Project 3: Inhibiting Oxidative Phosphorylation in Pancreatic Cancer

项目3：总结/摘要 胰腺导管腺癌（PDAC）占美国所有癌症死亡的6.9%，占美国所有癌症死亡的1.5%。 美国人一生中将被诊断为PDAC。目前，先进的一线治疗 PDAC是多药化疗，最常见的是FOLFIRINOX或吉西他滨和nab-紫杉醇。尽管 更好地了解基因组景观和肿瘤微环境的重要性， 这种疾病的总生存率没有任何有意义的变化。一个新兴的概念是， KRAS和其他典型癌基因也直接驱动PDAC和其他肿瘤的加速生长 通过增加营养物质的获取，再加上下游代谢途径的通量增加，重新编程细胞代谢。对KRAS的差异依赖性也与代谢依赖性的改变有关。上述结果表明，PDAC的异质性不仅局限于基因组上， 和细胞水平，但也由致癌信号控制的独特代谢程序定义。 然而，到目前为止，一些肿瘤或肿瘤细胞亚群对OXPHOS的依赖性已被证实， 尚未被用于治疗。德克萨斯大学MD安德森癌症中心应用癌症科学研究所（IACS）开发了IACS-010759，一种有效的电子复合物I抑制剂， 运输链。IACS化合物使PDAC模型中OXPHOS抑制的扩展研究成为可能 建立了在两种情况下在患者中评价IACS-010759的临床前依据：（i） 对OXPHOS抑制具有内在敏感性的未经治疗或难治性肿瘤，以及（ii）化疗治疗后的代谢适应性疾病。这项研究的目的是探索生物学 在这些情况下，使用离体和体内研究的组合，以及通过临床相关因素（转录组学特征，超极化）评价患者反应， 计划在未经治疗或难治性疾病患者（Ib期）或既往治疗有应答的患者中进行的Ib期和IIa期临床研究中， 标准治疗化疗（2a期）。这项研究意义重大，因为它将全面评估 用于特定疾病背景下PDAC患者的新靶向治疗方法，所述疾病背景包括（i）侵袭性， 间充质样肿瘤（“内在”敏感性）和用化学毒性剂治疗后的代谢适应性肿瘤（“适应性”敏感性），这是该患者群体的当前护理标准。这项研究是创新的，因为它将评估一种全新的PDAC患者的靶向治疗方法， 它可以在特定的疾病背景下使用，并采用创新的生物物理和代谢成像表征。是 预计这项研究可能会产生与代谢依赖性可能相似的其他疾病适应症相关的数据，我们从这项研究中获得的发现可能是开发IACS-010759的一个步骤， 其他肿瘤的临床研究也是如此。

PROJECT 3: Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) contributes to 6.9% of all cancer deaths in the US, and >1.5% of the US population will be diagnosed with PDAC in their lifetime. At present, the front-line therapy for advanced PDAC is multi-agent chemotherapy, most commonly, FOLFIRINOX or gemcitabine and nab-paclitaxel. Despite a better understanding of the genomic landscape and the importance of the tumor’s microenvironment, there has been no meaningful shift in the overall survival for this disease. An emerging concept is that mutations in KRAS and other canonical oncogenes that drive accelerated growth in PDAC and other tumors also directly reprogram cellular metabolism by augmenting nutrient acquisition, coupled to an increased flux through down-stream metabolic pathways. Differential dependence on KRAS has also been linked with altered metabolic de-pendencies. The findings above indicate that the heterogeneity of PDAC is not only defined on the genomic and cellular levels, but also defined by distinctive metabolism programs controlled by oncogenic signaling. However, to date, the documented dependency of some tumors or tumor cell subpopulations on OXPHOS has not yet been exploited therapeutically. The University of Texas MD Anderson Cancer Center Institute for Ap-plied Cancer Science (IACS) has developed IACS-010759, a potent inhibitor of complex I of the electron transport chain. The IACS compound has enabled expanded studies of OXPHOS inhibition in PDAC models that establish the preclinical rationale for evaluating IACS-010759 in patients in two contexts: (i) patients with treatment-naïve or refractory tumors that possess intrinsic sensitivity to OXPHOS inhibition, and (ii) in metabol-ically adapted disease following treatment with chemotherapy. The aims of this study are to explore the biology of response to treatment with IACS-010759 in these contexts, using a combination of ex vivo and in vivo stud-ies, as well as evaluating patient response via clinical correlatives (transcriptomic signatures, hyperpolarized pyruvate-magnetic resonance imaging, quantitative CT scan) in planned phase 1b and phase 2a clinical stud-ies in patients with treatment-naïve or refractory disease (phase 1b) or patients who have responded to prior standard-of-care chemotherapy (phase 2a). This research is significant because it will evaluate a completely novel targeted therapy approach for patients with PDAC in specific disease contexts that include (i) aggressive, mesenchymal-like tumors (“intrinsic” sensitivity) and metabolically adapted tumors post-treatment with chemo-toxic agents (“adaptive” sensitivity), the current standard of care for this patient population. The research is in-novative because it will evaluate a completely novel targeted therapy approach for patients with PDAC in these specific disease contexts, and it employs innovative biophysical and metabolic imaging characterizations. It is anticipated that this research may yield data relevant for other disease indications where metabolic dependen-cies may be similar, and our findings from this research may be a step toward developing IACS-010759 for clinical studies in other tumors as well.