UCSF Project 1

项目总结 肿瘤发生的特定分子驱动因素的发现导致了癌症治疗的转变 患者，从使用传统的细胞毒性化疗转向分子治疗 通常更有效、毒性更低的靶向药物(例如，EGFR和ALK抑制剂和免疫- 检查点抑制免疫疗法)。然而，靶向抑制剂和免疫疗法的成功已经 强调了抗药性的挑战和重要性。虽然患者通常受益于初始和 对这些当前治疗的深刻反应，绝大多数反应是不完整的，并导致 残留疾病状态，作为后续肿瘤进展的前奏(获得性耐药)。而当 一些研究已经描述了各种靶向治疗获得性耐药的机制 抑制剂和免疫疗法，对不完全反应和免疫治疗的机制知之甚少 在最初的治疗中残留的疾病。这是一个关键的知识空白，需要填补才能理解纵向 癌细胞在治疗过程中形成耐药肿瘤的轨迹导致临床死亡 病人。 在项目1中，我们将剖析靶向治疗的不完全反应和抵抗的基础和 确定新的治疗策略，以中和或消除残留病和预防耐药性。我们 建议通过肺癌的棱镜来实现这一点，肺癌是全球癌症死亡的首要原因， 说明靶向治疗的成功和挑战的范式定义的恶性肿瘤(和 免疫疗法)。我们项目的一个独特且具有变革性的特点是能够捕获临床样本 这包括从接受靶向治疗的患者纵向进行液体和肿瘤活检(和 免疫治疗)，治疗开始后早期和最大放射学肿瘤反应(残留 疾病)。再加上我们在创新方法方面的专业知识，如肿瘤分子图谱、基因 和药理学筛选，以及有机物和患者来源的异种移植模型，这种能力捕获 来自残留病患者的临床样本提供了一个前所未有的窗口来了解 患者的反应和抵抗力可以被用来在治疗上针对残留疾病状态 提高患者的反应幅度和持续时间。我们将与发现工作相补充 重点分析我们已经发现的残留疾病的候选调节因子。我们建议2 具体目的是确定非小细胞肺癌靶向治疗期间残留疾病的特征并在治疗上加以抑制： 目标1将定义分子画像并确定靶向治疗残留病的靶点 癌基因驱动的非小细胞肺癌(NSCLC)。目标2将从功能上测试目标的影响 参与消除癌基因驱动的非小细胞肺癌患者衍生的器官和患者的残留病 衍生异种移植(PDX)模型。

PROJECT SUMMARY The discovery of specific molecular drivers of oncogenesis has led to a shift in the treatment of cancer patients, with a move away from the use of conventional cytotoxic chemotherapy and towards molecularly targeted agents that are often more effective and less toxic (e.g. EGFR and ALK inhibitors and immune- checkpoint inhibitor immunotherapies). However, this success of targeted inhibitors and immunotherapy has highlighted the challenge and importance of drug resistance. While patients often benefit from an initial and profound response to these current treatments, the vast majority of responses are incomplete and result in a residual disease state that serves as a prelude to subsequent tumor progression (acquired resistance). While several studies have delineated mechanisms of acquired resistance to treatment with various targeted inhibitors and immunotherapy, very little is known about the mechanisms underlying incomplete response and residual disease during initial treatment. This is a critical knowledge gap to fill to understand the longitudinal trajectories cancer cells take during treatment to form a drug-resistant tumor that leads to the clinical demise of patients. In Project 1, we will dissect the basis of incomplete response and resistance to targeted therapy and identify new treatment strategies to neutralize or eliminate residual disease and forestall resistance. We propose to do so through the prism of lung cancer, the foremost cause of cancer mortality worldwide and a paradigm-defining malignancy that illustrates both the successes and challenges of targeted therapy (and immunotherapy). A unique and transformative feature of our project is the ability to capture clinical specimens that include both liquid and tumor biopsies longitudinally from patients treated with targeted therapy (and immunotherapy), both early following treatment initiation and at maximal radiographic tumor response (residual disease). Coupled with our expertise in innovative methodologies such as tumor molecular profiling, genetic and pharmacologic screens, and organoid and patient-derived xenograft modeling, this capability to capture clinical samples from patients with residual disease affords an unprecedented window into the evolution of response and resistance in patients that can be leveraged to therapeutically target the residual disease state to enhance the magnitude and duration of response in patients. We will complement discovery efforts with the focused analysis of candidate modulators of residual disease that we have already uncovered. We propose 2 Specific Aims to characterize and therapeutically suppress residual disease during targeted therapy in NSCLC: Aim 1 will define the molecular portrait and identify therapeutic targets in targeted therapy residual disease in oncogene-driven non-small cell lung cancer (NSCLC). Aim 2 will functionally test the impact of target engagement to eliminate residual disease in oncogene-driven NSCLC patient-derived organoid and patient- derived xenograft (PDX) models.