WO2019083457A1 - Varlitinib destiné à être utilisé dans le traitement du cancer chez un patient identifié comme ayant une mutation de la voie de la bêta-caténine - Google Patents

Varlitinib destiné à être utilisé dans le traitement du cancer chez un patient identifié comme ayant une mutation de la voie de la bêta-caténine

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Publication number
WO2019083457A1
WO2019083457A1 PCT/SG2018/050537 SG2018050537W WO2019083457A1 WO 2019083457 A1 WO2019083457 A1 WO 2019083457A1 SG 2018050537 W SG2018050537 W SG 2018050537W WO 2019083457 A1 WO2019083457 A1 WO 2019083457A1
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WIPO (PCT)
Prior art keywords
cancer
varlitinib
catenin
compound
formula
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PCT/SG2018/050537
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English (en)
Inventor
Ann Gee Lisa OOI
Qihui SEET
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Aslan Pharmaceuticals Pte Ltd
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Publication of WO2019083457A1 publication Critical patent/WO2019083457A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Definitions

  • VARLITINIB FOR USE IN TREATING CANCER IN A PATIENT IDENTIFIED AS
  • the present disclosure relates to a therapy, for example a monotherapy or combination therapy comprising a type I tyrosine kinase inhibitor for the treatment of cancer, for example liver cancer, such as hepatocellular carcinoma, in patients who are identified as having a mutation in the beta- catenin pathway.
  • a therapy for example a monotherapy or combination therapy comprising a type I tyrosine kinase inhibitor for the treatment of cancer, for example liver cancer, such as hepatocellular carcinoma, in patients who are identified as having a mutation in the beta- catenin pathway.
  • Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. This is a problem that many patients with cancer encounter, and it obviously limits the therapeutic alternatives that are effective and worsens the prognosis.
  • Cancer therapy guidelines describe the sequence of therapies, which are recommended and in which sequence, so that if a patient shows disease progression on the first therapy ("first line”), then a next therapy (“second line”) is recommended, and so on. These therapy recommendations are based on available scientific data and experience, and illustrate that resistance to one therapy does not exclude that another therapy may be effective and prolong life or shrink a tumor. At late stages cancers do not respond, no more avenues of therapy exist, and are completely therapy refractory. Thus, unless new therapies can be found, which are effective, these cancers cannot be treated.
  • Varlitinib is in clinical trials for the treatment of cancer.
  • the present inventors have data that suggest the molecule is particularly effective in the treatment of a subcategory of cancers, namely those where cancer cells have a mutation in the beta-catenin pathway. These cancers seem to be sensitive to treatment with Varlitinib.
  • Varlitinib is an inhibitor of a mutated beta- catenin pathway.
  • a method of treating a patient for cancer by administering a compound of formula (I):
  • liver cancer such as hepatocellular carcinoma
  • biliary tract cancer such as gall bladder cancer
  • breast cancer such as none ER+ breast cancer
  • prostate cancer colorectal cancer
  • ovarian cancer cervical cancer
  • lung cancer gastric cancer
  • pancreatic bone cancer
  • bladder cancer head and neck cancer
  • thyroid cancer skin cancer
  • renal cancer and oesophagus cancer and combinations of two or more of the same.
  • each dose of the compound of formula (I) is in the range 100 to 900mg, for 100, 200, 300, 400, 500, 600, 700, 800 or 900mg.
  • a method according to paragraph 13, wherein each dose of the compound of formula (I) is in the range 200 to 500mg or 100 to 500mg, for example 250 mg or 490 mg.
  • each dose is lOOmmg, 200mg, 300g or 400mg (such as 300mg or 400mg).
  • the chemotherapeutic agent is independently selected from the group comprising a platin (such as cisplatin or oxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI and FOLFIRINOX.
  • liver cancer such as hepatocellular carcinoma
  • biliary tract cancer such as gall bladder cancer
  • breast cancer such as none ER+ breast cancer
  • prostate cancer colorectal cancer
  • ovarian cancer cervical cancer
  • lung cancer gastric cancer
  • pancreatic bone cancer
  • bladder cancer head and neck cancer
  • thyroid cancer skin cancer
  • renal cancer and oesophagus cancer and combinations of two or more of the same.
  • each dose of the compound of formula (I) is in the range 200 to 500mg or 100 to 500mg, for example 250 mg or 490 mg.
  • each dose is lOOmg, 200mg, 300mg or 400mg (such as 300mg or 400mg).
  • a chemotherapeutic agent is independently selected from the group comprising a platin [such as cisplatin or oxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI and FOLFIRINOX.
  • liver cancer such as hepatocellular carcinoma
  • biliary tract cancer such as biliary tract cancer
  • gall bladder cancer such as none ER+ breast cancer
  • prostate cancer colorectal cancer
  • ovarian cancer cervical cancer
  • lung cancer gastric cancer
  • pancreatic bone cancer
  • bladder cancer head and neck cancer
  • thyroid cancer skin cancer
  • renal cancer and oesophagus cancer and combinations of two or more of the same.
  • each dose of the compound of formula [I) is in the range 100 to 900mg, for 100, 200, 300, 400, 500, 600, 700, 800 or 900mg.
  • each dose of the compound of formula [I) is in the range 200 to 500mg or 100 to 500mg, for example 250 mg or 490 mg.
  • each dose is lOOmg, 200mg, 300mg or 400mg [such as 300mg or 400mg).
  • combination therapy comprises a chemotherapeutic agent.
  • chemotherapeutic agent is independently selected from the group comprising a platin (such as cisplatin or oxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI and FOLFIRINOX.
  • the mutated beta-catenin localises in a cell's cytoplasm and/or nucleus.
  • the cancer is both HER2 activated and HER3 activated.
  • the cancer has at least one of the following:
  • the biliary duct cancer is in a location selected from intrahepatic bile ducts, left hepatic duct, right hepatic duct, common hepatic duct, cystic duct, common bile duct, Ampulla of Vater and combinations thereof.
  • the biliary duct cancer is in an intrahepatic bile duct. In one embodiment the biliary duct cancer is in a left hepatic duct. In one embodiment the biliary duct cancer is in a right hepatic duct. In one embodiment the biliary duct cancer is in a common hepatic duct. In one embodiment the biliary duct cancer is in a cystic duct. In one embodiment the biliary duct cancer is in a common bile duct. In one embodiment the biliary duct cancer is in an Ampulla of Vater. In one embodiment the biliary duct cancer is a cancer of the Papilla of Vater.
  • the cancer is a metastatic form of a cancer, in the patient population disclosed herein disclosed herein.
  • the cancer according the present disclosure has not metastasized in said patient population.
  • the compound of formula (I) is (i?)-N4-[3-Chloro-4-(thiazol-2- ylmethoxy)-phenyl]-N6-(4-methyl-4, 5,-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine:
  • the patient population is not activated for all of HER1, HER2, HER3 and HER4, for example the population is at least negative for HER1 and/or HER4.
  • the patient population is HER2 and/or HER3 and HER1 activated but not HER4 activated.
  • the patient population is HER2 and/or HER3 activated and HER4 activated but not HER1 activated.
  • the patient population is only HER2 and/or HER3 activated.
  • the patient population is only HER2 activated.
  • the patient population is only HER3 activated.
  • the patient population is both HER3 and HER4 activated.
  • the compound of formula (I) an enantiomer thereof or a pharmaceutically acceptable salt thereof is employed as a monotherapy, for example first line therapy or second line therapy, such as a first line monotherapy, in said patient population.
  • the compound of formula (I) an enantiomer thereof or a pharmaceutically acceptable salt thereof is employed in a combination therapy, for example in combination with a chemotherapy and/or a biological therapeutic, in particular as a first line therapy or a second line therapy in said patient population.
  • the compound of formula (I) an enantiomer thereof or a pharmaceutically acceptable salt thereof is employed as a second line monotherapy, in said patient population.
  • CA19-9 is a marker employed in the management of cholangiocarcinoma.
  • a HER3 and HER4 positive or amplified patient has a 10, 20, 30, 40, 50, 60, 70, 80 or 90% decrease in CA19-9 level whilst on the therapy according to the present disclosure, wherein the level is decreased relative to the level of CA19-9 before initiation of said therapy.
  • This decrease in CA19-9 may be observed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or weeks after initiating therapy according to the present disclosure.
  • the compound of formula (I), according to the present disclosure is employed in a second line therapy together with a chemotherapy agent or chemotherapy regimen, for example gemcitabine, capecitabine, 5-FU, FOLFOX, a platin, such as cisplatin or oxaliplatin, and a combination thereof, in said patient population.
  • a chemotherapy agent or chemotherapy regimen for example gemcitabine, capecitabine, 5-FU, FOLFOX, a platin, such as cisplatin or oxaliplatin, and a combination thereof, in said patient population.
  • a chemotherapy agent or chemotherapy regimen for example gemcitabine, capecitabine, 5-FU, FOLFOX, a platin, such as cisplatin or oxaliplatin, and a combination thereof, in said patient population.
  • the compound of formula [I), according to the present disclosure is administered orally.
  • the compound of formula (I), according to the present disclosure such as Varlitinib, is administered at a dose in the range lOOmg to 900mg on each occasion, in particular 200 mg, 300mg, 400mg or 500mg each dose, such as 400mg, 250mg or 490 mg, for example administered once or twice daily, such as twice daily.
  • the compound of formula (I), according to the present disclosure such as Varlitinib is administered twice daily.
  • the compound of formula (I), according to the present disclosure such as Varlitinib, is administered for a 28 days, referred to herein as a 28 day treatment cycle.
  • the compound of formula (I), according to the present disclosure such as Varlitinib, is administered as pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients.
  • the compound of formula (I), according to the present disclosure such as Varlitinib, or a formulation comprising the same is administered orally, for example as tablet or capsule.
  • the treatment is adjuvant therapy, for example after surgery or after chemotherapy, in said patient population.
  • the treatment is neoadjuvant therapy, for example before surgery, in particular to shrink the tumour or tumours, in said patient population.
  • the treatment according to the present disclosure is suitable for the treatment of secondary tumours, in said patient population.
  • the cancer is metastatic cancer, in said patient population.
  • the treatment according to the present disclosure is suitable for the treatment of primary cancer and metastases, in said patient population.
  • the treatment according to the present disclosure is suitable for the treatment of secondary cancer and metastases.
  • the treatment according to the present disclosure is suitable for the treatment of primary cancer, secondary cancer and metastases in said patient population.
  • the treatment according to the present disclosure is suitable for the treatment of cancerous cells in a lymph node, for a cancer of the present disclosure in said patient population.
  • the patient is a human.
  • a method comprising profiling an ex vivo sample from a patient to identify dysregulation in at least two genes independently selected from FM03, RORC, NAG, ADIRF, CES3, FAT4, S100A14, SLC16A14, AZGP1, PPL, LOC200772, TNNI1, SLC1A7, BCHE, CYP4A11, NOY6R, ENPEP, HA01, CYP3A5, BHMT, TMEM132A, EPO, FAM19A5, ASNS, HK2, TTBK1, NSMF, HAL, OBSL1, LOCI 00507194, GPC4, CERCAM, ADRA2C, SERPINE1 , SPARC, SLC6A8, SCARF2, HS6ST2, ADM and IRX3.
  • the dysregulation is upregulation (also referred to herein as activation) of at least one gene (for example 1, 2, 3, , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 genes) independently selected from FM03, RORC, NAG, ADIRF, CES3, FAT4, SI 00A14, SLC16A14, AZGP1, PPL, LOC200772, TNN11, SLC1A7, BCHE, CYP4A11, NOY6R, ENPEP, HAOl, CYP3A5, and BHMT.
  • upregulation also referred to herein as activation
  • at least one gene for example 1, 2, 3, , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 genes
  • the dysregulation is downregulation [also referred to herein as repression ⁇ of at least one gene (for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 genes] independently selected from TMEM132A, EPO, FAM19A5, ASNS, HK2, TTBK1, NSMF, HAL, OBSL1, LOC100507194, GPC4, CERCAM, ADRA2C, SERPINE1, SPARC, SLC6A8, SCARF2, HS6ST2, ADM and IRX3.
  • TMEM132A EPO
  • FAM19A5 for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 genes
  • the dysregulation is upregulation of at least one gene (for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 genes) independently selected from FM03, RORC, NAG, ADIRF, CES3, FAT4, S100A14, SLC16A14, AZGP1, PPL, LOC200772, TNNI1, SLC1A7, BCHE, CYP4A11, NOY6R, ENPEP, HAOl, CYP3A5, and BHMT, and downregulation of at least one gene (for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 genes) independently selected from TMEM132A, EPO, FAM19A5, ASNS, HK2, TTBK1, NSMF, HAL, OBSL1, LOC100507194, GPC4, CERCAM, ADRA2C, SERPINE1, SPARC, SLC6A8, SCARF2, HS6ST2, ADM and IRX3.
  • at least one gene for example 1,
  • the profiling is for diagnostic or prognostic purposes, for example to identify the patient as having cancer, or a subtype thereof.
  • the profiling is for identifying a patient as suitable for treatment with regime according to the present disclosure.
  • treatment of a new patient population comprising a cancer patient with dysregulation according to any one of paragraphs i), ii), iii) and iv).
  • treatment of a patient wherein said patient has been identified within the target population.
  • the CTNNB1 gene provides instructions for making a protein called beta-catenin.
  • This protein is present in many types of cells and tissues, where it is primarily found at junctions that connect neighboring cells (adherens junctions). Beta-catenin plays an important role in sticking cells together (cell adhesion) and in communication between cells.
  • the beta-catenin protein is also involved in cell signaling as an essential part of the Wnt signaling pathway. Certain proteins in this pathway attach (bind) to beta-catenin, which triggers a multi-step process that allows the protein to move into the nucleus. Once in the nucleus, beta-catenin interacts with other proteins to control the activity (expression) of particular genes.
  • the Wnt signaling pathway promotes the growth and division (proliferation) of cells and helps determine the specialized functions a cell will have (differentiation). Wnt signaling is known to be involved in many aspects of development before birth. In adult tissues, this pathway plays a role in the maintenance and renewal of stem cells, which are cells that help repair tissue damage and can give rise to other types of cells.
  • a mutations in ⁇ -catenin pathway refers to any mutation that impacts on the function of the said pathway, in particular a mutation in ⁇ -catenin and/or the gene encoding the same CTNNB1, including genetic alteration, including missense mutations and amplification.
  • the ⁇ -catenin mutation is T41A.
  • the T41A ⁇ -catenin mutation is thought to be constitutively active.
  • a pan-HER inhibitor such as Varlitinib in high p-ErbB2/3 expressing cancers, such as hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • the present inventors have shown that Varlitinib can selectively target cancers that have the T41A ⁇ - catenin mutation.
  • cancer patients such as HCC patients with the T41A CTNNB1 mutation may represent a specific patient population subset that is particularly responsive to treatment with a pan-HER inhibitor, such as Varlitinib.
  • HER2 and/or HER3 activated as employed herein refers to where the cancer expresses an increased level of said receptor, such as total levels of the receptor and/or levels of the activated form of the receptor, such as the phosphorylated form of the receptor, in comparison a corresponding non-cancerous cell and includes any of the following:
  • Phospho-ErbB2/p-ErbB2 or phospho-ErbB3/p-ErbB3 as used herein refers to the phosphorylated form of ErbB2 or ErbB3 respectively. It includes phosphorylation of the receptor at any suitable phosphorylation site.
  • Known phosphorylation sites for ErbB2 include but are not limited to: Tyr 877, Tyrl023, Tyrll39, Tyrll96, Tyrl221, Tyrl222 and Tyrl248.
  • Known phosphorylation sites for ErbB3 include but are not limited to Tyrl054, Tyrll97, Tyrll99, Tyrl222, Tyrl260, Tyrl262, Tyrl289 and Tyrl328.
  • phospho-ErbB2 refers to ErbB2 which has been phosphorylated at
  • phospho-ErbB3 refers to ErbB3 which has been phosphorylated at Tyrl289.
  • increased levels as employed herein refers to a level that is at least 1, 2 or 3, such as 2 standard deviations higher than the mean level in a non-cancerous cell.
  • increased levels as employed herein refers to a level that is above the level of the 95 th percentile of a population of non-cancerous cells. "In a patient population” refers to administration of the therapy to a patient characterised
  • identification in the context of the present disclosure refer to the patient is known to be in the requisite patient population before the administration of the therapy according to the present disclosure.
  • Liver cancer refers to cancer which starts in the liver, including starting from structures located within the liver, such as blood vessels, including hepatocellular carcinoma.
  • the liver cancer is, for example selected from the group hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, and hepatoblastoma, in particular hepatocellular carcinoma.
  • the primary liver cancer is stage 1, 2, 3 or 4.
  • the liver cancer is secondary or metastasized liver cancer.
  • liver cancer does not include biliary tract cancer, such as cholangiocarcinoma.
  • the cancer is liver cancer, for example a liver metastasis from a primary cancer, for example colon cancer, which has spread to the liver.
  • the liver cancer is HCC hepatocellular carcinoma.
  • Biliary duct cancer also referred to as biliary cancer as employed herein refers to cancer which starts in the bile ducts and includes cholangiocarcinoma and gallbladder cancer.
  • Cholangiocarcinoma as referred to herein is a form of cancer that is composed of mutated epithelial cells (or cells showing characteristics of epithelial differentiation) that originate in the bile ducts which drain bile from the liver into the small intestine, but not including gallbladder cancer.
  • biliary duct cancer General guidelines for operability of biliary duct cancer include: Absence of lymph node or liver metastases; Absence of involvement of the portal vein; Absence of direct invasion of adjacent organs; and Absence of widespread metastatic disease.
  • the cancer is gall bladder cancer.
  • Gallbladder cancer as employed herein cancer which starts in the gallbladder. The following stages are used for gallbladder cancer:
  • Stage 0 (carcinoma in situ): Abnormal cells are found in the inner (mucosal) layer of the gallbladder; these abnormal cells may become cancer and spread into nearby normal tissue; Stage I Cancer has formed and has spread beyond the inner (mucosal) layer to a layer of tissue with blood vessels or to the muscle layer; Stage II Cancer has spread beyond the muscle layer to the connective tissue around the muscle; Stage IIIA Cancer has spread through the thin layers of tissue that cover the gallbladder and/or to the liver and/or to one nearby organ (e.g., stomach, small intestine, colon, pancreas, or bile ducts outside the liver); Stage IIIB Cancer has spread to nearby lymph nodes and beyond the inner layer of the gallbladder to a layer of tissue with blood vessels or to the muscle layer; or beyond the muscle layer to the connective tissue around the muscle; or through the thin layers of tissue that cover the gallbladder and/or to the liver and/or to one nearby organ; Stage IVA Cancer has spread to a main blood vessel
  • the gastric cancer may have spread to nearby lymph nodes; and Stage IVB Cancer has spread to either lymph nodes along large arteries in the abdomen and /or near the lower part of the backbone or to organs or areas far away from the gallbladder.
  • the gastric cancer is selected from the group comprising adenocarcinoma of the stomach, squamous cell carcinomas, lymphoma of the stomach, gastric stromal tumor, and neuroendocrine tumors.
  • Prostate cancer refers to cancer of the prostate, for example ductal adenocarcinoma, transitional cell (urothelial cancer], squamous cell cancer, carcinoid of the prostate, small cell cancer or sarcoma and sarcomatoid cancer.
  • the prostate cancer is any one of the same.
  • Pancreatic cancer as employed herein includes exocrine cancers (including rare forms thereof such as cystitic tumours, and cancer of the acinar cells), endocrine pancreatic tumours (including gastrinomas, insulinomas, somatostatinomas, VIPomas, glucagonomas), pancreatoblastoma, sarcomas of the pancreas and lymphoma.
  • Colorectal cancer refers to cancer or the colon and/or rectum and includes squamous cell cancers, carcinoid tumours, sarcomas and lymphomas.
  • Breast cancer as employed herein refers to cancer of the breast and includes ductal cardinoma in situ, lobular carcinoma in situ, invasive ductal breast cancer, invasive lobular breast cancer, invasive breast cancer, Paget's disease, angiosarcoma of the breast and rare types of breast cancer such as medullary breast cancer, mucinous breast cancer, tubular breast cancer, adenoid cystic carcinoma of the breast metaplastic breast cancer, basal type breast cancer and papillary breast cancer.
  • the breast cancer is one selected from any one of the same.
  • the breast cancer is phyllodes or cystosarcoma phyllodes.
  • Lung cancers are classified according to histological type and are categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope.
  • two broad classes are distinguished: non-small cell lung carcinoma and small cell lung carcinoma.
  • the epithelial cancer is lung cancer, for example selected from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), such as NSCLC.
  • SCLC small-cell lung cancer
  • NSCLC non-small-cell lung cancer
  • Non-small-cell lung carcinoma The three main subtypes of NSCLC are adenocarcinoma, squamous-cell carcinoma and large-cell carcinoma.
  • adenocarcinoma Nearly 40% of lung cancers are adenocarcinoma, which usually originates in peripheral lung tissue.
  • a subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have a better long term survival.
  • Squamous-cell carcinoma accounts for about 30% of lung cancers. They typically occur close to large airways. A hollow cavity and associated cell death are commonly found at the center of the tumor. About 9% of lung cancers are large-cell carcinoma. These are so named because the cancer cells are large, with excess cytoplasm, large nuclei and conspicuous nucleoli.
  • SCLC Small-cell lung carcinonia-In small-cell lung carcinoma
  • the cells contain dense neurosecretory granules (vesicles containing neuroendocrine hormones), which give this tumor an endocrine/paraneoplastic syndrome association.
  • These cancers grow quickly and spread early in the course of the disease. Sixty to seventy percent have metastatic disease at presentation.
  • the cancer is non-small lung carcinoma.
  • treatment of renal cancer for example renal cell carcinoma and/or urothelial cell carcinoma.
  • renal cancer include squamous cell carcinoma, juxtaglomerular cell tumor [reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma, Wilms' tumor, mixed epithelial stromal tumor, clear cell adenocarcinoma, transitional cell carcinoma, inverted papilloma, renal lymphoma, teratoma, carcinosarcoma, and carcinoid tumor of the renal pelvis.
  • Renal cancer as employed herein refers to cancer of the kidney
  • the cancer is bladder cancer, for example is any of several types of malignancy arising from the epithelial lining (i.e., the urothelium) of the urinary bladder.
  • the epithelial lining i.e., the urothelium
  • the bladder cancers are transitional cell carcinoma.
  • the other 10% are squamous cell carcinoma, adenocarcinoma, sarcoma, small cell carcinoma, and secondary deposits from cancers elsewhere in the body.
  • the staging of is given below.
  • NX Regional lymph nodes cannot be assessed; NO No regional lymph node metastasis; Nl Metastasis in a single lymph node 2 cm or less in greatest dimension; N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension; N3 Metastasis in a lymph node more than 5 cm in greatest dimension
  • the current disclosure extends to any stage of bladder cancer.
  • Cancerous ovarian tumors can start from three common cell types: Surface Epithelium - cells covering the lining of the ovaries; Germ Cells - cells that are destined to form eggs; and Stromal Cells - Cells that release hormones and connect the different structures of the ovaries.
  • the present disclosure relates to treatment of ovarian cancer from any source, for example as described herein, in particular epithelium cells.
  • Epithelial ovarian carcinomas account for 85 to 90 percent of all cancers of the ovaries.
  • Epithelial ovarian tumors develop from the cells that cover the outer surface of the ovary. Most epithelial ovarian tumors are benign (noncancerous). There are several types of benign epithelial tumors, including serous adenomas, mucinous adenomas, and Brenner tumors. Cancerous epithelial tumors are carcinomas - meaning they begin in the tissue that lines the ovaries. These are the most common and most dangerous of all types of ovarian cancers. Unfortunately, almost 70 percent of women with the common epithelial ovarian cancer are not diagnosed until the disease is advanced in stage.
  • LMP tumors ovarian epithelial tumors whose appearance under the microscope does not clearly identify them as cancerous. These are called borderline tumors or tumors of low malignant potential (LMP tumors). The present disclosure includes treatment of the latter.
  • Germ Cell Tumors Ovarian germ cell tumors develop from the cells that produce the ova or eggs. Most germ cell tumors are benign (non-cancerous), although some are cancerous and may be life threatening. The most common germ cell malignancies are maturing teratomas, dysgerminomas, and endodermal sinus tumors. Germ cell malignancies occur most often in teenagers and women in their twenties. Today, 90 percent of patients with ovarian germ cell malignancies can be cured and their fertility preserved.
  • Stromal Tumors - Ovarian stromal tumors are a rare class of tumors that develop from connective tissue cells that hold the ovary together and those that produce the female hormones, estrogen and progesterone. The most common types are granulosa-theca tumors and Sertoli- Ley dig cell tumors. These tumors are quite rare and are usually considered low-grade cancers, with approximately 70 percent presenting as Stage I disease (cancer is limited to one or both ovaries).
  • Primary Peritoneal Carcinoma The removal of one's ovaries eliminates the risk for ovarian cancer, but not the risk for a less common cancer called Primary Peritoneal Carcinoma.
  • Primary Peritoneal Carcinoma is closely rated to epithelial ovarian cancer (most common type). It develops in cells from the peritoneum (abdominal lining) and looks the same under a microscope. It is similar in symptoms, spread and treatment.
  • stage of a tumor can be determined during surgery, when the doctor can tell if the cancer has spread outside the ovaries.
  • the treatment plan and prognosis (the probable course and outcome of your disease) will be determined by the stage of cancer you have.
  • Stage I - Growth of the cancer is limited to the ovary or ovaries.
  • Stage IA - Growth is limited to one ovary and the tumor is confined to the inside of the ovary. There is no cancer on the outer surface of the ovary. There are no ascites present containing malignant cells. The capsule is intact.
  • Stage IB - Growth is limited to both ovaries without any tumor on their outer surfaces. There are no ascites present containing malignant cells. The capsule is intact.
  • Stage IC The tumor is classified as either Stage IA or IB and one or more of the following are present: (1) tumor is present on the outer surface of one or both ovaries; (2) the capsule has ruptured; and (3) there are ascites containing malignant cells or with positive peritoneal washings.
  • Stage II - Growth of the cancer involves one or both ovaries with pelvic extension.
  • Stage HA The cancer has extended to and/or involves the uterus or the fallopian tubes, or both.
  • Stage IIB The cancer has extended to other pelvic organs.
  • Stage IIC The tumor is classified as either Stage HA or IIB and one or more of the following are present: (1] tumor is present on the outer surface of one or both ovaries; (2 ⁇ the capsule has ruptured; and (3) there are ascites containing malignant cells or with positive peritoneal washings.
  • Stage III - Growth of the cancer involves one or both ovaries, and one or both of the following are present: (1) the cancer has spread beyond the pelvis to the lining of the abdomen; and [2) the cancer has spread to lymph nodes.
  • the tumor is limited to the true pelvis but with histologically proven malignant extension to the small bowel or omentum.
  • Stage IIIA - During the staging operation, the practitioner can see cancer involving one or both of the ovaries, but no cancer is grossly visible in the abdomen and it has not spread to lymph nodes. However, when biopsies are checked under a microscope, very small deposits of cancer are found in the abdominal peritoneal surfaces.
  • Stage IIIB The tumor is in one or both ovaries, and deposits of cancer are present in the abdomen that are large enough for the surgeon to see but not exceeding 2 cm in diameter. The cancer has not spread to the lymph nodes.
  • Stage IIIC The tumor is in one or both ovaries, and one or both of the following is present: (1) the cancer has spread to lymph nodes; and/or (2) the deposits of cancer exceed 2 cm in diameter and are found in the abdomen.
  • Stage IV This is the most advanced stage of ovarian cancer. Growth of the cancer involves one or both ovaries and distant metastases [spread of the cancer to organs located outside of the peritoneal cavity) have occurred. Finding ovarian cancer cells in pleural fluid [from the cavity which surrounds the lungs) is also evidence of stage IV disease.
  • the ovarian cancer is: type I, for example IA, IB or IC; type II, for example IIA, IIB or IIC; type III, for example IIIA, IIIB or IIIC; or type IV.
  • Thyroid cancer refers to cancer of the thyroid originating from follicular or parafollicular thyroid cells and includes papillary thyroid cancer [75% to 85% of cases); follicular thyroid cancer [10% to 20% of cases); medullary thyroid cancer [5% to 8% of cases)- cancer of the parafollicular cells, often part of multiple endocrine neoplasia type 2; poorly differentiated thyroid cancer; anaplastic thyroid cancer [less than 5% of cases) is not responsive to treatment and can cause pressure symptoms, thyroid lymphoma, squamous cell thyroid carcinoma, sarcoma of thyroid.
  • the present disclosure extends to treatment of thyroid cancer.
  • Bladder cancer as employed herein refers to cancer of the bladder including transitional cell bladder cancer, carcinoma in situ, papillary cancer and rarer types of bladder cancer such as squamous cell cancer and adenocarcinoma.
  • the present disclosure extends to treatment of bladder cancer.
  • Esophageal cancer refers to cancer of the oesphagus including esophageal squamous-cell carcinomas, esophageal adenocarcinomas, and variants of squamous-cell carcinoma, and non-epithelial tumors, such as leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, lymphoma, among others.
  • the present disclosure relates to treatment of the esphageal cancer.
  • Head and neck cancer as employed herein refers to cancer of the neck and/or head, including mouth cancer, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus cancer and salivary gland cancer.
  • the present disclosure includes treatment of head and neck cancer.
  • the treatment of the present disclosure is neo-adjuvant therapy, for example to shrink the tumour/carcinoma before surgery to remove the cancerous tissue or before chemotherapy to improve the chances of success of the latter or to reduce the severity of the treatment required.
  • the treatment of the present disclosure is adjuvant therapy, for example following surgery to remove the cancerous tissue.
  • the treatment of the present disclosure is adjuvant therapy, for example following chemotherapy
  • combination adjuvant therapy comprising a compound of formula (I) and chemotherapy or radiotherapy.
  • First line therapy as employed herein is the first therapy employed for the treatment of the cancer and in some instances the first line therapy may be neo-adjuvant therapy, in this context surgery will generally be considered a treatment.
  • Second line therapy as employed herein is treatment following first line therapy and may be adjuvant therapy.
  • second line therapy is simply therapy other than first line therapy and includes, third line therapy, fourth line therapy etc.
  • Monotherapy as employed herein is wherein the compound of formula (I) an enantiomer thereof and/or a pharmaceutically acceptable salt thereof, is the only active agent being administered to the patient for the treatment of cancer.
  • treatment according to the present disclosure with a combination therapy comprising Varlitinib, for example Varlitinib and an anti-cancer therapy, such as chemotherapy.
  • a combination therapy comprising Varlitinib, for example Varlitinib and an anti-cancer therapy, such as chemotherapy.
  • Combination therapy refers to wherein the compound of formula [I) an enantiomer thereof or a pharmaceutically acceptable salt thereof is employed for the treatment of the cancer in conjunction with one or more further anticancer treatments, for example where the treatment regimens for the two or more active anticancer agents overlap or where the two or more anticancer agents are administered concomitantly.
  • the combination therapy according to the present disclosure comprises a RON inhibitor, for example as disclosed WO2008/058229, incorporated herein by reference.
  • the combination therapy comprises a checkpoint inhibitor, such as a CTLA4 inhibitor, a PD-1 inhibitor or a PD-Ll inhibitor, in particular an antibody or binding fragment thereof.
  • a checkpoint inhibitor such as a CTLA4 inhibitor, a PD-1 inhibitor or a PD-Ll inhibitor, in particular an antibody or binding fragment thereof.
  • Examples of pharmaceutically acceptable salts include but are not limited to acid addition salts of strong mineral acids such as HC1 and HBr salts and addition salts of strong organic acids, such as a methansulfonic acid salt, tosylates, furoates and the like, including di, tri salts thereof, such as ditosylates.
  • Chemotherapeutic agent and chemotherapy or cytotoxic agent are employed interchangeably herein unless the context indicates otherwise.
  • Chemotherapy as employed herein is intended to refer to specific antineoplastic chemical agents or drugs that are "selectively" destructive to malignant cells and tissues, for example alkylating agents, antimetabolites including thymidylate synthase inhibitors, anthracyclines, anti- microtubule agents including plant alkaloids, taxanes, topoisomerase inhibitors, parp inhibitors and other antitumour agents. Selectively in this context is used loosely because of course many of these agents have serious side effects.
  • the preferred dose may be chosen by the practitioner, based on the nature of the cancer being treated.
  • alkylating agents which may be employed in the method of the present disclosure include a platinum alkylating agent, nitrogen mustards, nitrosoureas, tetrazines, aziridines, platins and derivatives, and non-classical alkylating agents (such as procarbazine, altretamine and dacarbazine).
  • platinum containing chemotherapeutic agents include cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin and lipoplatin (a liposomal version of cisplatin), in particular cisplatin, carboplatin and oxaliplatin.
  • Others include eptaplatin, lobaplatin, miriplatin and dicycloplatin.
  • the dose for cisplatin ranges from about 20 to about 270 mg/m 2 depending on the exact cancer. Often the dose is in the range about 70 to about 100mg/m 2 .
  • Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan.
  • Nitrosoureas include V-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU] and semustine (MeCCNU), fotemustine and streptozotocin.
  • Tetrazines include dacarbazine, mitozolomide and temozolomide.
  • Aziridines include thiotepa, mytomycin and diaziquone (AZQ).
  • antimetabolites examples include anti-folates (for example methotrexate and pemetrexed), purine analogues (for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fludarabine (including the phosphate form), pentostatin and cladribine), pyrimidine analogues (for example fluoropyrimidines, such as 5-fluorouracil (5-FU) and prodrugs thereof such as capecitabine [Xeloda®]), floxuridine, gemcitabine, cytarabine, decitabine, raltitrexed (tomudex) hydrochloride, cladribine and 6-azauracil.
  • anti-folates for example methotrexate and pemetrexed
  • purine analogues for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fludarabine (including the
  • anthracyclines examples include daunorubicin (Daunomycin), daunorubicin (liposomal), doxorubicin (Adriamycin), doxorubicin [liposomal), epirubicin, idarubicin, valrubicin currently are used only to treat bladder cancer and mitoxantrone an anthracycline analog, in particular doxorubicin.
  • anti-microtubule agents examples include vinca alkaloids and taxanes.
  • Vinca alkaloids include completely natural chemicals for example vincristine and vinblastine and also semi-synthetic vinca alkaloids, for example vinorelbine, vindesine, and vinflunine
  • Taxanes include paclitaxel, docetaxel, abraxane, carbazitaxel and derivatives of thereof.
  • Derivatives of taxanes as employed herein includes reformulations of taxanes like taxol, for example in a micelluar formulations, derivatives also include chemical derivatives wherein synthetic chemistry is employed to modify a starting material which is a taxane.
  • Topoisomerase inhibitors which may be employed in a method of the present disclosure include type I topoisomerase inhibitors, type II topoisomerase inhibitors and type II topoisomerase poisons.
  • Type I inhibitors include topotecan, irinotecan, indotecan and indimitecan.
  • Type II inhibitors include genistein and ICR ng structure:
  • Type II poisons include amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin and fluoroquinolones.
  • the chemotherapeutic is a PARP inhibitor.
  • chemotherapeutic agents employed is, for example a platin and 5-FU or a prodrug thereof, for example cisplatin or oxaplatin and capecitabine or gemcitabine, such as FOLFOX.
  • the chemotherapy comprises a combination of chemotherapy agents, in particular cytotoxic chemotherapeutic agents.
  • the chemotherapy combination comprises a platin, such as cisplatin and fluorouracil or capecitabine.
  • the chemotherapy combination is capecitabine and oxaliplatin [XELOX].
  • the chemotherapy is a combination of folinic acid and 5-FU, optionally in combination with oxaliplatin (FOLFOX).
  • the chemotherapy is a combination of folinic acid, 5-FU and irinotecan (FOLFIRI), optionally in combination with oxaliplatin (FOLFIRINOX).
  • the regimen for example includes: irinotecan (180 mg/m 2 IV over 90 minutes) concurrently with folinic acid (400 mg/m 2 [or 2 x 250 mg/m 2 ] IV over 120 minutes); followed by fluorouracil (400-500 mg/m 2 IV bolus) then fluorouracil (2400-3000 mg/m 2 intravenous infusion over 46 hours). This cycle is typically repeated every two weeks.
  • the dosages shown above may vary from cycle to cycle.
  • the combination therapy employs a microtubule inhibitor, for example vincristine sulphate, epothilone A, N-[2-[(4-Hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide (ABT-751), a taxol derived chemotherapeutic agent, for example paclitaxel, abraxane, or docetaxel or a combination thereof.
  • the combination therapy employs an mTor inhibitor.
  • mTor inhibitors include: everolimus (RAD001), WYE-354, KU-0063794, papamycin (Sirolimus), Temsirolimus, Deforolimus(MK-8669), AZD8055 and BEZ235(NVP-BEZ235).
  • the combination therapy employs a MEK inhibitor.
  • MEK inhibitors include: AS703026, CI-1040 (PD184352), AZD6244 (Selumetinib), PD318088, PD0325901, AZD8330, PD98059, U0126-EtOH, BIX 02189 or BIX 02188.
  • the combination therapy employs an AKT inhibitor.
  • AKT inhibitors include: MK-2206 and AT7867.
  • the combination therapy employs an aurora kinase inhibitor.
  • aurora kinase inhibitors include: Aurora A Inhibitor I, VX-680, AZD1152-HQPA (Barasertib], SNS- 314 Mesylate, PHA-680632, ZM-447439, CCT129202 and Hesperadin.
  • the chemotherapy combination employs a p38 inhibitor, for example as disclosed in W02010/038086, such as N-[4-( ⁇ 4-[3-(3-teri-Butyl-l-p-tolyl-ltf-pyrazol-5- yl)ureido]naphthalen-l-yloxy ⁇ methyl)pyridin-2-yl]-2-methoxyacetamide.
  • a p38 inhibitor for example as disclosed in W02010/038086, such as N-[4-( ⁇ 4-[3-(3-teri-Butyl-l-p-tolyl-ltf-pyrazol-5- yl)ureido]naphthalen-l-yloxy ⁇ methyl)pyridin-2-yl]-2-methoxyacetamide.
  • the combination therapy employs a Bcl-2 inhibitor.
  • Bcl-2 inhibitors include: obatoclax mesylate, ABT-737, ABT-263(navitoclax) and TW-37.
  • the combination therapy comprises an antimetabolite such as capecitabine (xeloda), fludarabine phosphate, fludarabine (fludara), decitabine, raltitrexed (tomudex], gemcitabine hydrochloride and/or cladribine.
  • an antimetabolite such as capecitabine (xeloda), fludarabine phosphate, fludarabine (fludara), decitabine, raltitrexed (tomudex], gemcitabine hydrochloride and/or cladribine.
  • the combination therapy comprises ganciclovir, which may assist in controlling immune responses and/or tumour vasculation.
  • a monotherapy comprising a compound of formula (I), such as Varlitinib (as defined herein including doses described above) is employed, for example a maintenance therapy.
  • a monotherapy comprising a compound of formula (I), such as Varlitinib (as defined herein including doses described above) is employed, for example a maintenance therapy.
  • the combination therapy comprises a checkpoint inhibitor, for example selected from the group comprising:
  • AZD-7762 a CHK1 and CHK2 inhibitor (with competitive CHK1 inhibitor with a Ki of 0.49 nM an IC50 of about 5 nM in a cell-free assay, with in a cell free assay.
  • the molecule also VEGFR2, less potent activity against CAM, Yes, Fyn, Lyn, Aurora-A, FGFR3, Flt3, Fms (CSF-1R], Ret and Hck an Lck) Yes. It shows approximately 100 fold selectivity for CHK1 over CHK2)
  • V155422, V155991 and V158411 are CHKl and CHK2 inhibitors
  • LY2603618 is a selective potent CHKl inhibitor MK -8776 is a selective CHKl inhibitor
  • CHIR124 is CHKl inhibitor (is a novel and potent The molecule shows 500-fold selectivity inhibitor with IC50 of 0.3 nM in a cell-free assay. against CHK2) It shows 2,000-fold selectivity against CHK2 and
  • CP-466722 is a potent ATM inhibitor, which does not inhibit ATR.
  • the molecule and PIKK are a potent ATM inhibitor, which does not inhibit ATR.
  • KU55933 is a potent and selective ATM inhibitor (vis-a-vie DNA-PK, Pi3K/Pi4K, ATR and mTOR) with an IC50 of 13 nM and KI of 2.2 mM
  • KU60019 is an ATM inhibitor
  • N U6027 is a potent ATR inhibitor
  • VE-821 is a potent and selective ATP competitive inhibitor of ATR with a Ki of 13 nM and an IC50 of 26 nM
  • CCT241533 is a CHK2 inhibitor with about 63 fold selectivity over CHK1
  • BMN-673 (Talazoparib) a PARP-1 and
  • PAR-2 inhibitor (which is currently in Phase III trials for ovarian, breast and other solid cancers)
  • BGP-15 a PARP inhibitor (which has been E7016 (previously known as GPI-21016) a shown to protect against ischemia-reperfusion PARP inhibitor (undergoing Phase I trials in injury) combination with temozolomide for
  • INO-1001 (3-aminobenzamide) a potent inhibitor of PARP [with IC50 of ⁇ 50 nM in CHO cells and a mediator of oxidant-induced myocyte dysfunction during
  • checkpoint inhibitors Drugs Fut 2003, 28(9): 881 Cell cycle inhibitors for the treatment of cancer Kong, N., Fotouhi, N., Wovkulich, P.M., Roberts, J; Novel pyrrole derivatives as selective CHK1 inhibitors: design, regioselective synthesis and molecular modelling Med. Chem. Commun., 2015,6, 852-859; PLoS One 2010; 5(8): el2214. Binding of protein kinase inhibitors to synapsin I inferred from pair-wise binding site similarity measurements.
  • the checkpoint inhibitor is a PARP inhibitor.
  • the checkpoint inhibitor is an antibody or binding fragment specific to a checkpoint protein, in particular one disclosed herein.
  • the checkpoint kinase inhibitor is independently selected from: 3- [(Aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide hydrochloride; (3R,4S)-4-[[2-(5-Fluoro-2-hydroxyphenyl)-6,7-dimethoxy-4-quinazolinyl]amino]- a,a-dimethyl-3-pyrrolidinemethanol dihydrochloride; 4,4'-diacetyldiphenylurea bis(guanylhydrazone) ditosylate; 9-Hydroxy-4-phenyl-pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; (R)- -Amino-N-[5,6-dihydro-2-(l-methyl-lH-pyrazol-4-yl)-6-o
  • check point inhibitor is prexasertib.
  • Checkpoint kinase inhibitor as employed herein refers to an inhibitor that reduces or eliminates the biological activity of a cell regulatory checkpoint kinase 1 and/or 2.
  • Cells that suffer DNA damage activate the checkpoint kinases CHKl and CHK2, which signal to initiate the DNA repair processes, limit cell-cycle progression and prevent cell replication, until the damaged DNA is repaired.
  • Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.
  • FIG. 1 ErbB family expression and its phosphorylation in representative HCC PDXs and the anti-tumour effects of Varlitinib on 3 PDXs with activated ErbB2/3.
  • a and B Western blot shows the expression of EGFR, ErbB2, ErbB3, and its phosphorylation in representative HCC PDXs.
  • HCC29-0909A PDX model Mice bearing HCC29-0909A PDX were treated with vehicle control, 25, 50, or lOOmg/kg BID. Tumours were collected at day 2 (A) and day 14 (B) post-Varlitinib treatment. Two tumours from each condition were lysed and equal amount of the protein lysates were used for Western blot analysis. Blots were incubated with indicated antibodies. Representative blots were shown.
  • FIG. 3 Effects of Varlitinib on tumour cell proliferation, tumour cell death, and vessel normalisation in HCC29-0909A PDX model.
  • Mice bearing HCC29-0909A PDX were treated with vehicle control and lOOmg/kg BID.
  • Tumours collected at day 14 were processed for paraffin [for cleaved PARP and p-histone 3 SerlO staining] or Tissue-Tek embedding (for CD31 staining).
  • A Representative images of tumour sections from vehicle-treated and Varlitinib-treated mice stained for p-Histone H3 (SerlO), cleaved PARP, and CD31.
  • HCC PDX models The area-proportional Venn diagram analysis showing the common activated genes (left) and the common repressed genes (right in lOOmg/kg BID and 50mg/kg BID Varlitinib-treated HCC29-0909A model for 14 days.
  • B The heatmap showing the common Varlitinib-dysregulated 2331 genes in HCC29-0909A model.
  • C The area-proportional Venn diagram analysis showing the common activated genes (left) and the common repressed genes (right) in lOOmg/kg BID and 50mg/kg BID Varlitinib-treated HCCOl-0708 model.
  • FIG. 5 Dose-dependent ⁇ -catenin pathway inhibition and membrane translocation of ⁇ -catenin by Varlitinib in the tested HCC29-0909A and HCCOl-0708 PDX models.
  • Treatment was started when the tumours reached the size of approximately 120-150 mm 3 .
  • Two tumours from each condition were lysed and equal amount of the protein lysates were used for Western blot analysis for the ⁇ -catenin, its related signalling molecules, and downstream targets of ⁇ -catenin.
  • C Representative images of tumour sections from vehicle-treated (top) and Varlitinib-treated (bottom) HCC29- 0909A, HCC07-0409, and HCCOl-0708 PDXs stained for ⁇ -catenin.
  • FIG. 7 ErbB family expression in additional 28 hepatocellular carcinoma (HCC) patient-derived xenografts (PDXs) and the anti-tumour effects of Varlitinib on the high ErbB2 /3-expressing PDXs.
  • HCC hepatocellular carcinoma
  • PDXs patient-derived xenografts
  • a and B Western blot shows the expression of EGFR, EbB2, ErbB3, and its phosphorylation in 28 HCC PDXs.
  • HCCOl-0708 PDX model Mice bearing HCCOl-0708 PDX were treated with vehicle control, 25, 50, or lOOmg/kg BID. Tumours were collected at day 2 (A) and day 11 (B) post-Varlitinib treatment. Two tumours from each condition were lysed and equal amount of the protein lysates were used for Western blot analysis. Blots were incubated with indicated antibodies. Representative blots were shown.
  • HCC29-0909A PDX Dose-dependent inhibition of tumour cell proliferation, induction of apoptosis and formation of capillary-like blood vessels by Varlitinib in HCC29-0909A PDX model.
  • Mice bearing HCC29-0909A PDX were treated with vehicle control, 25, 50, or lOOmg/kg BID.
  • Tumours collected at day 14 were processed for paraffin [for cleaved PARP and p-histone 3 SerlO staining] or Tissue-Tek embedding (for CD31 staining).
  • Tumour regression by Varlitinib treatment in three other PDX models HCC01- 0708, HCC07-0409, and HCC21-0208.
  • Mice bearing indicated PDX were treated with vehicle control or lOOmg/kg BID.
  • Tumours collected at indicated day were processed for paraffin [for cleaved PARP and p-histone 3 SerlO staining] or Tissue- Tek embedding (for CD31 staining).
  • PLC/PRF/5, Hep3B, HepG2/C3A, and Huh7 are ERBB3H ⁇ gh cell lines and SNU182, SNU423, SNU449, and SNU475 are ERBB3Low cell lines.
  • Different doses of Varlitinib in normal culture medium with 1% DMSO were added into the 6-well plates seeded with different cell lines. The cell lines were cultured for 2-4 weeks, followed by fixation and Giemsa staining.
  • C Inhibition of ErbB receptor family and their downstream signalling molecules by Varlitinib.
  • the £7?Bi?J?High PLC/PRF/5 cell line was treated with 3 ⁇ of Varlitinib for indicated time. Blots were incubated with indicated antibodies. a-Tubulin was used as equal loading marker. See also Figure 25.
  • Varlitinib responder and non-responder PDXs Identification of Varlitinib responder and non-responder PDXs and the importance of ErbB2/3 dependence in HCC.
  • A In vivo effect of Varlitinib in treated PDXs.
  • FIG. 23 Transcriptomic analysis identifies dose-dependant responses and the potential inhibition mechanisms in responder PDXs.
  • A Three-way area proportional Venn diagram analysis of differential expressed gene (DEG) analysis from RNA-Seq analysed Varlitinib-treated PDXs.
  • B The normalised read counts were analysed based on gene sets of glycolysis and gluconeogenesis (left) and hypoxia (right). Data from control (indicated in blue box), 50mg/kg (indicated in red box), and lOOmg/kg BID (indicated in green box) ofVarlitinib-treated HCC29-0909A are shown.
  • PDXs Dose-dependent ⁇ -catenin pathway inhibition by Varlitinib. Western blot analysis of the protein lysates collected on day 14 post-treatment of Varlitinib in HCC29-0909A (A) and on day 11 post-treatment of Varlitinib in HCCOl-0708 (B). Two tumours from each condition were lysed and equal amount of the protein lysates were used for Western blot analysis. Blots were incubated with indicated antibodies. a-Tubulin was used as equal loading marker. Representative blots were shown. See also Figure 30. Analysis of ERBB3 m and ERBB3 Low liver cancer cell lines.
  • Varlitinib treatment in HCC PDXs (A) ErbB family expression in 56 HCC (PDXs. Western blot shows the expression of EGFR, ErbB2, ErbB3, and its phosphorylation in 56 HCC PDXs. Blots were incubated with indicated antibodies. ⁇ -Tubulin was used as equal loading marker. (B) In vivo effect of Varlitinib in treated non-responder PDXs.
  • C Principal component analysis ofquantile normalised gene expression dataset Smaller circle indicates Varlitinib responders, larger circle circle indicates non-responders. Triplicate samples of 3 responder PDXs and 9 non- responder PDXs were analysed by Affymetrix Human Genome U133 Plus 2.0 microarray.
  • D Heatmap of the DEG.
  • K Heatmap of the inhibition of embryonic stem cell core gene set in Varlitinib- treated HCCOl-0708. Control of HCC29-0909A, Control of HCC16-1014, and Varlitinib-treated HCC16-1014 are included for the comparison.
  • PDX models Western blot analysis of the protein lysates collected on day 14 post- treatment of lOOmg/kg QD Varlitinib in HCC07-0409 PDX model. Two tumours from each condition were lysed and equal amount of the protein lysates were used. Blots were incubated with indicated antibodies. a-Tubulin was used as equal loading marker. Representative blots were shown.
  • PDXs. (A-B) ⁇ -catenin pathway inhibition by Varlitinib.
  • Figure 31 shows hypothetical model of the Varlitinib-mediated tumour growth inhibition and vessel normalisation in HCC.
  • the antibodies against ERK1/2 and a-tubulin were from Santa Cruz Biotechnology Inc, Santa Cruz, CA, USA.
  • Anti-mouse CD31 antibody was from BioLegend, San Diego, CA, USA.
  • Varlitinib was obtained from ASLAN Pharmaceuticals Ltd, Singapore.
  • HCC tumours have previously been used to create patient-derived xenograft models(Huynh et al., 2006) of which the 56 models were used to screen for the expression of EGFR, ErbB2, ErbB3, p-EGFR, p-ErbB2 and p-ErbB3 by Western blot analysis.
  • mice bearing the HCC29-0909A, HCC07-0409, and HCC01- 0708 xenografts (8-10 mice per group) were orally given vehicle [3 parts Polyethylene glycol) average Mn 300 (PEG, Aldrich Cat#202371) and 7 parts 30% w/v Research Grade Captisol (Ligand Pharmaceuticals, San Diego, CA) or 3 doses of Varlitinib (25 or 50, 75 and 100 mg/kg BID) for indicated days. Treatment started when the tumours reached the size of approximately 120-150 mm 3 .
  • tumour xenografts received intravenously with 100 mg of Biotinylated Lycopersicon Esculentum (Tomato) Lectin (VectorLabs #B-1175) prepared in 100 ⁇ of 0.9% NaCl.
  • Tomato Biotinylated Lycopersicon Esculentum
  • the tumours were harvested 10 minutes after lectin perfusion, fixed in 10 % formalin buffer solution, embedded in paraffin.
  • Five ⁇ sections were prepared. After blocking endogenous peroxidase activity and nonspecific staining, the sections were incubated 1 hour at room temperature with Streptavidin Peroxidase (Lab Vision Corporation, Fremont, CA).
  • mice bearing indicated tumours were treated with vehicle, or 100 mg/kg Varlitinib BID for indicated days.
  • Mice were i.p. injected with pimonidazole hydrochloride (60 mg/kg, 2.5 ⁇ /g of mouse body weight) 1 hour before tumours harvested. Hypoxic regions of tumour were identified by staining the sections with Hypoxyprobe plus Kit HP2 (Chemicon) as described by the manufacturer.
  • RNA samples would be contaminated with mouse cells due to the growth of PDXs in immunocompromised SCID mouse, an extra filtering step to remove mouse component was introduced.
  • the raw sequencing reads were aligned to hgl9_mml0 mixed reference by Burrows-Wheeler Aligner (BWA) and the read pairs were removed as long as any of the paired reads mapped to mmlO chromosome and/or rRNA sequence to filter mouse contamination and rRNA reads, respectively.
  • BWA Burrows-Wheeler Aligner
  • the detected mouse read rates at genome and gene levels ranged from 0.68% to 11.2% and 0.21% to 5.12%, respectively. In average, 74 million to 90 million clean reads per sample were obtained.
  • the BAM files were then uploaded to Partek Flow for further analysis. Aligned reads were quantify to Partek E/M annotation model in Partek Flow (Partek Inc. St. Louis, MO, USA), followed by total count and add 0.0001 normalisation of gene counts and GSA differential expression detection from the comparisons of 50mg/kg varlitinib treatment vs control and lOOmg/kg varlitinib treatment vs control in both models using the cut-off threshold of >2 and -2 fold-change and FDR adjusted p-value ⁇ 0.05, followed by heatmap generation.
  • the global gene expression analysis was done by quantile normalized data from Affymetrix GeneChip Human Genome U133 Plus 2.0 Array with high stringent cut-off threshold of >2 and -2 fold-change and FDR adjusted p-value ⁇ 0.0001.
  • the identified gene lists were then compared using BioVenn online tool for the area-proportional Venn diagram analysis (Hulsen et al., 2008).
  • the KEGG Pathway Enrichment analysis was carried out in Partek Genomics Suite (Partek Inc. St. Louis, MO, USA) with the cut-off threshold as FDR adjusted p-value ⁇ 0.05.
  • Varlitinib suppresses tumour growth through dose-dependent inhibition of ErbB family pathways in HCC PDXs
  • Varlitinib is a best-in-class reversible pan-HER inhibitor with a good clinical safety profile.
  • HCC21-0208 was selected to serve as negative control because it has the very low level of ErbB2 and undetectable level of ErbB3 (Figure IB).
  • Mice bearing HCCOl-0708, HCC07-0409, and HCC29- 0909A tumours were treated with three different doses of Varlitinib (25, 50, and lOOmg/kg BID).
  • Figure 1C-1E showed that Varlitinib inhibited tumour growth in a dose-dependent manner. This correlated well with tumour weight at harvest.
  • HCCOl-0708 is a fast-growing PDX that tolerated Varlitinib at low dosing, but the tumour growth and weight of that were significantly suppressed at the highest tested dosing, suggesting that higher dosing of Varlitinib is able to overcome the drug tolerance (Figure 1C).
  • HCC07-0409 and HCC29-0909A were more sensitive to Varlitinib and showed better dose-dependent inhibition effect ( Figure ID and IE).
  • Statistically significant growth inhibition is also observed among all different dosing in these two models, meaning that these models are sensitive and respond to Varlitinib very well.
  • Varlitinib promotes vessel normalisation and tumour perfusion in HCC PDX
  • RNA-Seq total mRNA sequencing
  • KEGG pathways are ribosome pathway, RNA transport, steroid biosynthesis, central carbon metabolism in cancer, and HIFl signalling pathway (Table 1C).
  • the Ingenuity Pathway Analysis (IPA) demonstrated the suppression of EIF2, eIF4, p70S6K, and mTOR signalling with predicted HIF1A as the inhibited upstream regulator as well as activation of ILl-mediated inhibition of RXR function, FXR/RXR and LXR/RXR pathway with predicted HNF1A and PPARA activated upstream regulators (Table ID), showing that the repressed ErbB downstream pathways correlates with hepatic lipid differentiation.
  • IPA Ingenuity Pathway Analysis
  • the numbers of differentially expressed genes identified from different dosing in both models indicate that higher dosing of Varlitinib used, more genes will be affected.
  • Varlitinib could inhibit similar EPO-related pathway and distinct VEGF-dependent [PDGFA, VEGFB, PGF, and NRP2) and VEGF- independent [PDGFC and BMP2/FST) anti-angiogenic pathways in two different PDX models to facilitate the vessel normalisation (Andrae et al., 2008; Kertesz et al., 2004; Krneta et al., 2006; Li et al., 2010; Lin et al., 2014; Zuo et al, 2016).
  • Varlitinib enhances immune infiltration in the treated tumours
  • RNA-Seq reads that align to mouse genome reference, mmlO were used to analyse the stromal components in the PDX models. Myeloid cell-related markers were specifically analysed.
  • Varlitinib effectively inhibits mutated ⁇ -catenin pathways and mediates membrane translocation of mutated ⁇ -catenin
  • Varlitinib-sensitive PDXs Figure 13A and Table 13A.
  • the Varlitinib-resistant PDX, HCC21-0208 contains wild-type CTNNB1 but with much higher TGFBR1 /2, IGF2/IGFR/IRS1, NOTCH1 /JAG1, TEAD1 /2, and CYR61 expression and lower MST1 expression comparatively from the gene expression microarray data ( Figure 13B and Table 13B].
  • Varlitinib-resistant PDX exhibited highly activated TGF- ⁇ , NOTCH, and Hippo pathways.
  • HCC proposed molecular classes of HCC
  • the Varlitinib-resistant PDX, HCC21-0208 is related to Wnt/TGF- ⁇ class
  • the Varlitinib-sensitive PDXs, HCCOl-0708, HCC07-0409, and HCC29- 0909 are related to CTNNB1 class or more specifically CTNNB1 mutation class.
  • the gene signature of Varlitinib-potency of the two RNA-sequenced PDXs was determined and shown in Figure 14.
  • HCCOl-0708, HCC07-0409 and HCC29-0909A harbour T41A ⁇ -catenin mutation and the Wnt/ ⁇ -catenin-related genes/pathways are inhibited according to WES and RNA-Seq analysis separately we sought to further investigate if the mutated ⁇ -catenin and its related pathway members are suppressed at protein level and whether the localisation of mutated ⁇ -catenin is affected by the Varlitinib treatment.
  • Figure 5 and Figure 30B displayed marked inhibition of ⁇ - catenin and its related pathways in the lOOmg/kg BID Varlitinib-sensitive PDXs, HCC29-0909A, HCCOl-0708, and HCC07-0409 models, ⁇ -catenin upstream regulators, p-LRP6 and DVL3, as well as downstream targets, Axin2, survivin, c-Jun, c-Met, and N-cadherin were suppressed and E-cadherin expression was elevated by Varlitinib in the treated HCC29-0909A ( Figure 5A).
  • c-Jun was reported to physically interact with ⁇ -catenin and TCF4 and to stabilise interaction for the transcription of ⁇ -catenin-target genes and cancer development (Gan et al., 2008; Nateri et al., 2005].
  • the inhibition of p-c-Jun by Varlitinib suggested the transcription repression of ⁇ -catenin.
  • Varlitinib targets mutated ⁇ -catenin and its related pathways in ErbB-dependent tumours by inhibition of p-LRP6, p- ⁇ -catenin at Tyrl42, and p-RanBP3 Ser58, resulting in ⁇ -catenin membrane translocation and inhibiting downstream targets of ⁇ -catenin.
  • the varlitinib-resistant PDX has statistically significantly higher pathway activities of angiogenesis, epithelial adherent junction signalling, epithelial-mesenchymal transition signalling, embryonic stem cell pluripotency, RhoA signalling, and Hippo signalling with higher CD24 signalling predicted.
  • HNF4A is a key liver differentiation driver and CD24 is a tumour-initiating cell marker in HCC (Enane et al., 2017; Lee et al., 2011).
  • varlitinib sensitivity correlates with ErbB3 expression and differentiation status in in HCC PDXs.
  • HEY1 and SOX9 were showed significantly higher expression in HCCOl-0708 (48.88 and 28.90-fold, respectively) than those in HCC29-0909A (Table 5A). Furthermore, the pathway enrichment analysis also demonstrated (Table 5C) that HCCOl-0708 has much higher Hippo, Wnt, IGFR, and FGFR pathway activities, whereas HCC29-0909A retains stronger metabolic activities, revealing the impaired differentiation in the former model (Table 5D).
  • RNA-Seq comparison further showed that ⁇ -catenin, Notch, and Hippo targets, MYC, CTGF, CYR61, and YAPl were highly expressed in HCCOl-0708, but were significantly inhibited by high dosing of Varlitinib (Table 5E and Table 5F).
  • Activated Wnt, Hippo, Notch, IGF, and FGFR are related the tumour-initiating cells and chemoresistance in HCC (Lau et al., 2016; Liu et al., 2016; Martinez- Quetglas et al., 2016; Villanueva et al., 2012). Accordingly, our study demonstrated that Varlitinib potency correlates with a spectrum of sternness/differentiation level in ErbB3-expressing and ⁇ -catenin mutated HCC PDXs.
  • HCC29-0909A HCC07-0409
  • HCCCOl-0708 HCC PDX models which display high levels of p- ErbB2 and p-ErbB3.
  • HCC29-0909A possesses the highest p-ErbB3.
  • HCC21-0208 model has undetectable p-ErbB2 and p-ErbB3 demonstrated poor efficacy in the Varlitinib treatment.
  • Varlitinib sensitivity is determined by the levels of p- ErbB3 and/or pErbB2 and raises the possibility that p-ErbB3 and p-ErbB2 are more reliable biomarkers for patient selection than total ErbB2 or ErbB3.
  • p-ErbB3 and p-ErbB2 are more reliable biomarkers for patient selection than total ErbB2 or ErbB3.
  • p-ErbB3 and p-ErbB2 are more reliable biomarkers for patient selection than total ErbB2 or ErbB3.
  • higher Wnt, Hippo, Notch, IGF, and FGFR pathway signalling were observed in the HCCOl- 0708 PDX, which required high dosing of Varlitinib to achieve better tumour growth inhibition.
  • HIF-1 activity stimulates neovascularization by enabling tumour and host cells to produce a variety of proangiogenic factors like VEGF-A, PDGF-B, FGF-2, and angiopoietins that stimulate new blood vessel formation within hypoxic areas (Calvani et al., 2006; Okuyama et al., 2006).
  • VEGF-A vascular endothelial growth factor
  • PDGF-B vascular endothelial growth factor
  • FGF-2 fibroblast growth factor-2
  • angiopoietins that stimulate new blood vessel formation within hypoxic areas
  • Varlitinib induces blood vessel normalization by previous study showing that anti-HER2 therapies (trastuzumab) promote normalisation in HER2-positive breast cancer (Goel et al., 2011).
  • T41A mutations have been identified from 2% to 18.8% in analysed HCC and the ⁇ -catenin mutations are found to be associated with low-stage of HCC (Austinat et al., 2008; Boyault et al., 2007; Cleary et al., 2013; Enane et al., 2017; Guichard et al., 2012; Hoshida et al., 2009; Kan et al., 2013; Legoix et al., 1999; Nault et al., 2013; Nhieu et al., 1999; Waisberg and Saba, 2015; Wong et al., 2001).
  • ⁇ -catenin is ubiquitinated by ⁇ -TrCP ubiquitin ligases, followed by proteasomal degradation.
  • mutations at T41 is found to prevent GSK3-mediated p-phosphorylation at serines 37 and 33, further avoiding ⁇ -TrCP recognition (Aberle et al., 1997; Liu et al., 2002; MacDonald et al., 2009; Orford et al., 1997).
  • T41A mutation is further shown to be constitutively active mutant, which enhances nuclear localisation of TCF4, resulting in elevated expression of ⁇ -catenin-targets (Hsu et al., 2006). Since phosphorylation of ⁇ -catenin at tyrosine 654 and at tyrosine 142 is essential for binding to E-cadherin (Roura et al., 1999) and a-catenin (Aberle et al., 1996; Piedra et al., 2003; Pokutta and Weis, 2000) respectively, inhibition of tyrosine phosphorylation at these sites by Varlitinib would facilitate the interaction of E-cadherin and a-catenin with ⁇ -catenin. This could lead to the assembly of the E-cadherin- a-catenin ⁇ -catenin complex at the plasma membrane and to decreased ⁇ -catenin-dependent transcription.
  • Wnt/ ⁇ -catenin is one of the main classes.
  • the first FDA-approved targeted therapy in HCC, Sorafenib is found to modulate Wnt ⁇ -catenin signalling in in vitro and in vivo CTNNBl-class liver cancer models, demonstrated by reduced TCF/LEF luciferase-reporter activity and ⁇ -catenin expression (Boyault et al., 2007; Hoshida et al., 2009; Lachenmayer et al., 2012; Sia et al., 2017).
  • Wnt ⁇ -catenin has been comprehensively discussed (Pez et al, 2013; Vilchez et al., 2016).
  • Wnt/ ⁇ -catenin pathway inhibitor ICGOOl, FH535, and other small inhibitors have been tested in HCC in different in vitro and in vivo models (Delgado et al., 2014; Gedaly et al., 2014; Handeli and Simon, 2008). Cheng's group and Gedaly's group further proved that the combination of sorafenib and ICGOOl as well as the combination of sorafenib and FH535 had better treatment outcome in their experimental models (Galuppo et al, 2014; Lin et al, 2016).
  • Varlitinib would show high efficacy and potency in the specific subset of HCC which depends on both ErbB pathway and mutated ⁇ -catenin.
  • Varlitinib effectively targeted ⁇ -catenin with T41A mutation in ErbB-dependent HCC by inhibiting ⁇ - ⁇ -catenin Tyrl42 and p-RanBP3 Ser58 as well as downregulated p-LRP6 and DVL3.
  • the mutated ⁇ -catenin is transported from nucleus and cytoplasm to membrane.
  • Varlitinib is a clinically available pan-HER and mutated ⁇ - catenin inhibitor, that can be used to target p-ErbB2 and p-ErbB3-highly expressing and CTNNB1 subset of HCC.
  • the robust and tolerate anti-tumour activity of Varlitinib in HCC PDX models and its safety profile warrants the development of clinical trial with trial enrichment for Varlitinib in HCC.
  • Example 2 - Varlitinib induces apoptosis in HCC cell lines
  • HCC cells were grown in cell culture medium with 10% FBS and with varying concentrations of varlitinib. Apoptosis profiles were analysed at 24 hour and 48 hour timepoints, using Muse Annexin V & Dead Cell Assay kit and Muse Cell Analyser. Early apoptosis cells (identified as Annexin V-PE positive and Dead Cell Marker negative ⁇ were measured and plotted.
  • Figure 18 shows the results of the experiment.
  • varlitinib was able to induce early apoptosis in all of the HCC cell lines tested after 48 hours of incubation.
  • Varlitinib was particularly effective in sorafenib resistant cells (Huh7-SorR) where almost 70% early apoptosis was observed when high dose of varlitinib was used, suggesting that varlitinib could be effective in patients who progress on sorafenib.
  • Figure 19 shows the apoptosis profile for the PLC/PRF/5 (PLC) cells after 48 hour culture in the presence of varlitinib. Note the increase in percentage of apoptotic cells correlates with increasing varlitinib concentration.
  • Example 3 Varlitinib-mediated tumour growth inhibition and vascular normalisation in activated ErB2/3-dependent and mutated ⁇ -catenin hepatocellular carcinoma
  • Hep3B Sorafenib-resistant cell line (Hep3B- SorR), which we established by step-wise exposure to increasing amounts of Sorafenib until the maximal dose that the cell lines could tolerate, showed higher phosphorylation status of EGFR, ErbB2, and ErbB3. Upregulated ErbB pathway activity could therefore be an acquired Sorafenib resistance mechanism.
  • Varlitinib effectively suppresses in vivo tumour growth in high p-ErbB2/3 and NRG1 expressing HCC patient-derived xenografts (PDXs)
  • mice bearing PDX tumours were treated with Varlitinib (lOOmg/kg BID). Additional dosing of 25 and 50mg/kg BID were adopted to treat three PDXs, HCCOl-0708, HCC07-0409, and HCC29-0909A ( Figures 21A and 26B).
  • Varlitinib showed effective tumour growth inhibition in only three PDXs (HCCOl-0708, HCC07-0409, and HCC29-0909A), at the dose of lOOmg/kg BID.
  • HCC07- 0409 and HCC29-0909A were more sensitive to Varlitinib and showed superior dose-dependent inhibition (Figure 21A).
  • Statistically significant growth inhibition was also observed among all three doses in the two models (p-122 value ⁇ 0.0001).
  • the latter model exhibited dramatic tumour suppression even when treated with Varlitinib at 50mg/kg BID, signifying that Varlitinib is highly potent in the HCC29-0909A model.
  • HCCOl-0708 was a fast-growing PDX mouse model that tolerated Varlitinib at low dosing. Tumour growth was significantly suppressed at the highest dose, suggesting that a higher dosing of Varlitinib may overcome intrinsic drug resistance. Conversely Varlitinib at the dose of 100 mg/kg BID had no significant anti-tumour activity in the rest of the tested PDX models ( Figures 21A and 26B).
  • the PDXs were categorised into responders and non-responders according to their treatment responses. Three responders and two non-responders were reassessed by Western blot (Figure 21B). As shown in Figure 21B, the three responders showed much higher p-ErbB2/3 and ErbB2/3 compared to the two non-responders. The expression of p-EGFR, total EGFR, p-Erkl/2, and p-Akt were similar in all tested PDXs, suggesting that responders are highly dependent on activated ErbB2/3 signalling.
  • Varlitinib responders We further sought to understand the molecular differences between Varlitinib responders and non-responders.
  • Three responders HCCOl-0708, HCC07-0409, and HCC29-0909A
  • 9 non- responders HCCOl-0909, HCC06-0606, HCC13-0109, HCC21-0208, HCC25-0705A, HCC26-0808A, HCC26-0808B, HCC29-1104, and HCC30-0805B
  • all 3 responders grouped together based on the principal component analysis (Figure 26C).
  • GSEA Gene set enrichment analysis
  • Transcriptome analysis reveals the molecular basis of Varlitinib-mediated tumour suppression Although HCCOl-0708 and HCC29-0909A PDX models highly expressed activated ErbB3, they had distinct, differentiated responses to Variitinib. Maximal dosing (lOOmg/kg BID) of Variitinib was needed to suppress HCCOl-0708 tumour growth, whereas a lower dose [50mg/kg BID) was sufficient to suppress HCC29-0909A tumour growth ( Figure 21A).
  • RNA-Seq total mRNA sequencing
  • the top 20 commonly activated and repressed genes in HCC29-0909A are shown in Tables 1A and IB, respectively.
  • the top 6 significantly suppressed KEGG pathways were the ribosome pathway, RNA transport, steroid biosynthesis, central carbon metabolism in cancer, and HIF1 signalling pathway (Table 1C).
  • IPA Ingenuity Pathway Analysis
  • Varlitinib inhibits glycolysis, HIF1A pathway, and angiogenesis in the treated PDXs
  • FIGS 28C-E further revealed that Varlitinib could inhibit the EPO pathway, VEGF-dependent ⁇ PDGFA, VEGFB, PGF, and NRPZ) and VEGF-independent ⁇ ANG, PDGFC and BMP2) pro-angiogenic pathways to facilitate vessel normalisation (Krneta et al, Kertesz et al and Andrae et al).
  • LGR5 ⁇ -catenin upstream regulator
  • YAP1, IRX3, and MYC were downregulated in both treated HCC29-0909A and HCCOl-0708 models.
  • expression of CDH1 was enhanced ( Figures 23E and 28F).
  • LEF1 was reduced in the treated HCC29- 0909A model ( Figure 28G).
  • Figures 24A, 24B, 30A and 30B displayed marked inhibition of ⁇ -catenin and its related pathways in the Varlitinib responder PDXs, HCC29-0909A, HCCOl-0708, and HCC07-0409 models.
  • ⁇ -catenin upstream regulators, p-LRP6 and DVL3, as well as downstream targets, Axin2, survivin, c- Jun, c-Met, and N-cadherin, were suppressed.
  • E-cadherin expression was elevated by Varlitinib in the treated PDXs ( Figure 24A).
  • c-Jun was reported to physically interact with ⁇ -catenin and TCF4 to stabilise ⁇ - ⁇ 3 ⁇ / ⁇ 4 interaction for the transcription of ⁇ -catenin target genes and cancer development (Nateri et al).
  • the inhibition of p-c-Jun by Varlitinib suggested the transcriptional repression of ⁇ -catenin.
  • Varlitinib targets mutated ⁇ -catenin and its related pathways in ErbB-dependent tumours - by inhibiting ⁇ -catenin upstream regulator LGR5 and p-LRP6, ⁇ - ⁇ -catenin at Tyrl42 and Tyr654, nuclear export regulator p-RanBP3 at Ser58, as well as upregulating E-Cadherin expression. These, in turn, result in ⁇ -catenin membrane translocation, thereby inhibiting downstream targets of ⁇ - catenin. T41A ⁇ -catenin mutation is thought to be constituitively active. However, our study demonstrates that its nuclear localisation and ⁇ -catenin-driven genes could be inhibited by Varlitinib in high p-ErbB2/3 expressing HCC.
  • ERBB3 is upregulated in a subset of HCC.
  • Varlitinib a small molecule pan-ErbB inhibitor, effectively inhibited high £7?£?£fJ?-expressing HCC in vitro.
  • in vivo efficacy was demonstrated in the responder PDXs, HCC29-0909A, HCC07-0409, and HCCOl-0708 in immune-deficient NOD/SCID mice, which displayed high levels of p-ErbB2/3, total ErbB2/3, and NRG1 gene expression.
  • Varlitinib sensitivity is determined by the quantitative expression of p-ErbB3 and/or pErbB2 and raises the possibility that the presence of p-ErbB2/3 could potentially be specific for patient treatment stratification.
  • expression of ERBB2 and ERBB3 are known to have prognostic value, whereas that of NRG1 has the same trend in our Singapore HCC dataset ( Figure 21D).
  • ERBB2/3 expression belong to both the G6 subgroup and CTNNB1 subclass in the non-proliferation class of HCC, whereas the 14 tested non-responder PDXs are related to the HCC subgroups with TGF and IGF/IGF1R pathways and S1/S2 tumours in the proliferation class of HCC (Llovet et al 2017,Boyault et al 2007,Lachenmayer et al ). It indicates the strong correlation of the ErbB family and ⁇ -catenin pathways in the specific subclass of HCC PDXs, that could be effectively inhibited by Varlitinib.
  • Varlitinib was especially potent against HCC29-0909A. It may be due to the low activity of mutated ⁇ -catenin in the model, as indicated by the IPA pathway enrichment analysis ( Figure 281).
  • ⁇ -catenin-driven cancers require YAPl for tumour progression (Rosenbluh et al).
  • YAPl and its related sternness properties are also associated with drug resistance in multiple cancers (Zanconato et al). Lin and colleagues previously identified through genetic screen that YAPl is the key resistance driver of RAF- and MEK- targeted therapies (Lin L et al).
  • HIF-1 activity stimulates neovascularisation by enabling tumour and host cells to produce a variety of proangiogenic factors like VEGF-A, PDGF-B, FGF-2, and angiopoietins that stimulate new blood vessel formation within hypoxic areas (Okuyama et al, Calvani et al).
  • ⁇ -catenin mutations are found to be associated with the earlier stages of HCC and the T41A mutation has been identified in up to 18.8% of analysed HCC (Guichard et al).
  • wild-type ⁇ -catenin is ubiquitinated by ⁇ - TrCP ubiquitin ligases, destined for proteasomal degradation.
  • mutations at T41 prevent GSK3-mediated phosphorylation at serines 33/37, avoiding ⁇ -TrCP recognition (Liu et al).
  • T41A mutation is also found to be a constitutively activated mutant, which enhances nuclear localisation of TCF4, resulting in elevated expression of ⁇ -catenin-targets (Hsu et al H-T et al). Since phosphorylation of ⁇ -catenin at tyrosines 142 and 654 is essential for binding to E-cadherin (Roura et al) and oc-catenin (Pokutta et al), inhibition of tyrosine phosphorylation at these sites by Varlitinib would facilitate the interaction of E-cadherin and a-catenin with ⁇ -catenin.
  • Sorafenib - a BRAF, C-RAF and VEGF-R inhibitor - can modulate Wnt/ -catenin signalling in in vitro and in vivo CTNNBl-class liver cancer models. This was demonstrated by showing reduced TCF/LEF luciferase-reporter activity and ⁇ -catenin expression following Sorafenib treatment (Boyault et al, Lachenmayer et al). There has been considerable exploration of targeting Wnt/ -catenin against HCC. Wnt/ -catenin pathway inhibitors ICGOOl, FH535, and other small inhibitors have been tested in HCC in different in vitro and in vivo models.
  • Varlitinib shows good efficacy in the specifically defined subset of HCC that is dependent on both the ErbB pathway and ⁇ -catenin mutation.
  • Varlitinib promotes apoptosis and vessal normalisation with reduction of tumour progression and hypoxia in this subset of HCC.
  • Varlitinib effectively inhibits ErbB receptors and their downstream oncogenic signalling such as MEK/Erk and AKT/mTOR pathways.
  • ⁇ -catenin targets ⁇ -catenin with T41A mutation in ErbB-dependent HCC by inhibiting ⁇ - ⁇ -catenin Tyrl42 /654 and p-RanBP3 Ser58, as well as inducing LGR5, p-LRP6, and DVL3 downregulation.
  • mutated ⁇ -catenin is transported from the nucleus and cytoplasm to the cell membrane, reducing the expression of ⁇ -catenin-driven genes.
  • Varlitinib has a comparably favorable safety profile compared to irreversible pan-ErbB inhibitors such as Neratinib and Dacomitinib.
  • the recommended dose of Varlitinib for clinical trials is between 200mg BID to 500mg BID, which is equivalent to 41mg/kg BID to 102.5mg/kg BID in mouse (calculation is based on Nair and Jacob (Hulsen et al).
  • Our study reveals that 50mg/kg BID in mice ( ⁇ 250mg BID in human) showed efficient growth supression in high p-ErbB2/3 expressing PDXs.
  • Intrinsic resistance demonstrated by high ⁇ - catenin/YAPl-related gene signature in high p-ErbB2/3 expressing PDX could be overcome by increasing the dose to lOOmg/kg BID in mice ( ⁇ 490mg BID in human). In contrast, even with very high dose of Varlitinib given to the mice (lOOmg/kg BID), there is no anti-tumour benefit in the non- responders. Expression of p-ErbB2/3 and/or ErbB2/3 could be a predictive biomarker in the clinical treatment of HCC with Varlitinib.
  • Varlitinib is a pan-ErbB and, as we report here, an inhibitor of mutated ⁇ - catenin - that can selectively target the p-ErbB2/3 highly-expressing and CTNNB1 subset of HCC.
  • Our data suggests that the selection of HCC patients with high p-ErbB2/3 expression could be a useful target and predictive biomarker for Varlitinib clinical efficacy.
  • the role of tailoring systemic therapies, whether molecular or immune modulating, can potentially optimise treatment efficacy based on HCC subtypes.
  • Three tumours from each condition (control, 50mg/kg, and lOOmg/kg Varlitinib treatment) of 95 HCC29-0909A and HCCOl-0708 and two tumours from each condition (control and lOOmg/kg treatment) of HCC16-1014 were used for transcriptome analysis.
  • a total of 200 ng of total RNA was used for illumina TruSeq mRNA library prep, followed by 150bp paired-end sequencing on an illumina HiSeq4000 platform by BGI HK, Ltd.
  • the raw sequencing reads were aligned to mouse mmlO genome reference and human hg38 genome reference by Spliced Transcripts Alignment to a Reference (STAR) aligner version 2.5.3a, separately using Partek Flow (Partek Inc. St. Louis, MO). In average, 74 million to 90 million clean reads per sample were obtained. The total human alignments ranged from 70 million to 87 million per samples. Aligned reads were then quantify to hg38 - RefSeq Transcripts 85 -2018-05-02 annotation model using Partek E/M algorithm, followed by low expressed gene filtering and total count and add 0.0001 gene counts normalisation.
  • GSA differential expression detection model was used to compare 50mg/kg Varlitinib treatment vs control and lOOmg/kg Varlitinib treatment vs control in PDX models using the cut-off threshold of >2 and -2 fold-change and FDR adjusted p-value ⁇ 0.05, followed by heatmap generation.
  • the gene expression analysis was done by quantile normalised data from Affymetrix GeneChip Human Genome U133 Plus 2.0 Array with cut-off threshold of >2 and -2 fold-change and high stringent FDR adjusted p-value ⁇ 0.0001.
  • the identified gene lists were compared using BioVenn online tool for the area-proportional Venn diagram analysis (Hulsen et al).
  • the KEGG Pathway Enrichment analysis was carried out in Partek Genomics Suite (Partek Inc. St Louis, MO) with the cut-off threshold of FDR adjusted p-value ⁇ 0.05.
  • IPA Ingenuity Pathway Analysis
  • GSEA Gene Set Enrichment Analysis
  • MSigDB Molecular Signature Database
  • Table 1 Transcriptome analysis of Varlitinib treatment in HCC29-0909A.
  • A Top 20 common activated genes and
  • B top 20 common repressed genes in lOOmg/kg and 50mg/kg BID Varlitinib- treated HCC29-0909A. FDR adjusted p-values are shown.
  • C KEGG pathway analysis showing the enriched pathways generated from the gene lists of significant differentially expressed genes with the threshold of >2 and ⁇ -2 fold-change with FDR adjusted p-values ⁇ 0.05.
  • D Ingenuity Pathway Analysis showing the predicted repressed and activated pathways with enrichment FDR adjusted p- values ⁇ 0.05.
  • Table 2 Transcriptome analysis of Varlitinib treatment in HCCOl-0708.
  • A Top 20 common activated genes and
  • B top 20 common repressed genes in lOOmg/kg and 50mg/kg BID Varlitinib- treated HCCOl-0708.
  • FDR adjusted p-values are shown.
  • C Ingenuity Pathway Analysis showing the predicted repressed and activated pathways with enrichment FDR adjusted p-values based on the gene lists of significant differentially expressed genes with the threshold of >2 and ⁇ -2 fold- change with FDR adjusted p-values ⁇ 0.05.
  • Table 4 Identification of Varlitinib-resistant gene signature by global gene expression analysis.
  • A The top 20 highly expressed genes and
  • B the top 20 lowly expressed genes identified in Varlitinib-sensitive PDXs, HCC29-0909A, HCCOl-0708, and HCC07-0409 models.
  • C Ingenuity Pathway Analysis showing the predicted repressed and activated pathways with enrichment FDR adjusted p-values ⁇ 0.05. ** indicates p-value ⁇ 0.01, *** indicates p-value ⁇ 0.001, **** indicates p- value ⁇ 0.0001.
  • HCM Hypertrophic cardiomyopathy
  • B the top 20 lowly expressed genes identified in higher Varlitinib-potent PDX HCC29-0909A when compared to lower Varlitinib-potent HCCOl- 0708.
  • C Ingenuity Pathway Analysis showing the predicted activated pathways with enrichment FDR adjusted p-values ⁇ 0.05. Pathways activated in HCC29-0909A Innchment Score Enrichment p-value
  • Table 6 Gene enrichment analysis in Varlitinib responder and non-responder PDXs.
  • the enriched gene sets with q-value ⁇ 0.05 are shown.
  • ES refers to enrichment scores
  • NES refers to normalised enrichment scores.
  • ERBBf £f?8B3 L0W Table 7 - Analysis of ERBB3TM and
  • MCC29-0909A Responds r R5J 1 PliTOA, I6S5 ⁇ Nit NI! T41A Hepatitis B positive
  • Table 10 Transcriptome analysis of Varlitinib treatment in HCC29-0909A, HCCOl-0708, and HCC16-1014.
  • H2-AU HC class il 40.00 7,18 x 10 " '
  • H2-DMO MHC class 11 20 62 5.46 10
  • H2-Ea-ps MHC class il 22.40 2,28 x 10 ;
  • A Differentially expressed myeloid-related genes. Gene symbol Fold-change FDR adjusted rvalue
  • Table 13 Identification of ⁇ -catenin mutation and the constitutively active ⁇ -catenin pathways in the Varlitinib-sensitive PDXs.
  • A Expression of ⁇ -catenin and its downstream targets and
  • B expression of Wnt/TGF -related targets, in the four analysed PDXs indicated by normalised probe intensity.

Abstract

L'invention concerne un inhibiteur de tyrosine kinase de type I, qui est le varlitinib, ou une formulation pharmaceutique le comprenant en tant que monothérapie ou polythérapie, pour une utilisation dans un procédé de traitement d'une population de patients atteints d'un cancer particulier, les patients portant une mutation dans la voie de la bêta-caténine.
PCT/SG2018/050537 2017-10-25 2018-10-25 Varlitinib destiné à être utilisé dans le traitement du cancer chez un patient identifié comme ayant une mutation de la voie de la bêta-caténine WO2019083457A1 (fr)

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US10849899B2 (en) 2015-09-04 2020-12-01 Aslan Pharmaceuticals Pte Ltd Combination therapy comprising Varlitinib and an anticancer agent
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