WO2019083455A1 - Varlitinib destiné à être utilisé dans le traitement du cancer chez un patient identifié comme présentant des cellules cancéreuses à récepteurs her1, her2 et/ou her3 activés - Google Patents

Varlitinib destiné à être utilisé dans le traitement du cancer chez un patient identifié comme présentant des cellules cancéreuses à récepteurs her1, her2 et/ou her3 activés

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Publication number
WO2019083455A1
WO2019083455A1 PCT/SG2018/050535 SG2018050535W WO2019083455A1 WO 2019083455 A1 WO2019083455 A1 WO 2019083455A1 SG 2018050535 W SG2018050535 W SG 2018050535W WO 2019083455 A1 WO2019083455 A1 WO 2019083455A1
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WIPO (PCT)
Prior art keywords
cancer
varlitinib
receptor
activated
catenin
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PCT/SG2018/050535
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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 WO2019083455A1 publication Critical patent/WO2019083455A1/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

Definitions

  • VARLITINIB FOR USE IN TREATING CANCER IN A PATIENT IDENTIFIED AS HAVING ACTIVATED HER1 , HER2 AND/OR HER3 RECEPTOR CANCEROUS CELLS
  • 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 HER1 activated, HER2 activated and/or HER3 activated cancer (such as HER2 activated and/or HER3 activated cancer].
  • 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 HER1 activated, HER2 activated and/or HER3 activated cancer (such as HER2 activated and/or HER3 activated cancer].
  • 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
  • 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, are completely therapy refractory, and no more avenues of therapy exist 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 activated HER1, HER2 and/or activated HER3 receptors (HER2 and/or activated HER3 receptors], in particular where the receptors are phosphorylated.
  • HER1, HER2 and/or activated HER3 receptors HER2 and/or activated HER3 receptors
  • These cancers seem to be sensitive to treatment with Varlitinib.
  • the target patient population has increased levels of activation of the relevant receptors.
  • patients within the group may also have increased levels of HER2 and/or HER3.
  • cancer therapies are not directed at patients which have activated HER3 cancer.
  • HER3 has only weak activity it frequently co-expresses and interacts with other receptor tyrosine kinases. It is well suited to activation of the PI-3K/Akt pathway, which is associated with tumorgenesis.
  • the C-terminal tail of HER3 has multiple tyrosine residues, which when phosphorylated is able to bind the p85 subunit of PI-3K.
  • HER3 serves as a critical co-receptor of HER2 and its expression is essential for HER2-mediated breast cancer cell survival and proliferation.
  • HER3 is overexpressed in n50 to 70% of breast cancers. It may also have a role in many human cancers, for example colorectal cancer, gastric cancer, breast cancer, melanoma, ovarian cancer, head and neck cancer, pancreatic cancer and cervical cancer.
  • HER3 is implicated in resistance, distant metastasis, tumor size and risk of local reoccurrence.
  • the present therapy may fill an unmet need because at the present time such patient populations have no therapies that particularly focused on their treatment
  • a method of treating a patient for cancer by administering a compound of formula (I :
  • the compound of formula (I) is Varlitinib or a pharmaceutically acceptable salt thereof, wherein the patient has been identified as having activated HER1 receptor cancerous cells, HER2 receptor cancerous cells, HER3 receptor cancerous cells, or any combination thereof, for example where the cancer is a solid tumor.
  • liver cancer such as hepatocellular carcinoma], biliary tract cancer, 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, oesophagus cancer and combinations of two or more of the same.
  • the cancer is selected from liver cancer, such as hepatocellular carcinoma, gallbladder cancer, cholangiocarcinoma and a combination of two or more the same, such as hepatocellular carcinoma.
  • the cancer is cholangiocarcioma and is located in an intrahepatic bile duct, left hepatic duct, right hepatic duct, common hepatic duct, cystic duct, common bile duct, Ampulla of Vater or a combination thereof.
  • each dose of the compound of formula (I) is in the range 100 to 500mg or 200 to 500mg, such as 250 mg or 490 mg.
  • each dose is lOOmg, 200mg, 300mg or 400mg (such as 300mg or 400mg).
  • chemotherapeutic agent is independently selected from the group comprising a platin (such as cisplatin or oxaliplatin], gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI and FOLFIRINOX.
  • a platin such as cisplatin or oxaliplatin
  • gemcitabine gemcitabine
  • capecitabine 5-FU
  • FOLFOX FOLFIRI
  • FOLFIRINOX fluoride
  • 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.
  • anti-cancer agent is selected from: patritumab (U3-1287), seribantumab (mm-121], elgemtumab (LJM716), AV- 203, KTN-3379 or GSK2849330.
  • a compound of formula (I] as disclosed above an enantiomer thereof or a pharmaceutically acceptable salt of any one of the same, for example wherein the compound of formula (I] is Variitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer patient identified as having activated HER1 receptor cancerous cells, HER2 receptor cancerous cells, HER3 receptor cancerous cells, or any combination thereof, for example wherein the cancer is a solid tumour.
  • Paragraph 43 is written in the style of an EPC2000 claim.
  • the present disclosure explicitly includes EPC2000 style disclosure corresponding to paragraphs 2 to 41. These EPC 2000 style paragraphs will nominally be paragraphs 44 to 84.
  • a compound of formula (I) disclosed above an enantiomer thereof or a pharmaceutically acceptable salt of any one of the same, for example wherein the compound of formula (I) is Variitinib or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a cancer patient identified as having activated HER1 receptor cancerous cells, HER2 receptor cancerous cells, HER3 receptor cancerous cells, or any combination thereof, for example where the cancer is a solid tumour.
  • Paragraph 85 is written in the style of a Swiss claim. The present disclosure explicitly includes
  • the two-state receptor model suggests that the state of the receptor (such as activation) may affect the affinity of a chemical entity to the receptor. This theory does not usually apply to inhibitors but it may be that the compounds of formula (I), such as Variitinib, have greater affinity for receptors, such as HER3, in an activated state.
  • the cancer is both HER2 activated and HER3 activated.
  • the cancer has at least one of the following:
  • the cancer is HER1 activated. In one embodiment, the cancer is HER1 activated and HER2 activated. In one embodiment, the cancer is HER1 activated and HER3 activated. In one embodiment, the cancer is HER1 activated, HER2 activated and HER3 activated.
  • the HER3 is activated by NRG1 (neuregulin 1 also known as HRG -the ligand for HER3], for example wherein the expression of NRG1 is higher in the cancerous cells compared to normal cells.
  • NRG1 neuroregulin 1 also known as HRG -the ligand for HER3
  • the cancer patient has been identified as having increased levels of
  • NRG1 compared to a normal control.
  • the HER1 receptor has a R521K mutation.
  • the HER2 receptor has a P1170A mutation, an 1655 V mutation or both. In one embodiment, the HER2 receptor has a P1170A mutation. In one embodiment, the HER2 receptor has an I665V mutation. In one embodiment, the HER2 receptor has a P1170A mutation and an I665V mutation.
  • 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 to 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 such as Varlitinib, is administered orally.
  • the compound of formula [I], according to the present disclosure 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, for example, 250 mg or 490 mg, for example administered once or twice daily, such as twice daily (BID).
  • a dose in the range lOOmg to 900mg on each occasion in particular 200 mg, 300mg, 400mg or 500mg each dose, such as 400mg, for example, 250 mg or 490 mg, for example administered once or twice daily, such as twice daily (BID).
  • 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.
  • EGFR EGFR
  • HER1 HER1
  • ErbBl ErbBl
  • HER2 and ErbB2 are used interchangeably in this disclosure and are intended to refer to the same receptor.
  • Activation of a receptor refers to one or more of the following: relay of a signal (i.e. where the receptor sends the signal onwards); amplification (where the receptor increases the "in-coming” signal]; and integration [where the receptor allows or facilitates the signal being incorporated into another biochemical pathway).
  • dimerization is a pre-requisite to activation.
  • HER3 and ErbB3 are used interchangeably in this disclosure and are intended to refer to the same receptor.
  • HER1, 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 but is not limited any of the following:
  • the activation is independent of increased expression, for example is dimerization and/or phosphorylation.
  • Phospho-EGFR/p-EGFR, Phospho-ErbB2/p-ErbB2, or phospho-ErbB3/p-ErbB3 as used herein refers to the phosphorylated form of EGFR, ErbB2 or ErbB3 respectively. It includes phosphorylation of the receptor at any suitable phosphorylation site.
  • Known phosphorylation sites for EGFR include but are not limited to: Tyr 1068, Tyr 845, Ser 991 and Tyr 998.
  • Known phosphorylation sites for ErbB2 include but are not limited to: Tyr 877, Tyrl023, Tyrll39, Tyrl l96, 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-EGFR refers to EGFR [HER1] which has been phosphorylated at Tyr 1068.
  • phospho-ErbB2 refers to ErbB2 (HER2) which has been phosphorylated at Tyrl221 or Tryl222.
  • phospho-ErbB3 refers to ErbB3 (HER3) 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 as HER1, HER2 and/or HER3 activated.
  • the cancer has a mutation in the HER2 receptor, such as a P1170A mutation, an 1655 V mutation, or both, for example both P1170A and 1665 V mutations.
  • a mutation in the HER2 receptor such as a P1170A mutation, an 1655 V mutation, or both, for example both P1170A and 1665 V mutations.
  • the present inventors have established that cancers, such as a hepatocellular carcinoma (HCC] that have one or more of these mutations were significantly more responsive to treatment with a pan-HER inhibitor such as Varlitinib compared to cancers that did not have any of these mutations.
  • HCC hepatocellular carcinoma
  • patients with cancers having the P1170A mutation, an I655V mutation, or both P1170A and I655V mutations may represent a specific patient population subset that is particularly responsive to treatment with a pan-HER inhibitor, such as Varlitinib.
  • the target patient population has a P1170A mutation, an I655
  • the cancer has a mutation in the HER1 receptor, such as R521K.
  • R521K a mutation in the HER1 receptor
  • the present inventors have established that cancers, such as a hepatocellular carcinoma [HCC) that have the R521K mutation are more responsive to treatment with a pan-HER inhibitor such as Varlitinib compared to cancers that did not have any mutations in HER1.
  • HCC hepatocellular carcinoma
  • patients with cancers having the R521K mutation may represent a specific patient population subset that is particularly responsive to treatment with a pan-HER inhibitor, such as Varlitinib.
  • the target patient population has a R521K mutation in HER1.
  • the HER3 is activated by NRG1, for example wherein the expression of NRG1 is higher in the cancerous cells compared to normal cells.
  • NRG1 expression of NRG1
  • the present inventors found that cancers that have higher expression levels of NRG1 compared to normal cells are more responsive to treatment with a pan-HER inhibitor, such as Varlitinib. Accordingly, patients with cancers having raised levels of NRGl may mutations may represent a specific patient population subset that is particularly responsive to treatment with a pan-HER inhibitor, such as Varlitinib.
  • the cancer patient has been identified as having increased levels of NRGl compared to a normal control.
  • Downregulation of miR-203 and/or miR-542-3p may also be an indication of activation of a receptor according to the present disclosure.
  • identification in the context of the present disclosure refer to the fact 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 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 carcinoma-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.
  • renal cancer for example renal cell carcinoma and/or urothelial cell carcinoma.
  • Other examples of 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
  • about 90% of 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.
  • T4a Tumour invades prostate, uterus or vagina
  • T4b Tumour invades pelvic wall or abdominal wall
  • 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 [EOCs] 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- Leydig 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.
  • 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 IIC The tumor is classified as either Stage IIA 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
  • 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
  • stage IV disease (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 the same.
  • 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 relates to treatment of the same.
  • 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 extends to treatment of the same.
  • Head and neck cancer 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 relates to treatment of the same.
  • 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 of the patient population according to the present disclosure with 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 iV-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 (AZQJ.
  • 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 which may be employed in the present disclosure, 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 incl which has the following 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 rag/m 2 IV over 90 minutes) concurrently with folinic acid (400 mg/ra 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.
  • 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 (RADOOl), 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 (PD 184352), 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 combination therapy employs a p38 inhibitor, for example as disclosed in WO2010/038086, such as iV-[4-( ⁇ 4- [3-(3-tert-Butyl-l-p-tolyl-l//-pyrazol-5- yl)ureido]naphthalen-l-yloxy ⁇ methyl)pyridin-2-yl]-2-methoxyacetamide.
  • a p38 inhibitor for example as disclosed in WO2010/038086, such as iV-[4-( ⁇ 4- [3-(3-tert-Butyl-l-p-tolyl-l//-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 chemotherapy combination 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.
  • the combination therapy comprises a checkpoint inhibitor, for example selected from the group comprising:
  • PF-477736 is a CHK1 & 2 inhibitor (ATP-
  • AZD-7762 a CHK1 and CHK2 inhibitor (with an competitive CHK1 inhibitor with a Kj of 0.49 nM IC50 of about 5 nM in a cell-free assay, with less in a cell free assay.
  • the molecule also VEGFR2, potent activity against CAM, Yes, Fyn, Lyn, Hck Aurora-A, FGFR3, Flt3, Fms (CSF-1R), Ret and an Lck) Yes. It shows approximately 100 fold selectivit for CHKl over CHK2)
  • V155422, V155991 and V158411 are CHKl and CHK2 inhibitors
  • CP-466722 is a potent ATM inhibitor, which does not inhibit ATR.
  • the molecule also inhibits Pi3K and PIKK
  • 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 reperfusion]
  • BGB-290 a PARP-1 and PARP-2 inhibitor (structure not shown); MP-124 a PARP-1 inhibitor (structure not shown); or a pharmaceutically acceptable salt or solvate of any one of the same.
  • the following articles disclose certain 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 CHKl inhibitors: design, regioselective synthesis and molecular modelling Med. Chem. Commun., 2015,6, 852-859; PLoS One 2010; 5(8): el2214.
  • the checkpoint inhibitor is a PARP inhibitor.
  • PARP inhibitors are disclosed in US7,449,464 and US8,071,623. The compounds disclosed in this paragraph are incorporated herein by reference,
  • 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, x-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--
  • check point inhibitor is prexasertib.
  • Checkpoint kinase inhibitor 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.
  • 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.
  • 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 CD 31 staining).
  • 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 HCCO l-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. 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 l OOmg/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 HCCOl-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 ERBB3 ⁇ ⁇ 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 ERBB3H ⁇ g 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.
  • Varlitinib responders and one in Varlitinib non-responders are expressed in Varlitinib responders and nonresponders.
  • C Correlation analyses between ERBB3 and G6- related genes (LEF1 and AXIN2) and between ERBB3 and IGF1R. Pearson correlation analysis is used when both data passed normality test, whereas Spearman correlation analysis is used when one of the data did not pass normality test See also Figure 27.
  • 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) of Varlitinib-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.
  • ERBB3 m and ERBB3 ov/ liver cancer cell lines Analysis of ERBB3 m and ERBB3 ov/ liver cancer cell lines.
  • A Identification of ERBB3 m and ERBB3 ow liver cancer cell lines. Expression of ERBB3 was compared among 27 liver cancer cell lines in Cancer Cell Line Encyclopedia (CCLE) dataset. Median expression of ERBB3 in these 27 cell lines was used as as cut-off for ERBB3 Hi and ERBB3 l0V1 cell lines. **"p ⁇ 0.0001, unpaired t test.
  • B Expression of phospho- and total ErbES family receptors in selected ERBB3 m and £7?f3 ⁇ 4?.3 Low cell lines. Blots were incubated with indicated antibodies. ⁇ -Tubulin was used as equal loading marker.
  • 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.
  • HCC PDXs HCCOl-0909, HCC06-0606, HCC09-0913, HCC13-0109, HCC13-0212, HCC 5-0114, HCC17-0211, HCC25-0705A, HCC26- 0808B, HCC29-1104, and HCC30-0805B models.
  • C Principal component analysis of quantile 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.
  • PDX models Western blot analysis of the protein lysates collected on day 14 post- treatment of l OOmg/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 HCCOl- 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 H poxyprobe 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_mml 0 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 l OOmg/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-treated HCCOl-0708 model provided molecular insights to explain the tolerance ability of HCCOl-0708 at low dosing treatment Better treatment outcome was achieved only at the dose, where Varlitinib effectively inhibits its target activation.
  • 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 HIF1 signalling pathway (Table 1C].
  • the Ingenuity Pathway Analysis demonstrated the suppression of EIF2, eIF4, p70S6K, and mTOR signalling with predicted HIFIA 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 Due to the difference of Varlitinib efficacy in the tested PDXs, we have further investigated the gene signature that represents Varlitinib efficacy (Figure 12).
  • Whole exome sequencing (WES] was further performed for all five PDXs to determine if these PDXs contain any mutation on ⁇ - catenin and ErbB family members (Table 9).
  • WES data demonstrated that all three Varlitinib-sensitive PDXs contain ⁇ -catenin T41A mutation, whereas ErbB family members exhibit different mutational patterns.
  • Varlitinib-sensitive PDXs Figure 13A and Table 13A.
  • the Varlitinib-resistant PDX, HCC21-0208 contains wild-type CTNNB1 but with much higher TGFBRl /2, IGF2/IGFR/IRS1, NOTCHl/JAGl, TEADl/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.
  • c-Jun was reported to physically interact with ⁇ -catenin and TCF4 and to stabilise ⁇ - catenin/TCF4 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.
  • NRG1/ERBB3 pathway dependence and differentiation status correlate with Varlitinib treatment efficacy in PDXs
  • gene expression microarray was performed on four treatment-naive PDXs (HCCOl-0708, HCC07-0409, HCC29-0909A, and HCC21-0208), followed by gene set and pathway enrichment analyses (Figure 12].
  • differentially expressed genes were identified from the quantile normalised data of Affymetrix GeneChip Human Genome U133 Plus 2.0 Array with cut-off threshold of 2 fold-change and high stringent FDR adjusted p-value ⁇ 0.0001, followed by heatmap generation (Figure 12 A), In total, 2591 differentially expressed genes were detected, in which 1035 genes were highly expressed and 1556 genes were lowly expressed in the varlitinib-sensitive group. The gene lists with top 20 highly and lowly expressed genes are summarised in Table 4A and Table 4B, respectively. The most abundantly expressed gene in varlitinib-sensitive PDXs was NRG1 (fold-change > 500; Figure 12B].
  • the varlitinib-sensitive PDXs have much higher glutathione metabolism and FXR/RXR and PXR/RXR activation with higher HNF4A and HNF1A activity predicted (Table 4C).
  • 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 CD 24 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.
  • HEYl 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 5 C) 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 YAP1 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.
  • PDXs 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.
  • Varlitinib suppressed tumour cell proliferation and promoted apoptosis by inhibiting phosphorylation of ErbBl-3, RAS/RAF/MEK/MAPK, p70S6K, S6 ribosomal, 4EBP1, Cdk-2, Cdc-2, and retinoblastoma pathways in dose- and time-dependent manners.
  • Transcriptome and gene expression analyses have further revealed the Varlitinib- efficacy, -potency, and -inhibition gene signatures.
  • 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). Also, support to our observation that 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 oc-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 cc- catenin with ⁇ -catenin. This could lead to the assembly of the E-cadherin- oc-catenin ⁇ -catenin complex at the plasma membrane and to decreased ⁇ -catenin-dependent transcription.
  • 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).
  • 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.
  • Several clinical trials of Varlitinib in different cancer types, including cholangiocarcinoma and gastric cancer have been initiated and presented its safety profile with greatly improved toxicity profile compared to the irreversible pan-Her inhibitors such as Neratinib and Dacomitinib.
  • 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, HCCO l-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 Three responders (HCCOl-0708, HCC07-0409, and HCC29-0909A) and 9 non- responders (HCCOl-0909, HCC06-0606, HCC13-0109, HCC21-0208, HCC25-0705A, HCC26-0808A, HCC26-0808B, HCC29-1104, and HCC30-0805B] were analysed by gene expression microarray, followed by gene set enrichment analysis. Interestingly, all 3 responders grouped together based on the principal component analysis (Figure 26C).
  • GSEA Gene set enrichment analysis
  • 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].
  • total mRNA sequencing RNA-Seq] was used to analyse samples of vehicle-, 50mg/kg BID Variitinib-, and lOOmg/kg BID Var tinib-treated PDX samples.
  • 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 NRP2) and VEGF-independent [ANG, PDGFC and BMP2) pro- angiogenic pathways to facilitate vessel normalisation (Krneta et al, Kertesz et al and Andrae et al).
  • Expression of LGR5 ( ⁇ -catenin upstream regulator), YAPI, IRX3, and MYC were downregulated in both treated HCC29-0909A and HCCO l-0708 models.
  • expression of CDH1 was enhanced ( Figures 23E and 28F).
  • LEF1 was reduced in the treated HCC29- 0909A model ( Figure 28G).
  • Varlitinib treatment inhibits ErbB receptor pathways and promotes vessel normalisation and tumour perfusion in HCC PDX
  • Figures 24A, 24B, 30A and 30B displayed marked inhibition of ⁇ -catenin and its related pathways in the Varlitinib responder PDXs, HCC29-0909A, HCCO l-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).
  • 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?B£.3-expressing HCC in vitro.
  • in vivo efficacy was demonstrated in the responder PDXs, HCC29-0909A, HCC07-0409, and HCCOl-0708 in immunodeficient NOD/SCID mice, which displayed high levels of p-ErbB2/3, total ErbB2/3, and NRG1 gene expression.
  • HCC21-0208 and HCC16-1014 models expressed lower p-ErbB2 and p-ErbB3 levels, and were found to have poor efficacy to Varlitinib treatment.
  • 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).
  • 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 YAP1 for tumour progression (Rosenbluh et al].
  • YAP1 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 YAP1 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.
  • pan-ErbB inhibition effectively represses mutated ⁇ -catenin in in vivo models, linking ErbB receptor activities to mutated ⁇ -catenin localisation and functions in HCC. Further experiments will be needed to further confirm the proposed molecular mechanisms. Also, the effect of Varlitinib on other ⁇ -catenin mutations would need to be mechanistically explored.
  • the Wnt/ -catenin has been described as one of the main functional classes of molecular classification in HCC.
  • Sorafenib - a BRAF, C-RAF and VEGF-R inhibitor - can modulate Wnt/ ⁇ - catenin signalling in in vitro and in vivo CTNNB1 -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 Wnty ⁇ -catenin against HCC.
  • Wnty ⁇ -catenin pathway inhibitors ICGOOl, FH535, and other small inhibitors have been tested in HCC in different in vitro and in vivo models.
  • Several groups showed that the combination of Sorafenib and ICGOO l, and the combination of Sorafenib and FH535, resulted in better treatment outcomes in experimental models respectively (Galuppo et al, Gedaly et al).
  • studies have shown that inhibition of the ⁇ -catenin pathway in HCC is associated with the downregulation or degradation of wild-type ⁇ -catenin.
  • no small molecule inhibitor that directly targets mutant ⁇ -catenin exists.
  • Varlitinib could potentially reverse immunosuppression via vessel normalisation and targeting the activating ⁇ -catenin pathway in HCC. Combining Varlitinib with an immune checkpoint inhibitor in HCC would also be rational. To date, there are limited enrichment strategies for HCC clinical trials with any molecular targeted inhibitor (Llovet et al 2018).
  • 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 in different cancer types, including cholangiocarcinoma and gastric cancer, have been initiated.
  • 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 l OOmg/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 mm 10 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, M0). 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.
  • GSEA Gene Set Enrichment Analysis
  • Table 1 Transcriptome analysis of Varlitinib treatment in HCC29-0909A.
  • 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
  • A The top 20 activated and repressed genes commonly identified in 50 and l OOmg/kg BID Varlitinib-treated HCC29-0909A as well as lOOmg/kg BID Varlitinib-treated HCCOl-0708.
  • B KEGG pathway analysis showing the enriched pathways with FDR adjusted p-values ⁇ 0.05 generated from the lists of commonly dysregulated genes.
  • Table 3 The 3-way Venn diagram analysis revealing the Varlitinib-inhibition gene signature.
  • C Ingenuity Pathway Analysis showing the predicted repressed and activated pathways with enrichment 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
  • Ingenuity Pathway Analysis showing the predicted activated pathways with enrichment FDR adjusted p-values ⁇ 0.05.
  • D Ingenuity Pathway Analysis showing the predicted repressed pathways with enrichment FDR adjusted p-values ⁇ 0.05.
  • E The expression of CTGF, CYR61, MYC, and YAPl in HCCOl-0708 when compared to those in HCC29-0909A.
  • F The expression of CTGF, CYR61, MYC, and YAPl in lOOmg/kg BID Varlitinib-treated HCCOl-0708 when compared to those in vehicle control-treated HCCO l-0708.
  • 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.
  • HCO9O90SA Sesporsctet RSSIK m70A, i$55V mi m T4 H ⁇ st!tis 8 positte
  • BCOBi-0308 Sto esiWssier 8:i mi m m H «patW « 3 pos3 ⁇ 4fo «
  • Table 10 Transcriptome analysis of Varlitinib treatment in HCC29-0909A, HCCOl-0708, and HCC16-1014.
  • Table 13 Identification of ⁇ -catenin mutation and the constitutively active ⁇ -catenin pathways in the Variitinib-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.

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Abstract

La présente invention concerne un composé de formule (I), en particulier le Varlitinib, destiné à être utilisé dans une méthode de traitement d'une nouvelle population de patients cancéreux, les patients présentant les récepteurs HER1, HER2 et/ou HER3 activés sur leurs cellules cancéreuses, par exemple, un ou plusieurs des récepteurs étant phosphorylés.
PCT/SG2018/050535 2017-10-25 2018-10-25 Varlitinib destiné à être utilisé dans le traitement du cancer chez un patient identifié comme présentant des cellules cancéreuses à récepteurs her1, her2 et/ou her3 activés WO2019083455A1 (fr)

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US10682353B2 (en) 2015-09-04 2020-06-16 Aslan Pharmaceuticals Pte Ltd Varlitinib for use in the treatment of resistant or refractory cancer

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