Interrogating the Evolutionary Dynamics of Cancer for Clinical Benefit and Actionability

项目摘要 动脉导管未闭是最常见的胰腺肿瘤，很快将成为第二大常见致病因素。 美国的癌症死亡人数。I/II期患者的手术切除提供了唯一的机会 治愈，但80%的患者会在2-3年内复发并死于他们的疾病2。第三阶段和第三阶段的统计数字 IV期PDA更令人沮丧，中位总生存期分别为12个月和6个月。在外部 BRCA2突变使其对铂盐或PARP抑制或免疫检查点抑制物敏感 在错配修复缺陷患者中，PDA基因组中几乎没有可操作的靶点。因此，它是 至关重要的是，开发新的战略来延长生存。要做到这一点，一种创新的方法是“治疗” 进化与进化“。然而，我们首先要对PDA有一个深刻的理解 进化生物学。我们的努力将集中在三个问题上，具有明确的机械性和转换性 与这一最终目标的相关性。首先，临床相关的肿瘤内异质性的特征是什么？ 基因和转录水平？第二，细胞自主和非细胞自主因素是如何 影响掌上电脑的进化动态？第三，PDA疗法如何影响进化轨迹， 它们能在肿瘤的进化背景下得到更有效的利用吗？我们将依靠整个外星人 或原发癌和转移性胰腺癌组织的全基因组测序样本，单细胞 拷贝数改变或RNA表达的技术、长期进化实验、小鼠模型 和计算模型来解决这些问题。我们的目标是利用在这段时间内获得的信息 这项工作旨在开发将为临床管理提供信息的异质性度量标准，包括识别 根据患者的PDA的演变背景，选择最佳的给药药物和给药时机。是这样的 这些问题通常对癌症生物学有广泛的兴趣，并有很大可能影响其他 肿瘤类型也是如此。

Project Abstract PDA is the most common neoplasm of the pancreas, and is soon to be the second most common cause of cancer deaths in the United States. Surgical resection in Stage I/II patients provides the only opportunity for cure, yet >80% of patients will recur and die of their disease within 2-3 years2. The statistics for Stage III and Stage IV PDA are more dismal, having 12 and 6 month median overall survival times, respectively. Outside of BRCA2 mutations that confer sensitivity to platinum salts or PARP inhibition, or immune checkpoint inhibitors in patients with mismatch repair deficiency, there are few actionable targets in the PDA genome. Thus, it is essential that novel strategies are developed to extend survival. One innovative way to do so is to “treat evolution with evolution”. However, it is first imperative that we develop a deep understanding of PDA evolutionary biology. Our efforts will be focused on three questions with clear mechanistic and translational relevance to this ultimate goal. First, what are the features of clinically relevant intratumoral heterogeneity at the genetic and transcriptional level? Second, how do cell autonomous and non-cell autonomous factors influence the evolutionary dynamics of PDA? Third, how do PDA therapies influence evolutionary trajectories, and can they be more effectively used within the evolutionary context of a tumor? We will rely on whole exome or whole genome sequenced samples of primary and metastatic pancreatic cancer tissues, single cell technologies for copy number alterations or RNA expression, long-term evolution experiments, mouse models and computational models to address these questions. We aim to use the information gained over the period of this work to develop metrics of heterogeneity that will inform clinical management, including identification of the optimal agents and timing of administration based on the evolutionary context of the patients' PDA. Such questions are of broad interest in cancer biology in general and have a strong likelihood to impact upon other tumor types as well.