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.

该提案的目的是探索如何靶向pik3ca信号以治疗胰腺导管腺癌（PDAC）。这种致命的癌症对当前治疗方案具有高度抗性，包括带有检查点抑制剂的免疫疗法。超过90％的PDAC在KRAS中具有致癌突变，并且 PIK3CA是KRAS的直接效应子。我们的小组首先报道了胰腺中PIK3CA的遗传消融完全保护小鼠免受致癌性KRAS诱导的肿瘤的形成，随后报告说 PIK3CA通过屏蔽免疫系统来维持胰腺肿瘤在维持胰腺肿瘤中起着至关重要的作用。 Krasg12d的原位植入; TRP53R172H; PDX1-CRE（KPC）胰腺肿瘤细胞中的免疫能力肿瘤细胞小鼠引起100％致死性，而植入Pik3CA - / - KPC（PIK3CA-KO）KPC细胞的小鼠表现出具有100％动物生存的肿瘤回归。全基因组的基因缺失筛选，以搜索分子可以通过免疫系统鉴定出PCCB的PIK3CA-KO细胞消除PCCB，从而扭转了PCCB的催化丙酰辅酶A的羧化以产生甲基氨基甲酸-COA。 PCCB-NULL PIK3CA-KO KPC细胞为产生的，当植入小鼠时，这些肿瘤没有被宿主免疫系统清除。二将测试假设：1）PIK3CA的致癌KRAS激活调节PCCB调节的代谢有利于免疫消除胰腺癌的环境； 2）alpelisib抑制 PIK3CA增强了抗PD1和抗PCSK9对胰腺肿瘤的活性。目标1 研究了PIK3CA的KRAS激活调节PCCB调节的代谢机制有利于免疫逃避胰腺癌的环境，包括上调免疫检查点和T细胞耗尽。肿瘤浸润T细胞将通过单细胞RNA和T细胞分离并分析受体（TCR）V（D）J测序，流式细胞术和IHC。收养T细胞传输实验将是进行的以确定先前暴露于PCCB-NULL PIK3CA-KO肿瘤的T细胞是否会消除PIK3CA- 植入SCID小鼠的KO肿瘤。 PCCB-NULL PIK3CA-KO VS的细胞代谢和免疫学概况。 PIK3CA-KO和父母KPC细胞系将测量以更好地了解代谢改变由PIK3CA和PCCB控制，以及这些变化如何导致免疫抑制。目标2是测试PIK3CA抑制剂Alpelisib的疗效，结合中和的治疗研究针对PD-1和PCSK9的抗体使用原始植入的KPC治疗胰腺癌鼠标模型。肿瘤浸润T细胞也将通过单细胞测序分离和分析。在总而言之，该提案将调查PIK3CA信号如何调节代谢和免疫学胰腺癌的特征。 Alpelisib，抗PD1抗体和抗PCSK9抗体都是FDA批准的临床用途。成功完成我们的研究可能会导致这些批准的药物进行临床试验治疗胰腺癌。