The role of PI3K in pancreatic cancer genetics and progression

胰腺癌(PDAC)是美国癌症相关死亡的第三大原因， 五年存活率为4%。它也是VA患者人群死亡的主要原因。 寻找新的PDAC治疗策略迫在眉睫，因为目前的治疗方法几乎没有 对患者生存的影响。超过90%的PDAC存在Kras基因的致癌突变。这个 肌醇磷脂3-激酶p110α催化亚基(基因名PIK3CA)是Kras的下游效应因子。我们 先前报道，胰腺特异的PIK3CA消融完全保护小鼠免受肿瘤的影响 KrasG12D诱导的肿瘤形成。目前的建议是研究PIK3CA在胰腺肿瘤后的作用 已经形成了。侵袭性KrasG12D和Trp53R172H(KPC)细胞原位移植于小鼠胰腺 免疫功能正常的小鼠会导致宿主动物肿瘤的快速发展和死亡。然而，当PIK3CA 沉默后，种植的KPC肿瘤完全消退。令人惊讶的是，移植的PIK3CA-Null KPC肿瘤 进展并杀死免疫缺陷小鼠，但过继转移T淋巴细胞完全保护了 这些肿瘤中的小鼠。因此，我们假设在肿瘤细胞中抑制PIK3CA，而不是 抑制免疫细胞中的PI3K信号，将允许免疫介导的胰腺癌消退。 在目标1中，我们将研究PIK3CA-Null与亲本KPC的信号通路和基因图谱 为了更好地了解肿瘤细胞被敲除后引起的免疫学变化。我们还将 检查宿主T细胞的反应，以更好地了解胰腺肿瘤如何逃避免疫监视。在……里面 目的2，我们将评估抑制胰腺癌细胞中p110α的策略的治疗潜力。 而不抑制细胞毒T淋巴细胞的PI3K信号转导。成功完成这项提案将 洞察PI3K调节的机制，使PDAC逃避免疫系统并取得进展 一种致命的疾病。这一理解可能会让未来的研究阐明最合适的方法 靶向PDAC中的PIK3CA信号通路以改善这种致命癌症的治疗。

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the U.S.A., with a five-year survival rate of 4%. It is also a major cause of mortality among the VA patient population. There is great urgency to identify new therapeutic strategies for PDAC because current treatments have little impact on patient survival. More than 90% of PDACs have oncogenic mutations in the Kras gene. The phosphoinositide 3-kinase p110α catalytic subunit (gene name Pik3ca) is a downstream effector of Kras. We previously reported that pancreas-specific ablation of Pik3ca completely protected mice from oncogenic KrasG12D-induced tumor formation. The current proposal investigates the role of Pik3ca after pancreatic tumors have formed. Invasive KrasG12D and Trp53R172H (KPC) cells orthotopically implanted in the pancreas of immunocompetent mice leads to rapid tumor progression and death of the host animal. However, when Pik3ca was silenced, implanted KPC tumors completely regressed. Surprisingly, implanted Pik3ca-null KPC tumors progressed and killed immunodeficient mice, but adoptive transfer of T lymphocytes completely protected the mice from these tumors. Therefore, we hypothesize that inhibition of Pik3ca in the tumor cells, without inhibiting PI3K signaling in the immune cells, will allow an immune-mediated regression of pancreatic cancer. In Aim 1, we will investigate the signaling pathways and genetic profiles of Pik3ca-null versus parental KPC cells to better understand the immunological changes caused by the knockout tumor cells. We will also examine the host T-cell response to better understand how pancreatic tumors evade immune surveillance. In Aim 2, we will assess the therapeutic potential of a strategy that inhibits p110α in pancreatic cancer cells without inhibiting PI3K signaling in cytotoxic T lymphocytes. Successful completion of this proposal will produce insights into PI3K-regulated mechanisms that allow PDAC to evade the immune system and progress to a deadly disease. This understanding may allow future studies to elucidate the most appropriate means of targeting Pik3ca signaling pathways in PDAC to improve therapy for this deadly cancer.