EP-4115907-B1 - COMBINATION DRUG OF KINASE INHIBITORS FOR USE IN THE TREATMENT OF PANCREATIC CANCER
Inventors
- SONOSHITA MASAHIRO
- SEKIYA Sho
- HIRANO SATOSHI
Dates
- Publication Date
- 20260506
- Application Date
- 20210301
Claims (3)
- A pharmaceutical combination of Trametinib and at least one kinase inhibitor selected from the group consisting of AD80, BI-831266 and Y-27632 for use in the treatment of pancreatic cancer.
- A kinase inhibitor for use in combination with Trametinib for use in the treatment of pancreatic cancer, the kinase inhibitor being selected from the group consisting of AD80, BI-831266 and Y-27632.
- Trametinib for use in combination with at least one type of kinase inhibitor selected from the group consisting of AD80, BI-831266 and Y-27632, for use in the treatment of pancreatic cancer.
Description
FIELD The present invention pertains to a pharmaceutical combination of at least two types of kinase inhibitors for treatment of pancreatic cancer, and a kinase inhibitor for use in the pharmaceutical combination. BACKGROUND Pancreatic cancer is one of the most difficult cancers to treat. At present, pancreatic cancer is the fourth leading cause of cancer death and expected to be second within 10 years, raising concerns about major social problems. Pancreatic ductal carcinoma developing in the pancreatic duct accounts for 90% of pancreatic cancer or more, and is characterized by the absence of subjective symptoms even after onset. For this reason, patients frequently miss the opportunity for diagnosis and have cancer cells metastasized to other organs when diagnosed. Metastasis accounts for poor prognosis. Therefore, the survival rate of pancreatic cancer patients is the lowest among the patients of all types of cancer. Therefore, development of therapies for prevention and treatment of pancreatic cancer has been an extremely important issue for many years. Pancreatic cancer is known to show extremely high resistance to drug therapy, and development of new drugs has been extremely difficult. Even the few approved drugs such as gemcitabine, an antimetabolic agent, and erlotinib, an EGFR inhibitor, have been pointed out to have problems such as insufficient efficacy and toxicity. Pancreatic cancer frequently harbors four gene mutations, which are KRAS gene mutation inducing KRAS activation, TP53 gene mutation inducing TP53 inactivation, CDKN2A gene mutation inducing CDKN2A inactivation and SMAD4 gene mutation inducing SMAD4 inactivation. Patients with pancreatic cancer with the poorest prognosis are known to have all of the above four gene mutations (Non-Patent Literature 1). Therefore, animal models with the above four gene mutations and research on therapies by using the animal models are of great importance in developing therapies for pancreatic cancer. However, to date, no animal model mimicking the abnormality of these four genes has been produced, and therefore remaining major obstacle in the research field. In recent years, use of Drosophila as an animal model has been attracting attentions. As a useful animal model Drosophila has the following characteristics: high genetic conservation with mammals (for example, 75% or more of genes altered in human diseases are present also in Drosophila); conserved internal structures (epithelial structure, main organs and the like) functionally corresponding to those in mammals; a wide variety of genetic analysis tools (siRNA knockdown lines and mutants for almost all genes are available); and rapid and inexpensive rearing (in 10 days for production of next generation, rearing cost at one-thousandth of that for mice). Inventors of the present invention reported on the exploration for kinases involved in medullary thyroid cancer and screening of anticancer agents basing upon the kinase information with use of a Drosophila strain ptc>dRetM955T, which expresses a mutant form of RET, a receptor tyrosine kinase associated with medullary thyroid cancer, as an animal model (Patent Literature 1, Non-Patent Literatures 2 to 4). The ptc>dRetM955T fly is modified to express the RET mutant in epithelial cells localized to a wing disc of larva with use of ptc promotor and gal4-UAS system, which is a binary system capable of forcing the expression of foreign genes in Drosophila. ptc>dRetM955T flies exhibit the property of producing tumor-like lesions that cause all individuals to die without reaching adulthood. Thus, using Drosophila as an animal model is an effective means for developing cancer therapies. However, since the ptc>dRetM955T fly is a model for medullary thyroid cancer, it is necessary to create a new animal model for pancreatic cancer in order to explore therapies for pancreatic cancer. CITATION LIST PATENT LITERATURE Patent Literature 1: Japanese Translation of PCT Application Publication No. 2019-528279 NON PATENT LITERATURES Non Patent Literature 1: Qian et al., JAMA Oncol. 2018; 4(3): e173420.Non Patent Literature 2: Sonoshita et al., Curr. Top. Dev. Biol. 2017; 121:287-309Non Patent Literature 3: Sonoshita et al., Nat. Chem. Biol. 2018; 14(3): 291-298.Non Patent Literature 4: Ung, Sonoshita et al., PLoS Comput. Biol. 2019; 15(4): e1006878. WO2018203219 relates to a pharmaceutical combination comprising (a) a Raf inhibitor and (b) a MEK inhibitor. WO2012167247 relates to methods for treatment of various cell proliferative disorders by administering a MEK inhibitor in combination with a selective inhibitor of Aurora A kinase. Walters et al relates to inhibition of growth of patient derived pancreatic cancer cell lines with Trametinib (MEK inhibitor) combined with lapatinib (EGFR/HER2 inhibitor). WO2020010280 relates to methods for treating pancreatic cancer using a MEK inhibitor and a CDK4/6 inhibitor. WO2015041533 relates to combined use of inhibitors of ROCK p