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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.

该方案的目的是探索如何靶向PIK3CA信号转导治疗胰管疾病。腺癌(PDAC)。这种致命的癌症对目前的治疗方案高度耐药，包括使用检查点抑制剂的免疫疗法。超过90%的PDAC在KRAS中存在癌基因突变，并且 PIK3CA是KRAS的直接效应因子。我们小组首次报道了胰腺中PIK3CA的基因消融完全保护小鼠免受致癌的KRAS诱导的肿瘤形成，随后报道 PIK3CA通过保护胰腺肿瘤免受免疫系统的攻击，在维持胰腺肿瘤的过程中发挥了关键作用。免疫活性KrasG12D、Trp53R172H、Pdx1-Cre(KPC)胰腺肿瘤细胞的原位移植小鼠100%致死，而植入PIK3CA-/-KPC(PIK3CA-KO)KPC细胞的小鼠表现出肿瘤消退，动物存活率100%。一种全基因组的基因缺失屏幕，以搜索可以逆转免疫系统识别的PCCB对PIK3CA-KO细胞的消除，从而催化丙酰辅酶A的羧化反应生成甲基丙二酰辅酶A。PCCB阴性的PIK3CA-KO KPC细胞当移植到小鼠体内时，这些肿瘤不会被宿主免疫系统清除。二假设将被检验：1)PIK3CA的致癌KRAS激活调节PCCB调节的代谢有利于胰腺癌从免疫消除中逃脱的环境；以及2)Alpelisib抑制 PIK3CA增强抗PD1+抗PCSK9治疗胰腺肿瘤的活性。目标1 研究PIK3CA的KRAS激活调节PCCB调节的代谢的机制有利于胰腺癌免疫逃逸的环境，包括上调免疫检查点和T细胞衰竭。将肿瘤浸润性T细胞分离出来，并用单细胞RNA和T细胞进行分析受体(TCR)V(D)J测序、流式细胞术和IHC。采用T细胞转移实验将是以确定先前暴露于PCCB阴性的PIK3CA-KO肿瘤的T细胞是否会消除PIK3CA-KO- 将KO瘤移植到SCID小鼠体内。PCCB缺失的PIK3CA-KO与PIK3CA-KO的细胞代谢和免疫学特性将测量PIK3CA-KO和亲本KPC细胞系，以更好地了解代谢变化由PIK3CA和PCCB控制，以及这些变化如何导致免疫抑制。目标2是一个一项测试PIK3CA抑制剂alpelisib与中和联合治疗效果的治疗研究抗PD-1和PCSK9抗体原位植入KPC治疗胰腺癌老鼠模型。肿瘤浸润性T细胞也将被分离并通过单细胞测序进行分析。在……里面综上所述，本提案将研究PIK3CA信号如何调节代谢和免疫学胰腺癌的侧写。Alpelisib、抗PD1抗体和抗PCSK9抗体都是FDA批准的用于临床应用。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胰腺癌的治疗。