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Rational Combination of MAP4K4 Inhibition and Immunotherapy in Pancreatic Cancer

MAP4K4抑制与免疫治疗在胰腺癌中的合理结合

基本信息

批准号：
10343661
负责人：
AJAY NMN RANA
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-10-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343661
关键词：
Address Affect Aging Animal Cancer Model Animal Model Animals Antibodies Antineoplastic Agents Apoptosis Apoptotic Cancer Etiology Cell Death Cell Line Cells Cessation of life Chemoresistance Combined Modality Therapy Cytotoxic T-Lymphocytes Data Desmoplastic Development Devices Diabetes Mellitus Ductal Epithelial Cell FDA approved Future Granzyme Human Immune Immunity Immunotherapy Incidence Infiltration Inflammation Inflammatory KPC model KRAS oncogenesis KRAS2 gene Laboratories Link MAP4K4 gene Malignant Neoplasms Malignant neoplasm of pancreas Mus Mutation Neoplasm Metastasis Oncogenic Outcome Paclitaxel Pancreas Pancreatic Ductal Adenocarcinoma Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Peripheral Pharmaceutical Preparations Phenotype Phosphotransferases Physiological Play Protein Family Reporting Research Resistance Role Series Severities Signal Pathway Survival Rate T-Lymphocyte TNF gene Therapeutic Therapeutic Intervention Time Tissues Treatment Efficacy Tumor Burden Tumor-infiltrating immune cells United States Veterans Vietnam War base cancer therapy chemotherapeutic agent clinically significant conventional therapy druggable target effector T cell efficacy testing expectation experimental study gemcitabine improved inhibitor interest mutant neoplastic novel overexpression pancreatic ductal adenocarcinoma model pre-clinical response treatment strategy tumor tumor microenvironment upstream kinase

项目摘要

Summary/Abstract: Pancreatic Ductal Adenocarcinoma (PDAC) remains remarkably lethal with a 5-year survival rate of less than 9%. Due to its widespread resistance to conventional therapy, PDAC is expected to be the second most common cause of cancer-related death in the United States by 2030. Oncogenic KRAS mutations are nearly uniform in PDAC, affecting over 90% of patients. The mutant KRAS is a key driver in the neoplastic phenotype, and leads to hyper-activation of KRAS, permitting for sustained proliferation, the evasion of apoptosis, as well as facilitating metastasis and the development of chemo-resistance. In spite of the importance of KRAS in PDAC pathobiology and extensive research aimed at the discovery of RAS-directed therapeutics, there are no FDA-approved drugs directed to target RAS; and RAS family proteins are largely considered `un-druggable'. Therefore, there is a need to identify either alternative- druggable target(s) or better approaches in hopes of improving patient outcomes. The inflammatory pathway is known to play significant roles in many cancer, including pancreatic cancer. Number of reports suggest that there is a direct link between inflammation and pancreatic cancer. We identified MLK3, a novel kinase that is activated by TNFα and plays role in pancreatic cancer pathogenesis. Recently we identified an MLK3 upstream kinase, MAP4K4, which is also activated by TNFα, suggesting perhaps, TNFα- MAP4K4-MLK3 axis might play a role in pancreatic cancer, which was corroborated by a recent report indicating worst outcomes in PDAC patient with high expression of MAP4K4. Considering our observation, we treated animal model of PDAC with a specific inhibitor of MAP4K4, GNE-495. Interestingly, the GNE-495 was able to ameliorate PDAC in the pre-clinical animal model, a significant decrease in stroma and increased cell death in cancerized ductal cells. Since immune cells play vital roles in cancer therapy, we examined peripheral immune compartment that had no effect of GNE-495. We rationalized to treat animals with 4-1BB agonistic antibody to activate effector T cells. The combined treatment of GNE-495 along with 4-1BB mab had profound effect on animal survival and almost stroma/Desmoplasia was absent in tumors. The overall objective of this proposal is to elucidate the role of MAP4K4 in PDAC and strategize a rational approach to combine MAP4K inhibitor and immunotherapies to overcome pancreatic cancer. The central objective will be addressed by: (1) defining the role of MAP4K4 in PDAC, (2) determining the impact of MAP4K4 inhibition in TME, and (3) determining impact of MAP4K inhibition along with immunotherapy on host immunity. Upon completion of these three aims, it is our expectation, that first, we will be able to establish the role of MAP4K4 in PDAC. Second, we would establish clinical significance of targeting MAP4K4, along with rationalized immunotherapy for an alternative pancreatic cancer treatment strategy.

摘要/文摘: