Interrogating the Evolutionary Dynamics of Cancer for Clinical Benefit and Actionability

探究癌症的进化动力学以获得临床益处和可操作性

• 批准号: 10226957
• 负责人: Christine A Iacobuzio-Donahue
• 金额: $ 89.56万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10226957
• 关键词: Address; BRCA2 Mutation; Biology; Cancer Biology; Cancer Etiology; Cells; Cessation of life; Clinical; Clinical Management; Common Neoplasm; Computer Models; Diagnosis; Disease; Evolution; Excision; Genetic Transcription; Genome; Goals; Heterogeneity; Immune checkpoint inhibitor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mismatch Repair Deficiency; Neoplasm Metastasis; Operative Surgical Procedures; PARP inhibition; Patients; Platinum; Research; Salts; Sampling; Therapeutic; Time; Tissues; United States; Work; base; clinically relevant; exome; experimental study; innovation; interest; mouse model; novel strategies; pancreatic neoplasm; single cell technology; statistics; tumor; tumor heterogeneity; whole genome

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.

项目摘要 PDA 是胰腺最常见的肿瘤，并且很快将成为胰腺癌的第二常见原因 美国癌症死亡人数。 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 年内复发并死于疾病2。第三阶段和第三阶段的统计数据 IV 期 PDA 更令人沮丧，中位总生存时间分别为 12 个月和 6 个月。之外 BRCA2 突变导致对铂盐、PARP 抑制或免疫检查点抑制剂敏感 在错配修复缺陷的患者中，PDA 基因组中几乎没有可操作的靶点。因此，它是 制定新策略以延长生存至关重要。一种创新的方法是“治疗 进化与进化”。然而，我们首先必须深入了解 PDA 进化生物学。我们的努力将集中在三个具有明确机制和转化的问题上 与这个最终目标的相关性。首先，临床相关的瘤内异质性有哪些特征？ 遗传和转录水平？二、细胞自主因素和非细胞自主因素如何作用 影响PDA的进化动力学？第三，PDA疗法如何影响进化轨迹， 它们能否在肿瘤的进化背景下得到更有效的利用？我们将依赖全外显子组 或原发性和转移性胰腺癌组织、单细胞的全基因组测序样本 拷贝数改变或 RNA 表达技术、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此期间获得的信息 这项工作旨在开发异质性指标，为临床管理提供信息，包括识别 根据患者 PDA 的进化背景，选择最佳药物和给药时机。这样的 总体而言，问题在癌症生物学中引起了广泛的兴趣，并且很可能影响其他领域 肿瘤类型也是如此。