Targeting the Stroma for Pancreatic Cancer Treatment

项目总结 胰腺导管腺癌(PDAC)仍然是最致命的恶性肿瘤之一，尽管最近 在许多其他肿瘤类型中注意到的免疫治疗的范式转换成功。PDAC的新辅助治疗策略 为治疗干预提供了一个独特的机会来减少系统性复发，但这仍然是 对于正在接受治疗性手术的患者来说，这是一个实质性的问题。重要的促结缔组织基质， 免疫抑制和T细胞裸瘤微环境是免疫治疗的障碍 PDAC中的疗效。然而，新佐剂方法为全面和稳健提供了独特的优势 TME和基质的分析。这份提案描述了一项职业发展计划，与一项平行的 通过新辅助翻译方法精心设计的研究策略。这种方法特别是 提出的目的是为了巩固独立的职业生涯，成为翻译斯特罗马和TME的新发现的领导者 在PDAC中将生物学纳入未来以科学为导向的临床试验。作为一名专注于胰腺癌的肿瘤学家， 申请者的长期目标是成为胰腺癌领域的领导者，拥有翻译方面的专业知识 协作性实验室研究和患者生物样本分析的结果。这个受过指导的职业生涯 发展奖提案是基于对之前广泛的临床前和临床工作的持续关注 由申请人围绕TME的一个主调控子，称为粘着斑激酶(FAK)。这 该提案还基于对更深层次的临床-翻译实验学习机会的高度关注， 专家指导和密集的教学，将为未来的床到床到床边的调查和 翻译。拟议中的工作将在雷政博士和雷政博士的特殊指导下进行。 史蒂芬·J·潘多尔，胰腺癌研究的国际领导者。约翰·霍普金斯大学的环境 西德尼·基梅尔综合癌症中心、彭博基梅尔癌症免疫治疗研究所和 胰腺癌精准医学卓越中心是一个最佳的环境，从那里建议 研究可以产生新的发现，并培养独立的调查者。这份五年计划 包括：(1)进行一项临床试验，以评估肿瘤内T细胞的渗透、临床反应和 抗PD-1抗体pembrolizumab免疫治疗的安全性，加或不加FAK抑制剂(FAKI)， Defactinib，在高危可切除PDAC患者的新辅助化疗后，(2)采用 一种新的多重免疫组织化学技术检测TME反应的免疫机制 以及对培溴利珠单抗和地法替尼的耐药性，以及(3)培溴利珠单抗和地法替尼的影响 不加去甲替尼对成纤维细胞表型及与活性氧相关的免疫调节的影响 在TME中利用RNAseq和肿瘤/成纤维细胞共培养。这项提议的最终目标是能够 为PDAC患者产生新的假设和开发创新的治疗方法。

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies despite the recent paradigm shifting success of immunotherapy noted in many other tumor types. Neoadjuvant strategies in PDAC provide a distinctive opportunity for therapeutic intervention to decrease systemic recurrence, yet this remains a substantial problem for patients undergoing curative intent surgery. The significant desmoplastic stroma, immunosuppressive and T cell barren tumor microenvironment (TME) are obstacles for immunotherapeutic efficacy in PDAC. Yet, the neoadjuvant approach offers a unique advantage for comprehensive and robust analysis of the TME and stroma. This proposal describes a career development plan coupled with a parallel research strategy carefully designed through a neoadjuvant translational approach. This approach is specifically proposed in order to cement an independent career as a leader in translating novel findings of stromal and TME biology into future science-driven clinical trials in PDAC. As an oncologist focused on pancreas cancer, the applicant’s long-term goals are to become a leader in the field of pancreatic cancer with an expertise in translating findings from collaborative laboratory research and patient biospecimen analysis. This mentored Career Development Award proposal is based on a continued focus from previous extensive preclinical and clinical work by the applicant, surrounding a master regulator of the TME, known as focal adhesion kinase (FAK). This proposal is also grounded on a hyperfocus in opportunities for deeper clinical-translational experimental learning, expert mentorship, and intensive didactics that will inform future bedside-to-bench-to-bedside investigation and translation. The proposed work will be conducted under the exceptional mentorship of Dr. Lei Zheng and Dr. Stephen J Pandol, international leaders in pancreatic cancer research. The environment of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, the Bloomberg Kimmel Institute for Cancer Immunotherapy and the Pancreatic Cancer Precision Medicine Center of Excellence is an optimal setting from which the proposed studies can originate novel findings and develop an independent investigator. This five year proposal encompasses: (1) the conduct of a clinical trial to evaluate intratumoral T cell infiltration, clinical response and safety of immunotherapy with anti-PD-1 antibody, pembrolizumab, with or without FAK inhibitor (FAKi), defactinib, following neoadjuvant chemotherapy in subjects with high-risk resectable PDAC, (2) employing a novel multiplex immunohistochemistry technique to examine TME immune mechanisms underlying the response and resistance of pembrolizumab and defactinib, and (3) the investigation of the impact of pembrolizumab with and without defactinib on fibroblast phenotypes and immunomodulation associated with reactive oxygen species in the TME utilizing RNAseq and tumor/fibroblast co-culture. The ultimate goal of this proposal is to be able to generate new hypotheses and develop innovative treatment approaches for patients with PDAC.