Dana Farber/Harvard Cancer Center SPORE in Lung Cancer

项目摘要 本申请是对肺癌卓越研究专业计划（SPORE）的重新提交 源自Dana-Farber/哈佛癌症中心（DF/HCC）的肺癌项目。DF/HCC 肺癌孢子包括来自多个哈佛附属医院的研究人员，包括达纳- 法伯癌症研究所（DFCI）、马萨诸塞州总医院（MGH）、贝斯以色列女执事医疗中心 （BIDMC）、布里格姆妇女医院（BWH）、波士顿儿童医院（BCH）以及哈佛 医学院（HMS）和哈佛T.H. Chan School of Public Health（HSPH）以前，DF/HCC肺 癌症计划于2002年由肺癌孢子资助。随后成功续约 2007年开始实施，2013-2015年免费延长。那段时间伴随着 我们的研究人员的卓越生产力，包括表皮生长因子受体的初步描述， MGH和DFCI的研究者检测EGFR突变，鉴定和开发第三代 EGFR酪氨酸激酶抑制剂（TKI）目前已在临床上广泛使用，并迅速转化为有效的 ALK/ROS靶向治疗，以及其他成就。然而，尽管有巨大的积极影响， 靶向治疗，他们未能治愈晚期肺腺癌。在过去的六年里，自从我们 在SPORE结束之前，DF/HCC肺项目已经发展并变得更加合作。我们有 维持一个发展研究计划，以支持一个新的调查骨干，谁建立了强大的 为我们长期以来的肺癌靶向治疗研究传统增添了更多的专业领域， 包括先天性和适应性免疫、SCLC生物学、循环肿瘤DNA和肺癌筛查。的 DF/HCC肺癌计划因此寻求SPORE资金，以使综合团队能够利用 这些新的和成熟的研究人员的优势，以实现我们的共同目标，消除肺癌 死亡这个孢子的首要目标是：A）设计免疫疗法，利用这两个 先天性和适应性免疫系统克服ALK抑制剂耐药性并增强PD-1疗效 非小细胞肺癌（NSCLC）免疫检查点阻断（项目1和2）; B）开发创新 治疗EGFR和ALK驱动的肺癌的方法，有可能通过癌症疫苗改善长期生存 或消除耐药性持续存在细胞或癌症疫苗（项目1和3）; SMARCA 4突变型NSCLC中的复制应激或EGFR TKI中的衰老程序等脆弱性 DTP（项目2和3）; D）促进机构间合作，包括交流肺癌模型 和患者样本（所有项目）;和E）继续支持和开发下一代肺癌 来自我们才华横溢的研究员和早期职业调查人员的翻译科学家，重点是 增加多样性和公平性。

PROJECT SUMMARY This application is a resubmission of a Specialized Program of Research Excellence (SPORE) in Lung Cancer originating from the Lung Cancer Program of the Dana-Farber/Harvard Cancer Center (DF/HCC). The DF/HCC SPORE in Lung Cancer includes researchers from multiple Harvard-affiliated hospitals including the Dana- Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center (BIDMC), Brigham and Women’s Hospital (BWH), and Boston Children’s Hospital (BCH), as well as Harvard Medical School (HMS) and Harvard T.H. Chan School of Public Health (HSPH). Previously, the DF/HCC Lung Cancer Program was funded by a Lung Cancer SPORE in 2002. This was followed by a successful renewal application in 2007 and a no-cost extension from 2013-2015. That period of time was accompanied by remarkable productivity by our investigators, including the initial description of epidermal growth factor receptor (EGFR) mutations by investigators at both MGH and DFCI, identification and development of 3rd generation EGFR tyrosine kinase inhibitors (TKIs) which are now in widespread clinical use, and rapid translation of effective ALK/ROS targeted therapies, among other accomplishments. However, despite the immense positive impact of targeted therapies, they have failed to cure advanced lung adenocarcinoma. Over the past 6 years since our prior SPORE ended, the DF/HCC lung program has evolved and grown ever more collaborative. We have maintained a developmental research program to support a new cadre of investigators, who have built strong additional arenas of expertise that add to our longstanding tradition of targeted therapy research in lung cancer, including innate and adaptive immunity, SCLC biology, circulating tumor DNA, and lung cancer screening. The DF/HCC Lung Cancer Program thus seeks SPORE funding to enable integrated teams that capitalize on the strengths of these new and established investigators to achieve our common goal of eliminating lung cancer deaths. The overarching goals of this SPORE are to: A) Design immunologic therapies that harness both the innate and adaptive immune systems to overcome ALK inhibitor resistance and enhance efficacy of PD-1 immune checkpoint blockade in non-small cell lung cancer (NSCLC) (Projects 1 and 2); B) Develop innovative approaches to EGFR and ALK-driven lung cancer with potential to improve long term survival via cancer vaccines or elimination of drug tolerant persister (DTP) cells or cancer vaccines (Projects 1 and 3); C) Co-opt vulnerabilities such as replication stress in SMARCA4 mutant NSCLC or a senescence program in EGFR TKI DTPs (Projects 2 and 3); D) Foster inter-institutional collaboration, including exchange of lung cancer models and patient samples (all Projects); and E) Continue to support and develop the next generation of lung cancer translational scientists from our talented group of fellows and early career investigators, with an emphasis on increasing diversity and equity.