Targeting the Stroma for Pancreatic Cancer Treatment

项目摘要 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免疫疗法的范式转变成功。PDAC中的新辅助治疗策略 提供了一个独特的机会，治疗干预，以减少系统性复发，但这仍然是一个 这对于接受治疗性手术的患者来说是一个实质性问题。重要的促纤维增生间质， 免疫抑制和T细胞贫瘠肿瘤微环境（TME）是免疫抑制的障碍 PDAC的功效然而，新辅助治疗方法提供了一个独特的优势，全面和强大的 TME和基质的分析。该提案描述了一个职业发展计划， 通过新辅助翻译方法精心设计的研究策略。该方法具体为 提出，以巩固一个独立的职业生涯，作为一个领导者在翻译新的发现，基质和TME 将生物学应用于未来PDAC中的科学驱动的临床试验。作为一名专注于胰腺癌的肿瘤学家， 申请人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。 合作实验室研究和患者生物样本分析的结果。这一指导性的职业生涯 开发奖提案是基于对以前广泛的临床前和临床工作的持续关注 由申请人围绕TME的主调节因子，称为粘着斑激酶（FAK）。这 该提案还基于对更深入的临床转化实验学习机会的高度关注， 专家指导和强化教学，将告知未来的床边到长凳到床边的调查， 翻译.拟议的工作将在雷政博士和李博士的特别指导下进行。 Stephen J Pandol，胰腺癌研究的国际领导者。约翰霍普金斯的环境 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设置，从该建议 研究可以产生新的发现，并培养独立的调查员。这个五年计划 包括：（1）进行临床试验以评估肿瘤内T细胞浸润、临床反应和 使用抗PD-1抗体、派姆单抗（pembrolizumab），伴或不伴FAK抑制剂（FAKi）进行免疫治疗的安全性， 在高风险可切除PDAC受试者的新辅助化疗后，（2）采用 一种新的多重免疫组织化学技术，用于检查TME免疫应答机制 Pembrolizumab和defactinib的耐药性，以及（3）研究Pembrolizumab对 和无defactinib时对成纤维细胞表型和与活性氧相关的免疫调节的影响 在利用RNAseq和肿瘤/成纤维细胞共培养的TME中。该提案的最终目标是能够 提出新的假设，为PDAC患者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.