10 Lung Cancer

项目摘要/摘要 肺癌计划(LCP)有70名成员(34名初级成员，35名助理成员，1名附属成员)，来自19个 各部门。该项目由约翰·海马赫博士领导，他是生物标记物驱动的临床试验和 监督该项目的治疗靶向；杰克·罗斯博士，外科医生兼科学家，该大学的联合PI 以及领导该项目临床研究和指导的劳伦·拜尔斯博士 实习生、研究员和初级教员。LCP的主要科学目标是开发更有效的和 肺癌个体化治疗方法。为了实现这一目标，该计划有三个具体目标 它们集中在3个主题上：1)肺癌信号和治疗靶点；2)免疫系统和 微环境；3)局部和晚期肺癌的综合治疗。年度直通车 同行评审的资助总额为570万美元，其中包括NCI肺癌孢子、Stand Up 2癌症梦之队 奖，以及3个CPRIT多研究者研究奖。在全部资金中，340万美元(60%)来自NCI赠款。 自上次竞争性续签以来，经同行评审的年度直接成本资金总额增加了93%。自.以来 最后一次提交，该计划发表了999篇论文：550篇(55%)计划内合作，355篇 (36%)方案间协作，607(61%)外部协作。44%的人 论文出现在IF&>5的期刊上，15%出现在IF&>10的期刊上，包括《科学》。 N Engl J Med，Proc Natl Acad Sci USA，癌症Discov和Lancet Onol。在上一个授权期内，计划 成员在改变护理标准的研究中发挥领导作用，包括Aura3研究(建立 Osimertinib用于EGFR T790M突变的非小细胞肺癌)和一项证明局部巩固的益处的研究 少转移非小细胞肺癌的治疗。我们先前在小细胞肺中识别新靶点的发现 癌症(SCLC)已在随后的临床研究中得到验证。成员们还确定了KRAS的3个子集- 突变型非小细胞肺癌基于共生的基因组改变，表现出明显的生物学、免疫模式和 系统参与度和治疗漏洞。最后，他们确定了上皮到间充质的作用。 通过miR200/ZEB1/PD-L1轴调节肿瘤免疫抑制的转变，在 促进非小细胞肺癌转移。在未来几年，成员们将在这些发现的基础上确定新的 以小细胞肺癌和KRAS突变非小细胞肺癌为重点的肺癌亚群靶向治疗方法；调查 增强抗肿瘤免疫的策略和免疫治疗抵抗的机制；并开发 整合免疫治疗和靶向药物的多学科范式作为一种改善 肺癌患者的存活率。

PROJECT SUMMARY/ABSTRACT The Lung Cancer Program (LCP) includes 70 members (34 primary, 35 associate, 1 adjunct) from 19 departments. The program is led by Dr. John Heymach, an expert in biomarker-driven clinical trials and therapeutic targeting who oversees the program; Dr. Jack Roth, a surgeon-scientist and co-PI of the University of Texas Lung SPORE; and Dr. Lauren Byers, who leads the program's clinical research efforts and mentoring of trainees, fellows, and junior faculty. The major scientific goal of the LCP is to develop more effective and personalized approaches for the treatment of lung cancer. To achieve this goal, the program has 3 specific aims that focus on 3 themes: 1) lung cancer signaling and therapeutic targets; 2) targeting the immune system and microenvironment; and 3) the multimodal treatment of localized and advanced lung cancer. The annual direct peer-reviewed funding totals $5.7M, including an NCI Lung Cancer SPORE, a Stand Up 2 Cancer Dream Team Award, and 3 CPRIT Multi-Investigator Research Awards. Of the total funding, $3.4M (60%) is from NCI grants. Since the last competitive renewal, total annual peer-reviewed direct-cost funding has increased by 93%. Since the last submission, the program has published 999 papers: 550 (55%) intra-programmatic collaborations, 355 (36%) inter-programmatic collaborations, and 607 (61%) external collaborations. Forty-four percent of the publications appeared in journals with an IF >5, and 15% appeared in journals with an IF >10, including Science, N Engl J Med, Proc Natl Acad Sci USA, Cancer Discov, and Lancet Oncol. During the last grant period, program members had leadership roles in standard-of-care–changing studies, including the AURA3 study (establishing osimertinib for EGFR T790M–mutant NSCLC) and a study demonstrating the benefit of local consolidative therapy for patients with oligometastatic NSCLC. Our previous findings identifying novel targets in small cell lung cancer (SCLC) have been validated in subsequent clinical studies. Members also identified 3 subsets of KRAS- mutant NSCLC based on co-occurring genomic alterations that exhibit distinct biology, patterns of immune- system engagement, and therapeutic vulnerabilities. Finally, they identified a role for epithelial-to-mesenchymal transition in regulating tumor immunosuppression via an miR200/ZEB1/PD-L1 axis, playing a central role in promoting NSCLC metastasis. In upcoming years, members will build on these findings to identify new approaches to target subsets of lung cancer, with a focus on SCLC and KRAS-mutant NSCLC; investigate strategies for enhancing antitumor immunity and mechanisms of immunotherapy resistance; and develop multidisciplinary paradigms integrating immunotherapy and targeted agents as an approach to improve the survival of lung cancer patients.