Project 1: Targeting Metabolic Dependencies in PDAC

摘要-项目1（针对PDAC中的代谢缺陷） 胰腺导管腺癌（PDAC）是美国第四大癌症死亡原因 中位生存期不到6个月，5年生存率低至7%。高度恶性 PDAC的性质很大程度上是驱动>90%肿瘤中致癌Kras突变（Kras*）的结果，以及 疾病在基因组和细胞水平上的异质性。到目前为止，没有药物直接 靶向Kras* 的药物已经进入临床，临床试验中的Kras* 效应通路抑制剂已经实现了 只有最小的反应，随后是侵袭性疾病的复发。此外，PDAC的免疫靶向 到目前为止还没有成功。因此，迫切需要确定PDAC中新的治疗弱点。 在我们之前的资助周期中，项目1和我们的P01团队确定了Kras* 在肿瘤维持中的作用， 在体内，它控制着支持癌症相关合成代谢过程的关键代谢酶，反过来， Kras* 驱动的PDAC维护需要。使用我们的诱导型Kras* PDAC模型，我们还鉴定了一种 具有肿瘤起始细胞（TIC）特性的肿瘤细胞亚群，可以在Kras* 灭绝后存活，并可能导致 癌基因切除后肿瘤复发。这些抗Kras抗体细胞的特征之一 KRC是从有氧糖酵解到线粒体氧化代谢的转变，以维持细胞活力。我们 P01团队进一步证明，虽然PDAC表现出高基础自噬，但KRC中的自噬通量是 进一步增强以提供线粒体氧化磷酸化（OXPHOS）的底物， 自噬或OXPHOS有效地消除了KRC以防止肿瘤复发。因此，协同工作 来自我们P01团队的研究强烈表明，PDAC的有效治疗方法不仅应该针对球员， 这是Kras* 依赖性肿瘤维持所必需的，也是维持KRC所需的途径。这些数据 是在上一个资助周期期间开始的开发新型OXPHOS抑制剂化合物的倡议的基础 在PDAC，IACS-10759中，在应用癌症科学研究所。在下一个周期，项目1将继续我们的 努力更好地定义维持Kras* 依赖性肿瘤以及KRC的代谢程序， 探索靶向代谢过程的翻译潜力，包括用IACS靶向OXPHOS- 10759.项目1将与核心密切合作，核心在病理学、临床前 治疗学和计算生物学，并将与项目2高度整合，以表征 自噬调节途径。我们的研究还将与项目3整合，使用我们的诱导型Kras* 小鼠 模型，以探索Kras* 依赖性和非依赖性代谢程序对肿瘤免疫的影响 和对免疫检查点疗法的反应。从这些高度综合的研究中获得的知识旨在 为未来的临床试验提供信息。

Abstract - Project 1 (Targeting Metabolic Dependencies in PDAC) Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of less than 6 months and a dismal 5-year survival rate of 7%. The highly malignant nature of PDAC is largely the result of driving oncogenic Kras mutations (Kras*) in >90% of tumors, as well as the heterogeneous nature of the disease at both the genomic and cellular levels. To date, no drug directly targeting Kras* has reached the clinic, and inhibitors of Kras* effector pathways in clinical trials have achieved only minimal responses followed by relapse of aggressive disease. Furthermore, immune targeting of PDAC has so far been unsuccessful. Thus, a critical need remains to identify new therapeutic vulnerabilities in PDAC. In our previous grant cycle, Project 1 and our P01 team established a role for Kras* in tumor maintenance in vivo wherein it controlled key metabolism enzymes supporting cancer-relevant anabolic processes that, in turn, are required for Kras*-driven PDAC maintenance. Using our inducible Kras* PDAC model, we also identified a subset of tumor cells with tumor-initiating cell (TIC) properties that can survive Kras* extinction and may lead to tumor recurrence following oncogene ablation. One of the hallmarks of these Kras* extinction-resistant cells (KRCs) is the shift from aerobic glycolysis to mitochondrial oxidative metabolism to sustain cell viability. Our P01 team further demonstrated that, while PDAC exhibits high basal autophagy, autophagic flux in KRCs was further enhanced to supply substrate for mitochondrial oxidative phosphorylation (OXPHOS), and targeting autophagy or OXPHOS effectively eliminated KRCs to prevent tumor relapse. Therefore, the collaborative work from our P01 team strongly suggests that effective therapeutics for PDAC should target not only players essential for Kras*-dependent tumor maintenance, but also pathways required to maintain KRCs. These data are the basis for an initiative begun during the last grant cycle to develop a novel OXPHOS inhibitor compound in PDAC, IACS-10759, at the Institute for Applied Cancer Science. In this next cycle, Project 1 will continue our efforts to better define the metabolism programs that sustain Kras*-dependent tumors as well as KRCs and to explore the translational potential of targeting metabolic processes, including targeting OXPHOS with IACS- 10759. Project 1 will work closely with the Cores, which have extensive expertise in pathology, preclinical therapeutics, and computational biology, and will be highly integrated with Project 2 to characterize the role of autophagy-regulating pathways. Our studies will also integrate with Project 3, using our inducible Kras* mouse model to explore the effects of Kras*-dependent and –independent metabolism programs on tumor immunity and response to immune checkpoint therapy. The knowledge gained from these highly integrated studies aims to inform future clinical trials opportunities.