The Memorial Sloan Kettering Cancer Center SPORE in Pancreas Cancer

项目概要-总体 越来越多的研究表明，一些胰腺导管腺癌（PDAC）患者 对治疗的特殊和持久反应，包括标准治疗和更罕见的免疫基础治疗。 治疗有一个独特的机会来了解遗传和分子机制， 这些异常反应或定义了对治疗的内在抗性机制，以前瞻性地指导 临床管理，并最终提高所有胰腺癌患者的总生存率。我们提出 纪念斯隆凯特琳癌症中心胰腺癌卓越研究的专门计划 (the MSK Pancreas SPORE）利用胰腺生物学和临床的尖端分子知识 创新以推进胰腺癌的转化研究。我们的长期目标是 证明了前瞻性的下一代分子方法与最先进的临床 治疗可以改善胰腺恶性肿瘤患者的预后。我们将特别关注 最具挑战性的疾病环境，局部晚期和转移性PDAC，其中临床需求最多 深刻为了实现这一目标，我们提出了三个具体目标。在目标1中，我们将利用当前的状态- 最先进的和新的疗法，以改善III期和IV期PDAC患者的结局， 细胞毒性和靶向治疗的发展，并将这些药物和组合应用于新的疾病 设置.在目标2中，我们将应用PDAC分子表征的创新来推动临床管理 通过建立我们在成像，分子诊断，生物标志物开发和单- 细胞分析，以开发和验证治疗反应和耐药性的前瞻性生物标志物。在目标3中， 我们将研究克服PDAC内在免疫治疗耐药性的两种途径：合成致死性 联合PARP抑制和免疫检查点阻断，并通过激活白细胞介素-33-基 2先天性淋巴样细胞（IL 33-ILC 2）轴。我们期望，成功实现这些目标将为我们提供新的 深入了解PDAC生物学，建立新的合作，改变治疗模式，并最终改善 胰腺癌的无病生存率和总生存率。

PROJECT SUMMARY –OVERALL An increasing number of studies indicate that some patients with pancreas ductal adenocarcinoma (PDAC) have exceptional and durable responses to therapy, both standard of care and, more rarely to immune-based therapies. There is a unique opportunity to understand the genetic and molecular mechanisms that underlie these exceptional responses or define mechanisms of intrinsic resistance to therapy to prospectively guide clinical management and ultimately increase overall survival for all patients with pancreas cancer. We propose a Specialized Program of Research Excellence in Pancreas Cancer at Memorial Sloan Kettering Cancer Center (the MSK Pancreas SPORE) to leverage cutting-edge molecular knowledge of pancreas biology and clinical innovations to advance translational research in pancreas cancer. Our long-term translational objective is to demonstrate that prospective, next-generation molecular approaches combined with state-of-the-art clinical management can improve outcomes of patients with pancreas malignancies. We will specifically focus on the most challenging disease settings, locally advanced and metastatic PDAC, where the clinical needs are most profound. To achieve this objective, we propose three specific aims. In Aim 1, we will leverage current state-of- the-art and novel therapies to improve outcomes for patients with stage III and IV PDAC by building upon recent developments in cytotoxic and targeted therapies and apply these agents and combinations in novel disease settings. In Aim 2, we will apply innovation in molecular characterization of PDAC to drive clinical management by building upon our extensive expertise in imaging, molecular diagnostics, biomarker development, and single- cell analyses to develop and validate prospective biomarkers of treatment response and resistance. In Aim 3, we will investigate two avenues of surmounting intrinsic immunotherapy resistance in PDAC: synthetic lethality of combination PARP inhibition and immune checkpoint blockade, and via activation of the interleukin-33 – group 2 innate lymphoid cell (IL33-ILC2) axis. We expect that successful completion of these aims will provide new insights into PDAC biology, establish new collaborations, alter treatment paradigms, and ultimately improve disease-free and overall survival in pancreas cancer.