences results in a signal corresponding to the complementary sequence at that position.

[0144] Sequencing methods of the present disclosure may provide information useful for various applications, such as, for example, identifying a disease (e.g., cancer) in a subject or determining that the subject is at risk of having (or developing) the disease. Sequencing may provide a sequence of a polymorphic region. Sequencing may provide a length of a polynucleotide, such as a DNA (e.g., cfDNA). Further, sequencing may provide a sequence of a breakpoint or end of a DNA, such as a cfDNA. Sequencing may provide a sequence of a border of a protein binding site or a border of a Dnase hypersensitive site.Gene Expression Assays

[0145] Gene expression is determined, in part, by detecting and / or quantifying one or more gene expression products present in cellular material obtained from a subject. Cellular material may be obtained from a tissue sample isolated from [an organ]. The tissue sample may be isolated by any suitable means. In some instances, cellular material is obtained from blood, urine, tear, sweat, hair, plasma, and / or serum sample from the subject. In some embodiments, the one or more gene expression product is fully or partially isolated and / or purified from other cellular material prior to or during the detection and / or quantification of the gene expression product. In some embodiments, the gene expression product is a RNA molecule. In some embodiments, the gene expression product is a polypeptide.WSGR Docket No. 47612-752.601

[0146] In some embodiments, a microarray is employed for detection and / or quantification of a gene expression product in a gene expression profile. The manufacture and use of biochips such as those involving microarrays, also known as bioarrays, are known in the art (For reviews of Biochips and microarrays see, e.g., Kallioniemi O. P., "Biochip technologies in cancer research," Ann Med, Mar; 33(2): 1427 (2001); and Rudert F., "Genomics and proteomics tools for the clinic," Curr Opin. Mol. Ther., Dec; 2(6):633 42 (2000)). Furthermore, a number of biochips for expression analysis are commercially available (See e.g., microarrays available from Sigma-Genosys (The Woodlands, Tex.); Affymetrix (Santa Clara, Calif.), and Full Moon Biosystems (Sunnyvale, Calif.)). In some embodiments, such microarrays are analyzed using blotting techniques similar to those discussed below for conventional techniques of detecting polynucleotides and polypeptides. In some embodiments, detailed protocols for hybridization conditions are available through manufacturers of microarrays. In some embodiments, a microarray provides for the detection and analysis of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50, 100, 200, 250, 500, 750, 1000, 2500, 5000, 7500, 10,000, 12,500, 25,000, 50,0000, or 100,000 gene expression products. Information regardingthe detection and / or quantification of a gene expression profile is a product and / or article of the microarray methods provided herein.

[0147] In some embodiments, for microarray expression analysis, isolated and / or purified RNAis amplified. Isolated and / or purified RNA is an article and / or product of the microarray expression analysis. Amplified RNAis an article and / or product of the microarray expression analysis. In some embodiments, the amplified RNA is then used for hybridization to sequence specific nucleic acid probes on a biochip. Hybridized RNA to sequence specific nucleic probes on a biochip is an article and / or product of the microarray expression analysis. In some embodiments, amplification is performed using a commercially available kit, such as MessageAMp™ RNA kit (Ambion Inc.). In some embodiments, isolated and / or purified RNA is labeled before contacting the biochip such that binding to the target array can be detected using streptavidin. In some embodiments, isolated and / or purified RNAis labeled with a detectable moiety, including, but not limited to, a fluorescent moiety, a dye, or a ligand, such as biotin. Labeled RNA is an article and / or product of the microarray expression analysis. In some embodiments, the nucleic acid probes of the microarray bind specifically to genes provided herein.

[0148] In some embodiments, hybridization of amplified nucleic acids to probes on a microarray is typically performed under stringent hybridization conditions. Conditions for hybridization reactions are well known in the art and are available from microarray suppliers. For example, in some embodiments, hybridization of a nucleic acid molecule with probes found on a microarray is performed under moderately stringent or highly stringent physiological conditions, as are known in the art. For example, in some embodiments, hybridization on a microarray is performed according to manufacturer's (Affymetrix) instructions. For example, in some embodiments, hybridization is performed for 16 hours at 45 °C in a hybridization buffer, such as 100 mM MES, 1 M [Na+], 20 mM EDTA, 0.01% Tween 20. In some embodiments, washes are performed in a low stringency buffer ((6*SSPE, 0.01% Tween 20) at 25 °C followed by a high stringency buffer (100 mM MES, 0. IM [Na+], 0.01% Tween 20) at 5 °C. In someWSGR Docket No. 47612-752.601 embodiments, washes are performed using progressively higher stringency conditions: 2*SSC / 0. 1% SDS at about room temperature (hybridization conditions); 0.2*SSC / 0. 1% SDS at about room temperature (low stringency conditions); 0.2*SSC / 0.1% SDS at about 42°C (moderate stringency conditions); and 0. 1*SSC at about 68°C (high stringency conditions). In some embodiments, washing is carried out using only one of these conditions, for example, high stringency conditions. In some embodiments, washing is carried out using each of the conditions. In some embodiments, washing is carried out using each of the conditions, for 10 to 15 minutes each, in the order listed above, optionally repeating any or all of the steps listed.

[0149] In some embodiments, other microfluidic devices and methods for analyzing gene expression products, including those in which more than one gene expression product can be analyzed simultaneously and those involving high-throughput technologies, are used for the methods provided herein. Information obtained during and after the analysis of gene expression products is an article and / or product of the methods provided herein.

[0150] Quantitative measurement of gene expression levels using bioarrays is also known in the art, and typically involves a modified version of a traditional method for measuring expression as described herein. For example, such quantitation can be performed by measuring a phosphor image of a radioactive-labeled probe binding to a spot of a microarray, using a phospohor imager and imaging software. Information regarding the measured gene expression levels is an article and / or product of the methods provided herein.

[0151] In some embodiments, the determined gene expression profile of a subject is analyzed by comparing it to a set of reference gene expression profiles. The reference set of gene expression profiles comprise gene expression products recovered from reference subjects with a known characteristic (e.g., cancer treated with a TEAD inhibitor). A deviation or correlation between the reference profiles and the subj ect gene expression profile is used to establish a characterization of melanoma. Many statistical techniques are known in the art, which can be used to determine whether a statistically significant difference or correlation in gene expression between a subject’s gene expression profile and a reference gene expression profile is observed at a 90% or preferably a 95% confidence level. In some embodiments, a statistical software program or module performed on a computer processor is used to determine whether a statistically significant difference or correlation in gene expression is observed at a given confidence level. Information regarding the statistical significance of a difference or correlation in gene expression level is an article and / or product of the statistical techniques provided herein.

[0152] In some embodiments, aRNAse protection assay is used where RNA is the gene expression product to be detected in the method. In this procedure, a labeled antisense RNA probe is hybridized to the complementary polynucleotide in the sample. The remaining unhybridized single-stranded probe is degraded by ribonuclease treatment. The hybridized, double stranded probe is protected from RNAse digestion. After an appropriate time, the products of the digestion reaction are collected and analyzed on a gel. In some embodiments, a software program or module performed on a computer processor is involved in the analysis of the digestion reaction products. Information regarding the analysis of digested reaction products is an article and / or product of the RNAse protection assay. As used herein, "RNAprobe" refers to aWSGR Docket No. 47612-752.601 ribonucleotide capable of hybridizing to RNAin a sample of interest. Those skilled in the art will be able to identify and modify the RNAse protection assay specific to the polynucleotide to be measured, for example, probe specificity, hybridization temperatures, and quantity of nucleic acid can be altered individually or collectively in part or in full. Additionally, a number of commercial kits are available, for example, RiboQuant™ Multi-Probe RNAse Protection Assay System (Pharmingen, Inc., San Diego, Calif.).

[0153] In another embodiment, a RNAmolecule in a sample is analyzed by a blotting procedure, typically a Northern blot procedure. For blotting procedures RNA molecules are separated on a gel and then probed with a complementary polynucleotide to the sequence of interest. For example, RNA is separated on a gel, transferred to nitrocellulose and probed with complementary DNA to one of the genes disclosed herein. In some embodiments, the complementary probe is labeled radioactively or chemically. In some embodiment^ the complementary labeled probe is detected and the Northern blot analyzed using a software program or module performed on a computer processor. Information regarding the analysis of a RNA molecule is an article and / or product of the blotting procedure described herein.

[0154] In some embodiments, detection of a RNAmolecule includes size fractionation. Methods of size fractionating RNA are well known to those of skill in the art, such as by gel electrophoresis, including polyacrylamide gel electrophoresis (PAGE). For example, in some embodiments, the gel is a denaturing 7 M or 8 M urea-polyacrylamide-formamide gel. In some embodiments, size fractionating the RNA molecule is accomplished by chromatographic methods known to those of skill in the art. In some embodiments, the chromatograph is produced and / or analyzed by a software program or module performed on a computer processor. Information regarding the detection of a RNAmolecule, including a chromatograph, is an article and / or product of the size fractionating methods described herein.

[0155] In some embodiments, the detection of RNAis performed by using radioactively labeled probes. In some embodiments, any radioactive label is employed which provides an adequate signal. Other labels include ligands, colored dyes, and fluorescent molecules, which, in some embodiments, serve as a specific binding pair member for a labeled ligand, and the like. The labeled preparations are used to probe for a RNA molecule by the Southern or Northern hybridization techniques, for example. RNA obtained from samples are transferred to filters that bind polynucleotides. After exposure to the labeled polynucleotide probe, which will hybridize to RNA nucleotide fragments, the binding of the radioactive probe to RNA fragments is identified by autoradiography. In some embodiments, the autoradiograph image is analyzed using a software program or module performed on a computer processor. The analyzed image is an article and / or product of the RNA detection methods provided herein. The particular hybridization technique is not essential to the performance of the method provided. As improvements are made in hybridization techniques, they can readily be applied in the method of the invention.

[0156] In some embodiments, probes for use in the methods provided selectively hybridize to a target gene or gene expression product. In some embodiments, the probes are spotted on a bioarray using methods known in the art. As used herein, the term "selective hybridization" or "selectively hybridize," refers to hybridization under moderately stringent or highly stringent conditions such that a nucleotide sequenceWSGR Docket No. 47612-752.601 preferentially associates with a selected nucleotide sequence over unrelated nucleotide sequences to a large enough extent to be useful in detecting expression of a gene. It will be recognized that some amount of nonspecific hybridization is unavoidable, but is acceptable provide that hybridization to a target nucleotide sequence is sufficiently selective such that it can be distinguished over the non-specific cross-hybridization, for example, at least about 2-fold more selective, generally at least about 3 -fold more selective, usually at least about 5-fold more selective, and particularly at least about 10-fold more selective, as determined, for example, by an amount of labeled oligonucleotide that binds to target nucleic acid molecule as compared to a nucleic acid molecule other than the target molecule, particularly a substantially similar (i.e. , homologous) nucleic acid molecule other than the target nucleic acid molecule.

[0157] In some embodiments, conditions that allow for selective hybridization are determined empirically, or estimated based, for example, on the relative GC:AT content of the hybridizing oligonucleotide and the sequence to which it is to hybridize, the length of the hybridizing oligonucleotide, and the number, if any, of mismatches between the oligonucleotide and sequence to which it is to hybridize (see, for example, Sambrook et al., "Molecular Cloning: A laboratory manual (Cold Spring Harbor Laboratory Press 1989)). An example of progressively higher stringency conditions is as follows: 2*SSC / 0.1% SDS at about room temperature (hybridization conditions); 0.2*SSC / 0.1% SDS at about room temperature (low stringency conditions); 0.2*SSC / 0. 1% SDS at about 42EC (moderate stringency conditions); and 0.1 *SSC at about 68EC (high stringency conditions). In some embodiments, washing is carried out using only one of these conditions, e.g., high stringency conditions, or each of the conditions can be used, e.g., for 10-15 minutes each, in the order listed above, repeating any or all of the steps listed. However, as mentioned above, optimal conditions will vary, depending on the particular hybridization reaction involved, and can be determined empirically.

[0158] In another embodiment, provided are methods for obtaining gene expression data from amplified nucleic acids that compensates for variability in amplification reactions. In this method, relative expression of a target gene and a control gene is compared to obtain relevant expression data. In some embodiments, the expression comparison is accomplished by utilizing a software program or module performed on a computer processor. Accordingly, in certain embodiments, a ACt value is determined in order to identify gene expression changes. In some embodiments, this value and method is used to identify differential gene expression in any sample containing cellular material, including tissue obtained from the tape stripped methods provided herein. Such method is especially useful, where it is relatively difficult to obtain sufficient RNAfrom a control sample. In some embodiments, the ACt value is determined using a software program or module performed on a computer processor. The ACt value and related gene expression data are articles and / or products of the method provided herein.

[0159] The Ct value is the experimentally determined number of amplification (e.g. PCR) cycles required to achieve a threshold signal level (statistically significant increase in signal level (e.g. fluorescence) over background) for mRNAxand a reference or control mRNA (Gibson, Heid et al. 1996; Heid, Stevens et al. 1996). The Ct values are typically determined using a target nucleic acid (e.g. mRNAx) primer and probeWSGR Docket No. 47612-752.601 set, and a reference or control mRNA primer and probe set. A A Ct value is calculated by calculating a difference in the number of amplification cycles required to reach a threshold signal level between the target nucleic acid molecule and the reference or control nucleic acid molecule. A difference in the A Ct value at a target area versus another area of a subject's skin, such as a normal area, or an unaffected area, is indicative of differential gene expression of the target nucleic acid molecule at the target area. A difference in the A Ct value at a target area versus another area from a reference sample with a melanoma characteristic, is indicative of differential gene expression of the target nucleic acid molecule at the target area. Using this value, differential expression is detected by comparing expression of the target nucleic acid molecule with expression of a control nucleic acid molecule. Using this value, correlated expression is detected by comparing expression of the target nucleic acid molecule with expression of a control nucleic acid molecule. In some embodiments, the comparison is performed by a software program or module performed on a computer. The A Ct value is useful for characterizing the physiologic state of the skin without reference to a calibration site. Such methods provide the advantage that it is not necessary to obtain a nucleic acid sample from a control site, where it may be difficult to obtain sufficient nucleic acid molecules. In some embodiments, the ACt value is determined using a software program or module performed on a computer processor. The ACt value and information regarding the characteristic of a target area of skin are articles and / or products of the method provided herein.

[0160] Accordingly, provided herein is a method for detecting a difference or correlation between gene expression profiles in a subject and a reference or control sample. In certain aspects, the method is used to detect an expression level for one or more genes described herein to assist in a characterization of a treatment for cancer. In some embodiments the gene expression product is a nucleic acid, such as RNA, which is then amplified. In some embodiments, RNA from a reference or control sample is isolated and amplified. In some instances, the reference or control RNA is isolated and / or amplified at a different point in time than the RNA obtained from the subject. In some embodiments, information regarding the amplified reference or control RNA is maintained in a reference or control profile for comparison to information obtained from the subject. In some embodiments, a A Ct value is obtained by calculating a difference in the number of amplification cycles required to reach a threshold signal level between the RNA obtained from the subject and the reference or control RNA, wherein a difference in the A Ct value is indicative of a characteristic of the pigmented skin lesion in a subject. In some embodiments, a A Ct value is obtained by calculating a difference in the number of amplification cycles required to reach a threshold signal level between the RNA obtained from the subject and the reference or control RNA, wherein a correlation in the A Ct value is indicative of a characteristic of the pigmented skin lesion in a subj ect. In some embodiments, the target and control nucleic acids are identified using a software program or module performed on a computer processor. In some embodiments, A Ct value is obtained using a software program or module performed on a computer processor. In some embodiments, the A Ct values are determined in the same amplification experiment (e.g. using separate reaction wells on the same multi-well reaction plate) using similar reaction conditions to other reactions. In some embodiments, the ACt value is determined using a software programWSGR Docket No. 47612-752.601 or module performed on a computer processor. The ACt value and information regarding the characteristic of a pigmented skin lesion are articles and / or products of the method provided herein.

[0161] In some embodiments, the method for detecting a gene expression profile is used along with the other embodiments provided herein to characterize an expected response to a TEAD inhibitor or to determine a response to a TEAD inhibitor.

[0162] In some embodiments, the gene expression profile is determined by identifying and / or quantifying one or more polypeptide products present in cellular material obtained from a subject. Cellular material may be obtained from a tissue sample isolated from an individual. In some instances, cellular material is obtained from a blood, urine, tear, sweat, hair, plasma, and / or serum sample from the subject. In some embodiments, a polypeptide is fully or partially isolated and / or purified from other cellular material prior to or during the detection of the polypeptide. In some instances, a polypeptide is isolated and / or purified from other cellular materials by standard protein purification techniques including, but limited to, ammonium sulfate precipitation, ion exchange chromatography, size exclusion chromatography, affinity chromatography, immunoprecipitation, ultracentrifugation, hydrophobicity chromatography, and any combination thereof. The isolated and / or partially purified polypeptides are articles and / or products of the methods described herein. Information regarding the identification and / or quantification of a polypeptide are articles and / or products of the methods described herein.

[0163] In some embodiments, polypeptide products expressed from the genes provided in Tables 1 -4 herein are detected and / or quantified in a sample to determine a gene expression profile, some embodiments, the levels of such polypeptide gene expression products are indicative of suitability of treatment with a TEAD inhibitor or a response to treatment with a TEAD inhibitor when compared to reference or control polypeptide products in a similar sample. In some instances, the sample is a tissue sampled from the tumor of a subject. In this regard, the sample, as described herein, is used as a source to isolate polypeptides. For example, in some embodiments, following tissue collection, cells isolated from tissue are lysed by any number of means, and polypeptides are obtained from the cells. In some embodiments, these polypeptides are identified and / or quantified using detection methods known to those of skill in the art, for example by protein microarrays, ELISA, immunohistochemistry, immunophenotyping, fluorescent in situ hybridization (FISH), mass spectrometry, absorbance measurement, and / or any combination thereof. In some embodiments, polypeptide gene expression products are identified and / or quantified using either polyclonal or monoclonal antibodies specific for the protein expression product. Examples include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence activated cell sorting (FACS). In some embodiments, the gene expression profile is obtained and / or analyzed using a software program or module performed on a computer processor. The gene expression profile and information regarding the gene expression profile are articles and / or products of the methods described herein.Samples

[0164] In some embodiments of the various methods described herein, the sample is from a subject. A subject may be any animal, including but not limited to, a cow, a pig, a mouse, a rat, a chicken, a cat, a dog,WSGR Docket No. 47612-752.601 etc., and is usually a mammal, such as a human. Sample polynucleotides are often isolated from a cell-free sample from a subject, such as a tissue sample, bodily fluid sample, or organ sample, including, for example^ blood sample, or fluid sample containing nucleic acids (e.g., saliva). In some cases, the sample is treated to remove cells, or polynucleotides are isolated without a cellular extractions step (e.g., to isolate cell -free polynucleotides, such as cell-free DNA). Other examples of sample sources include those from blood, urine, feces, nares, the lungs, the gut, other bodily fluids or excretions, materials derived therefrom, or combinations thereof. In some embodiments, the sample is a blood sample or a portion thereof (e. g. , blood plasma or serum). Serum and plasma may be of particular interest, due to the relative enrichment for tumor DNA associated with the higher rate of malignant cell death among such tissues. In some embodiments, a sample from a single individual is divided into multiple separate samples (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more separate samples) that are subjected to methods of the disclosure independently, such as analysis in duplicate, triplicate, quadruplicate, or more. Where a sample is from a subject, the reference sequence may also be derived from the subject, such as a consensus sequence from the sample under analysis or the sequence of polynucleotides from another sample or tissue of the same subject. For example, a blood sample may be analyzed for cfDNA mutations, while cellular DNA from another sample (e.g., buccal or skin sample) is analyzed to determine the reference sequence.

[0165] Polynucleotides may be extracted from a sample according to any suitable method. A variety of kits are available for extraction of polynucleotides, selection of which may depend on the type of sample, or the type of nucleic acid to be isolated. Examples of extraction methods are provided herein, such as those described with respect to any of the various aspects disclosed herein. In one example, the sample may be a blood sample, such as a sample collected in an EDTA tube (e.g., BD Vacutainer). Plasma can be separated from the peripheral blood cells by centrifugation (e.g., 10 minutes at 1900xg at 4°C). Plasma separation performed in this way on a 6mL blood sample will typically yield 2.5 to 3 mL of plasma. Circulating cell - free DNA can be extracted from a plasma sample, such as by using a QIAmp Circulating Nucleic Acid Kit (Qiagene), according to the manufacturer’s protocol. DNA may then be quantified (e.g., on an Agilent 2100 Bioanalyzer with High Sensitivity DNA kit (Agilent)). As an example, yield of circulating DNA from such a plasma sample from a healthy person may range from Ing to lOng per mL of plasma, with significantly more in disease (e.g., cancer) patient samples.

[0166] In some embodiments, the plurality of polynucleotides comprises cell-free polynucleotides, such as cell-free DNA (cfDNA), cell-free RNA (cfRNA), circulating tumor DNA (ctDNA), or circulating tumor RNA (ctRNA). Cell-free DNA circulates in both healthy and diseased individuals. Cell-free RNA circulates in both healthy and diseased individuals. cfDNA from tumors (ctDNA) is not confined to any specific cancer type but appears to be a common finding across different malignancies. According to some measurements, the free circulating DNA concentration in plasma is about 14-18 ng / ml in control subjects and about 180-318 ng / ml in patients with neoplasia. Apoptotic and necrotic cell death contribute to cell -free circulating DNA in bodily fluids. For example, significantly increased circulating DNA levels have been observed in plasma of prostate cancer patients and other prostate diseases, such as Benign ProstateWSGR Docket No. 47612-752.601Hyperplasia and Prostatitis. In addition, circulating tumor DNA is present in fluids originating from the organs where the primary tumor occurs. Thus, breast cancer detection can be achieved in ductal lavages; colorectal cancer detection in stool; lung cancer detection in sputum, and prostate cancer detection in urine or ejaculate. Cell-free DNA may be obtained from a variety of sources. One common source is blood samples of a subject. However, cfDNA or other fragmented DNA may be derived from a variety of other sources. For example, urine and stool samples can be a source of cfDNA, including ctDNA. Cell -free RNA may be obtained from a variety of sources.

[0167] In some embodiments, polynucleotides are subjected to subsequent steps (e.g., circularization and amplification) without an extraction step, and / or without a purification step. For example, a fluid sample may be treated to remove cells without an extraction step to produce a purified liquid sample and a cell sample, followed by isolation of DNA from the purified fluid sample. A variety of procedures for isolation of polynucleotides are available, such as by precipitation or non-specific binding to a substrate followed by washing the substrate to release bound polynucleotides. Where polynucleotides are isolated from a sample without a cellular extraction step, polynucleotides will largely be extracellular or “cell -free” polynucleotides. For example, cell-free polynucleotides may include cell-free DNA (also called “circulating” DNA). In some embodiments, the circulating DNA is circulating tumor DNA (ctDNA) from tumor cells, such as from a body fluid or excretion (e.g., blood sample). Cell-free polynucleotides may include cell-free RNA (also called “circulating” RNA). In some embodiments, the circulating RNA is circulating tumor RNA (ctRNA) from tumor cells. Tumors may show apoptosis or necrosis, such that tumor nucleic acids are released into the body, including the blood stream of a subject, through a variety of mechanisms, in different forms and at different levels. Typically, the size of the ctDNA can range between higher concentrations of smaller fragments, generally 70 to 200 nucleotides in length, to lower concentrations of large fragments of up to thousands kilobases.Cancer

[0168] In aspects of methods, systems, and kits provided herein. Examples of cancers treatable in accordance with a method disclosed herein include, without limitation, Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblastic leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic thyroid cancer, Angioimmunoblastic T- cell lymphoma, Angiomyolipoma, Angiosarcoma, Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, BrownWSGR Docket No. 47612-752.601 tumor, Burkitt’s lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinoma of Unknown Primary Site, Carcinosarcoma, Castleman’s Disease, Central Nervous System Embryonal Tumor, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Choi angiocar cinoma, Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma, Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease, Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small round cell tumor, Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy -associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing’s sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget’s disease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer, Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer, Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Germ cell tumor, Germinoma, Gestational choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma, Granulosa cell tumor, Hairy Cell Leukemia, Hairy cell leukemia, Head and Neck Cancer, Head and neck cancer, Heart cancer, Hemangioblastoma, Hemangiopericytoma, Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin’s lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma, Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocytic leukemia, Kaposi Sarcoma, Kaposi’s sarcoma, Kidney Cancer, Klatskin tumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigo maligna melanoma, Leukemia, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma, Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma, Lymphoepithelioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia, Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, Malignant Mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mediastinal germ cell tumor, Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma, Medulloblastoma, Medulloepithelioma, Melanoma, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiple myeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplastic Disease, Myelodysplastic Syndromes, Myeloid leukemia, Myeloid sarcoma, Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, NasopharyngealWSGR Docket No. 47612-752.601Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Ocular oncology, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer, Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget’s disease of the breast, Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroid cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor of Intermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitary adenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonary blastoma, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer, Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell carcinoma, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15, Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter’s transformation, Sacrococcygeal teratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma, Secondary neoplasm, Seminoma, Serous tumor, Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma, Supratentorial Primitive Neuroectodermal Tumor, Surface epithelial -stromal tumor, Synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethral cancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma, Vulvar Cancer, Waldenstrom’s macroglobulinemia, Warthin’s tumor, Wilms’ tumor, and combinations thereof.

[0169] In some embodiments, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (R)-N-(l- hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

[0170] In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered once a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 25 mg administered once a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg administered once a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-WSGR Docket No. 47612-752.601 hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg administered once a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is 150 mg administered once a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 200 mg administered once a week.

[0171] In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered twice a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 25 mg administered twice a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg administered twice a week. In some embodiments, the therapeutically effective amount of (R)-N-(l- hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg administered twice a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is 150 mg administered twice a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 200 mg administered twice a week.

[0172] In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered daily for three days and the not administered for four days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5- (4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg administered twice a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 50 mg administered twice a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg administered twice a week. In some embodiments, the therapeutically effective amount of (R)-N-(l- hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 150 mg administered twice a week. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is 200 mg administered twice a week.

[0173] In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered daily for three days, and then not administered for the following four days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 25 mg administered daily for three days, and then not administered for the following four days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein theWSGR Docket No. 47612-752.601 therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 50 mg administered daily for three days, and then not administered for the following four days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 75 mg administered daily for three days, and then not administered for the following four days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 100 mg administered daily for three days, and then not administered for the following four days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 150 mg administered daily for three days, and then not administered for the following four days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 200 mg administered daily for three days, and then not administered for the following four days.

[0174] In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered daily for two days, and then not administered for the following five days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 25 mg administered daily for two days, and then not administered for the following five days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 50 mg administered daily for two days, and then not administered for the following five days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 75 mg administered daily for two days, and then not administered for the following five days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein theWSGR Docket No. 47612-752.601 therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 100 mg administered daily for two days, and then not administered for the following five days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 150 mg administered daily for two days, and then not administered for the following five days. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in a cycle length of one week, wherein the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is 200 mg administered daily for two days, and then not administered for the following five days.

[0175] In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in at least one cycle. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in at least two cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluorome1hyl)phenoxy)-2-naphthamide is administered in at least three cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l- hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in at least four cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in at least five cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in at least six cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluorome1hyl)phenoxy)-2-naphthamide is administered in at least seven cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l- hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in at least eight cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in at least nine cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in at least 10 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluorome1hyl)phenoxy)-2-naphthamide is administered in at least 11 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2- yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in at least 12 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in at least 18 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in at least 24 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluorome1hyl)phenoxy)-2-naphthamide is administered inWSGR Docket No. 47612-752.601 at least 36 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2- yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in at least 48 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in at least 60 cycles.

[0176] In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in one cycle. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in two cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in three cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in four cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in five cycles. In some embodiments, the therapeutically effective amount of (R)-N-( I -hydrox propan-2- l)-5-(4-(tri 11 uoromethyl)phenoxy)-2-naphthamide is administered in six cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in seven cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in eight cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in nine cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in 10 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in 11 cycles. In some embodiments, the therapeutically effective amount of (R)-N-( 1 -hydrox propan-2-yl)-5-(4-(tri fl uoromethyl)phenoxy)-2-naphthamide is administered in 12 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in 18 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in 24 cycles. In some embodiments, the therapeutically effective amount of (R)-N-( 1 -hydrox propan-2-yl)-5-(4-(tri fl uoromethyl)phenoxy)-2-naphthamide is administered in 30 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in 36 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in 48 cycles. In some embodiments, the therapeutically effective amount of (R)-N-( 1 -hydrox propan-2-yl)-5-(4-(tri fl uoromethyl)phenoxy)-2-naphthamide is administered in 60 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in 72 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-WSGR Docket No. 47612-752.601 naphthamide is administered in 84 cycles. In some embodiments, the therapeutically effective amount of (R)-N-( 1 -hydrox propan-2-yl)-5-(4-(tri fl uoromethyl)phenoxy)-2-naphthamide is administered in 96 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide is administered in 108 cycles. In some embodiments, the therapeutically effective amount of (R)-N-(l-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide is administered in 120 cycles.

[0177] In some embodiments, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is meningioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor. In some embodiments, the cancer is Schwannoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is bladder carcinoma. In some embodiments, the cancer is cutaneous neurofibromas. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is endometrial adenosquamous carcinoma. In some embodiments, the cancer is anaplastic thyroid carcinoma. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is esophageal adenocarcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is ovarian serous adenocarcinoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is breast cancer.Definitions

[0178] Whenever the term “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0179] Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0180] As used herein, the terms “genetic alteration”, “genetic mutation”, genetic variation”, used interchangeably herein, refer to a change in the DNA of a gene, including but not limited to a coding sequence, an intron sequence, a promoter sequence, or other sequence associated with the gene.WSGR Docket No. 47612-752.601

[0181] As used herein, the terms “polynucleotide”, “nucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably and generally refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides (DNA) or ribonucleotides (RNA), or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function. The following are non-limiting examples of polynucleotides: cell-free nucleic acids, cell-free DNA (cfDNA), cell-free RNA (cfRNA), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), short interfering RNA (siRNA), short -hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by nonnucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.

[0182] The term “subject” or “individual” as used interchangeably herein, generally refers to a vertebrate, such as a mammal (e.g., a human). Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets (e.g., a dog or a cat). Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed. The subject may be a patient. The subject may be symptomatic with respect to a disease (e.g., cancer). Alternatively, the subject may be asymptomatic with respect to the disease.

[0183] The term “biological sample” or “sample” as used interchangeably herein, generally refers to a sample derived from or obtained from a subject or an individual, such as a mammal (e.g., a human). Biological samples may include, but are not limited to, hair, finger nails, skin, sweat, tears, ocular fluids, nasal swab or nasopharyngeal wash, sputum, throat swab, saliva, mucus, blood, serum, plasma, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, earwax, oil, glandular secretions, bile, lymph, pus, microbiota, meconium, breast milk, bone marrow, bone, CNS tissue, cerebrospinal fluid, adipose tissue, synovial fluid, stool, gastric fluid, urine, semen, vaginal secretions, stomach, small intestine, large intestine, rectum, pancreas, liver, kidney, bladder, lung, and other tissues and fluids derived from or obtained from a subject. The biological sample may be a cell-free (or cell free) biological sample.

[0184] The term “cell-free biological sample,” as used herein, generally refers to a sample derived from or obtained from a subject or individual that is free from cells. Cell-free biological samples may include, but are not limited to, blood, serum, plasma, nasal swab or nasopharyngeal wash, saliva, urine, gastric fluid, tears, stool, mucus, sweat, earwax, oil, glandular secretion, bile, lymph, cerebrospinal fluid, tissue, semen, vaginal fluid, interstitial fluids, including interstitial fluids derived from tumor tissue, ocular fluids, spinal fluid, throat swab, breath, hair, finger nails, skin, biopsy, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk and / or other excretions.WSGR Docket No. 47612-752.601

[0185] “Treating” or “treatment of a condition or subject in need thereof’ refers to (1) taking steps to obtain beneficial or desired results, including clinical results such as the reduction of symptoms; (2) preventing the disease, for example, causing the clinical symptoms of the disease not to develop in a patient that is predisposed to the disease, for example a carrier of a genetic mutation in a gene associated with cancer, but does not yet experience or display symptoms of the disease; (3) inhibiting the disease, for example, arresting or reducing the development of the disease or its clinical symptoms; (4) relieving the disease, for example, causing regression of the disease or its clinical symptoms; or (5) delaying the disease.EXAMPLES

[0186] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.Example 1: Identifying Patients Suitable for Treatment Using Hippo Pathway Core Genes

[0187] Patients are screened for genetic alterations in Hippo pathway core genes (see Table 1) by next generation sequencing (NGS) of genomic DNA and whole transcriptome RNA sequencing. The expression of certain genes and levels of transcripts including NF2 are obtained by whole transcriptome RNA sequencing, which determines the mRNA transcript levels of the genes (such as NF2, LATS1, and LATS2) that may be silenced due to epigenetic regulation or lost by large deletions. With the genes being silenced by epigenetic regulation or lost by large deletions in certain cancer types and hence NGS not being able to detect the genetic alterations in the cancers, the whole transcriptome RNA sequencing will detect the loss of expression or reduced expression of any of the Hippo pathway core genes such as NF2.

[0188] Patients are also screened using proteomic assays to measure expression levels of proteins encoded by the genes in Table 1 whose normal expression levels and / or cellular localization is affected by the above- mentioned genetic alterations. For example, the level of GDF-15 in the blood, which has been shown to correlate with the aggressiveness of the epithelioid hemangioendothelioma (EHE) (Sandro Pasquali, 2024 YAP-TAZ-TEAD Telluride Workshop), a vascular sarcoma that is caused by oncogenic fusions involving YAP / TAZ rearrangements. GDF-15 is a YAP / TEAD target gene.

[0189] Patients are also screened using a fusion cRNA-ddPCR assay to look for the presence of the WWTR1(TAZ)-CAMTA1 fusion in EHE patients.

[0190] Patients identified to have one or more of the above genetic alterations are selected for treatment with a TEAD inhibitor. These patients have a better clinical outcome than patients who do not have any genetic alterations.WSGR Docket No. 47612-752.601Example 2: Identifying Patients Suitable for Treatment Using Predictive Gene Signature

[0191] Although genetic alterations of pathway components leading to TEAD activation have been reported in a variety of human malignancies, these alterations are not seen in many cancers. In order to find patients without Hippo- YAP pathway mutations who will likely respond to TEAD inhibitor treatment, a custom data-processing and normalization pipeline to process publicly available RNAseq datasets and train a random-forest based classifier using in vitro efficacy data from cell line screens. The algorithm showed early promise by classifying a model with in vivo efficacy as the most likely to respond.

[0192] This random-forest classifier was originally trained on public bulk RNAseq pan-cancer in vitro data set available in the Cancer Cell Line Encyclopedia (CCLE) using the TEAD inhibitor response data for a subset of the 252 CCLE cell lines. Binary response label (responder / non-responder) for each cell line was obtained by thresholding efficacy measures (ICso). Looking at results from the screen of 50 patient-derived Chinese liver cancer (CLC) cell models (Qiu et al., 2019, Cancer Cell.36(2): 179-193. el l. doi:10. 1016 / j.ccell.2019.07.001) , it was found that TEAD inhibitors were efficacious in several of these liver cancer models. This allowed verification of the classifier without any re-training on an independent dataset (CLC). Having established efficacy of predictions on both in vitro datasets, we re-trained the classifier using both CCLE and CLC datasets as input to achieve maximum predictive performance. The probability of response was predicted for 2056 patient-derived models and the top candidates were tested in vivo and demonstrated efficacy in vivo. The data for this is shown in FIG. 2. Table 3 provides genes selected based on knowledge in the literature predicting upregulation and activation in YAP -TEAD cancer cells that were subsequently validated using the random forest classifier trained on the TEAD inhibitor response dataset.Example 3: Identifying Patients Responsive to Treatment Using Pharmacodynamic Biomarkers

[0193] An individual with cancer is treated with a TEAD inhibitor. In order to determine efficacy of the TEAD inhibitor in treating the cancer, gene expression was measured for the genes shown in Table 4 using a nanostring assay on circulating tumor DNA and / or cRNA. A change in expression of one or more of these genes is indicative of a response in the patient to the TEAD inhibitor. Specifically, a reduction and / or early clearance of ctDNA and / or fusion cRNA in response to treatment predicts improved survival and in some cases may be used as an early endpoint.Example 4: Identifying Patients Responsive to Treatment Using Merlin / YAP Immunohistochemistry

[0194] Patients are screened using proteomic assays to measure expression levels of proteins encoded by the genes in Table 1 whose normal expression levels and / or cellular localization is affected by the above- mentioned genetic alterations. Expression of Merlin, the protein encoded by the NF2 gene, and the cellular localization of YAP that is regulated by NF2 / Merlin is examined by a Merlin / Y AP dual -label (duplex) immunohistochemistry (IHC) assay.

[0195] Patients identified to have altered Merlin / Y AP localization are selected for treatment with a TEAD inhibitor. These patients have a better clinical outcome than patients who do not have any genetic alterations.WSGR Docket No. 47612-752.601

[0196] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments described herein may be employed. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No. 47612-752.601CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a cancer in an individual in need thereof comprising administering a yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a genetic alteration in a Hippo pathway gene.

2. The method of claim 1, wherein the genetic alteration results in altered expression of the gene.

3. The method of claim 1 or claim 2, wherein the genetic alteration is a loss of function alteration.

4. The method of claim 3, wherein the loss of function alteration is in a gene selected from the group consisting of NF2, LATS1, LATS2, SAV1, SIK3, STK4, M0B1A, M0B1B, WWC1, FRMD6, TA0K1, TA0K2, and TA0K3.

5. The method of claim 1 or claim 2, wherein the genetic alteration is a gain of function alteration.

6. The method of claim 5, wherein the gain of function alteration is in a gene selected from the group consisting of YAP1, WWTR1 (TAZ), TEAD I. TEAD2, TEAD3, and TEAD4.

7. The method of claim 6, wherein the gain of function alteration is a YAP / WWTR1 rearrangement.

8. The method of claim 7, wherein the YAP / WWTR1 rearrangement is selected from the group consisting of YAP 1-TFE3, WWTR1(TAZ)-CAMTA1, YAP1-MAMLD1, YAP1-FAM118B, YAP1- S S 18, YAP 1 -MAML2, YAP 1 -NUTM1 , YAP 1 -MAML2, YAP 1-F AMI 18B, YAP 1 -PYGO 1 , YAP 1 -LMO 1 , AP1-KMT2A, YAP1-SHM1, YAP1-CFAP300(YAP1-C110RF70), and YAP1-MRPL48.

9. The method of any one of claims 1 to 8, wherein the yes- associated protein (YAP)Ztranscriptional enhancer activator domain (TEAD) inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein:R is Ci-Cefluoroalkyl; andWSGR Docket No. 47612-752.601(a) Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl;(b) Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl; or(c) Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogen unsubstituted Ci-Cealkyl.

11. The compound of claim 9 or claim 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OH.

12. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2, or unsubstituted pyrazinyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with pyridinyl.

14. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, - H2, -NHCH3, -N(CH3)2, and pyridinyl.

15. The compound of any one of claims 9 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF3.

16. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OR3; R3is hydrogen or unsubstituted Ci-Cealkyl; and R is -CF3.

17. The compound of claim 9, wherein the compound is selected from the group consisting of:WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601or a pharmaceutically acceptable salt or solvate thereof.

18. The compound of claim 9, wherein the compound is:pharmaceutically acceptable salt or solvate thereof.

19. The method of any one of claims 1 to 18, wherein the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer breast cancer, melanoma, hepatocellular carcinoma, low grade glioma, glioblastoma, ependymoma, ST-ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma.

20. The method of any one of claims 1 to 18, wherein the cancer is mesothelioma.

21. The method of any one of claims 1 to 20, wherein the genetic alteration is detected by nextgeneration sequencing of genomic DNA or whole transcriptome RNA.

22. The method of claim 21, wherein the genomic DNA or whole transcriptome RNA are derived from a tumor sample.

23. The method of claim 21, wherein the genomic DNA or whole transcriptome RNA are derived from a cell-free nucleic acid sample.WSGR Docket No. 47612-752.60124. The method of any one of claims 2 to 20, wherein alteration in expression of the gene is detected by next-generation sequencing of whole transcriptome RNA or a proteomic assay.

25. The method of claim 24, wherein the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.

26. The method of claim 24 or claim 25, wherein the proteomic assay is conducted on a tumor sample.

27. The method of any one of claims 1 to 20, wherein the genetic alteration is detected by a circulating RNA (cRNA)- digital droplet PCR (ddPCR) assay.

28. The method of claim 27, wherein the cRNA is derived from a blood sample or a cell-free nucleic acid sample.

29. A method of treating a cancer in an individual in need thereof comprising administering a es-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a genetic alteration in a gene that leads to constitutive activation of YAP / TAZ- TEAD activity.

30. The method of claim 29, wherein the genetic alteration results in altered expression of the gene.

31. The method of claim 29 or claim 30, wherein the genetic alteration is a loss of function alteration.

32. The method of any one of claims 29 to 31, wherein the genetic alteration is in a gene selected from the group consisting of FAT1, FAT2, FAT3, FAT4, GNAQ, GNA11, CDH1, RHOA, BAP1, ZFTA-RELA(Cllorf95-RELA), and CLDN18-ARHGAP.

33. The method of any one of claims 29 to 32, wherein the yes-associated protein (YAP)Ztranscriptional enhancer activator domain (TEAD) inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein:R is Ci-Cefluoroalkyl; andR1isWSGR Docket No. 47612-752.601(a) Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl;(b) Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl; or(c) Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl.

34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogen unsubstituted Ci-Cealkyl.

35. The compound of claim 33 or claim 34, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OH.

36. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2, or unsubstituted pyrazinyl.

37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with pyridinyl.

38. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, - H2, -NHCH3, -N(CH3)2, and pyridinyl.

39. The compound of any one of claims 33 to 38, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF3.

40. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OR3; R3is hydrogen or unsubstituted Ci-Cealkyl; and R is -CF3.

41. The compound of claim 33, wherein the compound is selected from the group consisting of:WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601or a pharmaceutically acceptable salt or solvate thereof.

42. The compound of claim 33, wherein the compound is:pharmaceutically acceptable salt or solvate thereof.

43. The method of any one of claims 29 to 42, wherein the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer breast cancer, melanoma, hepatocellular carcinoma, low grade glioma, glioblastoma, ependymoma, ST-ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma.

44. The method of any one of claims 29 to 42, wherein the cancer is mesothelioma.

45. The method of any one of claims 29 to 44, wherein the genetic alteration is detected by next-generation sequencing of genomic DNA or whole transcriptome RNA.

46. The method of claim 45, wherein the genomic DNA or whole transcriptome RNA are derived from a tumor sample.

47. The method of claim 45, wherein the genomic DNA or whole transcriptome RNA are derived from a cell-free nucleic acid sample.WSGR Docket No. 47612-752.60148. The method of any one of claims 30 to 47, wherein alteration in expression of the gene is detected by next-generation sequencing of whole transcriptome RNA or a proteomic assay.

49. The method of claim 48, wherein the proteomic assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.

50. The method of claim 48 or claim 49, wherein the proteomic assay is conducted on a tumor sample.

51. The method of any one of claims 29 to 50, wherein the genetic alteration is detected by a fusion circulating RNA (cRNA)- digital droplet PCR (ddPCR) assay.

52. The method of claim 51, wherein the cRNA is derived from a tumor sample or a cell-free nucleic acid sample.

53. A method of treating a cancer in an individual in need thereof comprising administering a es-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor to the individual when the individual has a high probability of response to the TEAD inhibitor, wherein the high probability of response is determined by: (a) measuring a gene expression level for CRIM1, ANKRD1, GADD45B, WTIP, AXL, TOP2A, BIRC5, CTGF, AMOTL2, AJUBA, ITGB2, FJX1, FOSL1, AS API, CDC20, CENPF, CYR61, DDAH1, FGF2, SERPINE1, and TGFB2 in a sample from the individual; and (b) processing the gene expression levels using an algorithm trained using gene expression levels of samples that are responsive to the TEAD inhibitor and gene expression levels of samples that are not responsive to the TEAD inhibitor, thereby determining a probability of response to the TEAD inhibitor in the individual .

54. The method of claim 53, wherein the algorithm is a random-forest based algorithm.

55. The method of claim 53 or claim 54, wherein the algorithm was developed using TEAD inhibitor response data and bulk RNA-seq data.

56. The method of any one of claims 53 to 55, wherein the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer breast cancer, melanoma, hepatocellular carcinoma, low grade glioma, glioblastoma, ependymoma, ST-ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma.

57. The method of any one of claims 53 to 55, wherein the cancer is mesothelioma.

58. The method of any one of claims 53 to 57, wherein gene expression is measured by assaying levels of RNA or levels of protein.

59. The method of claim 58, wherein the RNA or the protein are derived from a tumor sample.

60. The method of claim 58, wherein the RNA is derived from a tumor sample or a cell-free nucleic acid sample.

61. The method of any one of claims 54 to 60, wherein assaying levels of RNA comprises nextgeneration sequencing of RNA or quantitative PCR.WSGR Docket No. 47612-752.60162. The method of claim 61, wherein the assaying levels of protein comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.

63. The method of any one of claims 53 to 62, wherein the yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein:R is Ci-Cefluoroalkyl; andR1is(a) Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl;(b) Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl; or(c) Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl.

64. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogen unsubstituted Ci-Cealkyl.

65. The compound of claim 63 or claim 64, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OH.

66. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2, or unsubstituted pyrazinyl.

67. The compound of claim 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with pyridinyl.

68. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, - H2, -NHCH3, -N(CH3)2, and pyridinyl.

69. The compound of any one of claims 63 to 68, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF3.

70. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OR3; R3is hydrogen or unsubstituted Ci-Cealkyl; and R is -CF3.WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601or a pharmaceutically acceptable salt or solvate thereof.

72. The compound of claim 63, wherein the compound is:WSGR Docket No. 47612-752.601pharmaceutically acceptable salt or solvate thereof.

73. A method of measuring a response to a yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor comprising: (a) administering an individual with cancer the TEAD inhibitor; (b) measuring a gene expression level of a pharmacodynamics gene; and correlating the gene expression level of the pharmacodynamics gene to the response to the TEAD inhibitor.

74. The method of claim 73, wherein the pharmacodynamics gene is selected from the group consisting of AJUBA, AMOTL2, ANKRD1, ANKRD2, AREG, AXL, BIRC5, BUB1, CCDC80, CCN1 (aka, CYR61), CCN2 (aka, CTGF), CCND1, CD274, CDC20, CRIM1, FASN, FGF2, FJX1, FLT3, FOSL1,F0XM1, GADD45B, HK2, IL21R, IL6, ITGA11, LATS2, MYCN, NF2, NT5E, NUAK2, PLK1, PTPN14, SCD, SLC2A1, SLC2A14, SLC7A5, SOD2, VEGFA, and WTIP.

75. The method of claim 73 or claim 74, the cancer is selected from the group consisting of mesothelioma, meningioma, schwannoma, epithelioid hemangioendothelioma, sarcoma, head and neck cancer, renal cell carcinoma, lung cancer, gastric cancer, colon cancer, cervical cancer, ovarian cancer breast cancer, melanoma, hepatocellular carcinoma, low grade glioma, glioblastoma, ependymoma, ST- ependymoma, liposarcoma, soft-tissue sarcomas, well- and dedifferentiated liposarcomas (WD / DDLPS), and squamous cell carcinoma.

76. The method of claim 73 or claim 74, wherein the cancer is mesothelioma.

77. The method of any one of claims 73 to 76, wherein the gene expression level comprises RNA expression.

78. The method of claim 77, wherein RNA is isolated from a tumor sample, a blood sample, a serum sample, or a plasma sample.

79. The method of claim 77 or claim 78, wherein RNA is cell-free RNA or whole transcriptome RNA.

80. The method of any one of claims 73 to 76, wherein the gene expression comprises protein expression.

81. The method of claim 80, wherein protein is isolated from a tumor sample or a blood sample.

82. The method of claim 81, wherein the protein is in a formalin-fixed paraffin embedded sample.

83. The method of any one of claims 73 to 82, wherein the gene expression is measured using a quantitative RNA assay or a quantitative protein assay.

84. The method of claim 83, wherein the quantitative RNA assay comprises a nanostring assay, next-generation sequencing, or quantitative RT-PCR.WSGR Docket No. 47612-752.60185. The method of claim 83, wherein the quantitative protein assay comprises immunohistochemistry, enzyme linked immunosorbent assay, Western blot, or immunofluorescence.

86. The method of any one of claims 73 to 85, wherein the yes-associated protein (YAP) / transcriptional enhancer activator domain (TEAD) inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein:R is Ci-Cefluoroalkyl; andR1is(a) Ci-Cealkyl substituted with -OR3; and R3is hydrogen or unsubstituted Ci-Cealkyl;(b) Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2 or unsubstituted pyrazinyl; or(c) Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl.

87. The compound of claim 86, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OR3; and R3is hydrogen unsubstituted Ci-Cealkyl.

88. The compound of claim 86 or claim 87, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OH.

89. The compound of claim 86, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with 6-membered heteroaryl ring selected from unsubstituted pyridinyl, pyridinyl substituted with -NH2 or -N(CH3)2, or unsubstituted pyrazinyl.

90. The compound of claim 89, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with pyridinyl.

91. The compound of claim 86, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, - H2, -NHCH3, -N(CH3)2, and pyridinyl.

92. The compound of any one of claims 86 to 91, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF3.

93. The compound of claim 86, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is Ci-Cealkyl substituted with -OR3; R3is hydrogen or unsubstituted Ci-Cealkyl; and R is -CF3.WSGR Docket No. 47612-752.601WSGR Docket No. 47612-752.601or a pharmaceutically acceptable salt or solvate thereof.

95. The compound of claim 86, wherein the compound is:WSGR Docket No. 47612-752.601pharmaceutically acceptable salt or solvate thereof.

96. A kit for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a reagents for identifying a genetic alteration in a Hippo pathway gene; and (b) instructions for identifying the individual suitable for treatment with the TEAD inhibitor based on the genetic alteration in the Hippo pathway gene.

97. A kit for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a reagents for identifying a genetic alteration in a gene that leads to constitutive activation of the AP / TAZ-TEAD transcriptional activity; and (b) instructions for identifying the individual suitable for treatment with the TEAD inhibitor based on the genetic alteration in that gene that leads to constitutive activation of the YAP / TAZ-TEAD transcriptional activity.

98. A kit for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a reagents for measuring a gene expression level for CRIM1, ANKRD1, GADD45B, WTIP, AXL, T0P2A, BIRC5, CTGF, AM0TL2, AJUBA, ITGB2, FJX1, FOSL1, ASAP1, CDC20, CENPF, CYR61, DDAH1, FGF2, SERPINE1, and TGFB2 in a sample from the individual; (b) an algorithm for processing the gene expression levels using an algorithm trained using gene expression levels of samples that are responsive to the TEAD inhibitor and gene expression levels of samples that are not responsive to the TEAD inhibitor; and (c) instructions for identifying the individual suitable for treatment with the TEAD inhibitor based on the genetic alteration in the gene.

99. A kit for measuring a response to a TEAD inhibitor comprising: (a) reagents for measuring a gene expression level of a pharmacodynamics gene; and (b) instructions for correlating the gene expression level of the pharmacodynamics gene to the response to the TEAD inhibitor.

100. A system for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a) a computer configured to receive a user request to perform a detection of a genetic alteration in a Hippo pathway gene in a sample from the individual; (b) an assay unit that (i) performs an assay to detect the genetic alteration in the Hippo pathway gene; and (ii) computer processes results of the assay to determine whether the individual has the genetic alteration in the Hippo pathway gene; and (c) a report generator that sends a report to a recipient, wherein the report contains results indicating suitability of the individual for treatment with the TEAD inhibitor.

101. A system for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a) a computer configured to receive a user request to perform a detection of a genetic alteration in a gene that leads to constitutive activation of the YAP / TAZ-TEAD transcriptional activity in a sample from the individual; (b) an assay unit that (i) performs an assay to detect the genetic alteration that leads to constitutive activation of the YAP / TAZ-TEAD transcriptional activity; and (ii) computer processes results ofWSGR Docket No. 47612-752.601 the assay to determine whether the individual has the genetic alteration that leads to constitutive activation of the YAP / TAZ-TEAD transcriptional activity; and (c) a report generator that sends a report to a recipient, wherein the report contains results indicating suitability of the individual for treatment with the TEAD inhibitor.

102. A system for identifying an individual suitable for treatment with a TEAD inhibitor comprising: (a) a computer configured to receive a user request to perform a measurement of a gene expression level for a set of genes comprising CRIM1, ANKRD1, GADD45B, WTIP, AXL, TOP2A, BIRC5, CTGF, AM0TL2, AJUBA, ITGB2, FJX1, FOSL1, ASAP1, CDC20, CENPF, CYR61, DDAH1, FGF2, SERPINE1, and TGFB2 in a sample from the individual; (b) an assay unit that (i) performs an assay to detect the gene expression level of the set of genes; and (ii) computer processes results of the assay relative gene expression levels of the set of genes; and (c) a report generator that sends a report to a recipient, wherein the report contains results indicating suitability of the individual for treatment with the TEAD inhibitor.

103. A system for measuring a response to a TEAD inhibitor of an individual administered with the TEAD inhibitor comprising: (a) a computer configured to receive a user request to perform a detection of a gene expression level of a pharmacodynamics gene in a sample from the individual; (b) an assay unit that (i performs an assay to detect the gene expression level of the pharmacodynamics gene; and (ii) computer processes results of the assay to correlate the expression level of the pharmacodynamics gene with a response to the TEAD inhibitor; and (c) a report generator that sends a report to a recipient, wherein the report contains results indicating whether the individual is responding to the TEAD inhibitor.

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