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PIK3CA signaling and pancreatic cancer

PIK3CA 信号传导与胰腺癌

基本信息

批准号：
10722155
负责人：
RICHARD Z LIN
金额：
$ 22.06万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-08 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722155
关键词：
Ablation Animals Antibodies Cancer Etiology Cell Line Cells Cellular Metabolic Process Cessation of life Clinical Clinical Trials Data Disease Environment Exhibits Exposure to FDA approved Flow Cytometry Gene Deletion Genes Genetic Goals Growth Harvest Histocompatibility Antigens Class I Human Hyperlipidemia Hypoxia Immune Evasion Immune checkpoint inhibitor Immune response Immune system Immunocompetent Immunohistochemistry Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Implant Infiltration KPC model KRAS oncogenesis KRAS2 gene KRASG12D Laboratories Leucocytic infiltrate MHC Class I Genes Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Metabolic Mus Mutation Names Oncogenic Operative Surgical Procedures PIK3CA gene Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Pilot Projects Play Proteins RNA Reporting Resistance Role SCID Mice Signal Transduction T cell infiltration T cell therapy T-Cell Receptor T-Lymphocyte Target Populations Testing Therapeutic Therapeutic Studies Treatment Protocols Up-Regulation Work alpelisib anti-PD-1 anti-PD1 antibodies cancer cell cancer infiltrating T cells carboxylate carboxylation cell type effective therapy efficacy testing exhaustion experimental study genome-wide immune checkpoint immune clearance implantation improved in vivo imaging system in vivo monitoring inhibitor instrument metabolic profile methylmalonyl-coenzyme A mouse model neoplastic cell neutralizing antibody pancreatic cancer cells pancreatic neoplasm pharmacologic programmed cell death ligand 1 programmed cell death protein 1 propionyl-coenzyme A side effect single cell sequencing therapeutic target tumor tumor growth tumor progression tumor-immune system interactions

项目摘要

The goal of this proposal is to explore how to target PIK3CA signaling for treatment of pancreatic ductal adenocarcinoma (PDAC). This deadly cancer is highly resistant to current treatment regimens, including immunotherapy with checkpoint inhibitors. More than 90% of PDAC have oncogenic mutations in KRAS, and PIK3CA is a direct effector of KRAS. Our group first reported that genetic ablation of PIK3CA in the pancreas completely protected mice against oncogenic KRAS-induced tumor formation, and subsequently reported that PIK3CA plays a critical role in sustaining pancreatic tumors by shielding them from the immune system. Orthotopic implantation of KrasG12D;Trp53R172H;Pdx1-Cre (KPC) pancreatic tumor cells in immunocompetent mice caused 100% lethality, whereas mice implanted with Pik3ca-/- KPC (PIK3CA-KO) KPC cells exhibited tumor regression with 100% animal survival. A genome-wide gene deletion screen to search for molecules that can reverse the elimination of PIK3CA-KO cells by the immune system identified PCCB, which catalyzes the carboxylation of propionyl-CoA to produce methylmalonyl-CoA. PCCB-null PIK3CA-KO KPC cells were generated, and when implanted in mice, these tumors were not cleared by the host immune system. Two hypotheses will be tested: 1) Oncogenic KRAS activation of PIK3CA modulates a PCCB-regulated metabolic environment that favors evasion of pancreatic cancer from immune elimination; and 2) Alpelisib inhibition of PIK3CA enhances the activity of anti-PD1 plus anti-PCSK9 therapy against pancreatic tumors. Aim 1 investigates mechanisms by which KRAS activation of PIK3CA modulates a PCCB-regulated metabolic environment that favors immune evasion of pancreatic cancer, including upregulation of immune checkpoints and T cell exhaustion. Tumor infiltrating T cells will be isolated and analyzed by single-cell RNA and T cell receptor (TCR) V(D)J sequencing, flow cytometry and IHC. Adoptive T cell transfer experiments will be performed to determine if T cells previously exposed to PCCB-null PIK3CA-KO tumors will eliminate PIK3CA- KO tumors implanted in SCID mice. Cell metabolism and immunological profile of PCCB-null PIK3CA-KO vs. PIK3CA-KO and parental KPC cell lines will be measured to better understand the metabolic alterations controlled by PIK3CA and PCCB and how these changes may lead to immune suppression. Aim 2 is a therapeutic study that tests the efficacy of alpelisib, a PIK3CA inhibitor, in combination with neutralizing antibodies against PD-1 and PCSK9 for treatment of pancreatic cancer using the orthotopically implanted KPC mouse model. Tumor infiltrating T cells will also be isolated and analyzed by single-cell sequencing. In summary, this proposal will investigate how PIK3CA signaling regulates the metabolic and immunological profile of pancreatic cancer. Alpelisib, anti-PD1 antibodies and anti-PCSK9 antibodies are all FDA-approved for clinical use. Successful completion of our studies may lead to clinical trials with these approved drugs for treatment of pancreatic cancer.

本提案的目的是探索如何靶向PIK3CA信号治疗胰管