Neoadjuvant Stroma Modification in Pancreatic Cancer

项目总结 名为“胰腺癌新辅助间质改良”的项目正在寻求进展。 对胰腺导管腺癌(PDAC)这一高发病倾向的致命性疾病的认识 早期转移性播散。因此，单纯的手术很少治愈，而术前化疗和 放射治疗有可能增加长期存活和最终治愈的可能性。广泛的事前 我们小组在过去20年的工作已经确定，肿瘤的替代程度与 促结缔组织增生性瘢痕组织是生存的预后因素。这种特殊的形态模式是最近才出现的 以库克曼实验室为特征展示激活的β5整合素在癌症相关组织中的表达 成纤维细胞(CAF)作为生存预测生物标记物(eLife，2017)。PDAC细胞间的相互作用 而周围间质通过基因的表观遗传变化促进肿瘤生长和抵抗化疗 表情。因此，有效的PDAC治疗必须包括以间质“正常化”为目标的干预措施。 建立物理和/或生物化学抑制肿瘤的间质)，而不是破坏间质。在这里， 我们建议确定PDAC肿瘤对新辅助药物产生耐药的机制。 放化疗和试验策略旨在破坏PDAC-间质的相互作用。 在目标1中，我们将进行3种基质修饰药物(PHL：一种维生素D类似物)的I期可行性试验 在4-6周内部署帕利骨化醇、羟基氯喹和氯沙坦)以灭活PDAC CAF 诱导FOLFIRINOX放化疗和手术完成之间的窗口期。 在目标2中，我们将确定PHL治疗是否足以降低耐药的EMT PDAC的百分比 细胞和抑制激活的CAF。为了确定这些生物学特征，我们将部署单细胞RNA PDAC中激活的CAF的测序与我们手中建立的正交原位生物标记物相关联。 为了进行这项工作，我们组建了一个胰腺癌临床和基础科学专家团队， 在PDAC的创新疗法方面有良好的合作记录。因为我们预计PHL会很好 耐受性良好，我们的研究将为更大规模的II-III期试验铺平道路，以便评估PHL用于临床终点 疗效评价，如R0切除率、复发时间和总存活率。

PROJECT SUMMARY The project titled “Neoadjuvant Stroma Modification in Pancreatic Cancer” is seeking advancement in understanding of pancreatic ductal adenocarcinoma (PDAC) which is a deadly disease with high propensity for early metastatic dissemination. Hence, surgery alone is rarely curative, whereas preoperative chemo- and radiotherapy has a potential of increasing the possibility for long-term survival and ultimate cure. Extensive prior work by our group over the past two decades has established that the degree of tumor replacement with desmoplastic scar tissue is prognostic for survival. This specific morphological pattern has been recently characterized by the Cukierman lab to demonstrate expression of activated β5 integrins in cancer associated fibroblasts (CAFs) as a survival-predictive biomarker (eLife, 2017). Reciprocal interactions between PDAC cells and the surrounding stroma promote tumor growth and resist chemotherapy via epigenetic changes in gene expression. Therefore, effective PDAC therapy must include interventions aimed at stroma “normalization” (re- institution of physically and/or biochemically tumor-suppressive stroma), rather than stroma destruction. Herein, we propose to determine mechanisms of resistance arising in PDAC tumors exposed to neoadjuvant chemoradiotherapy and test strategies aimed to disrupt the PDAC-stroma interactions. In aim 1, we will conduct a phase I feasibility trial of 3 stroma-modifying drugs (PHL: a vitamin D analog paricalcitol, hydroxychloroquine, and losartan) deployed to inactivate the PDAC CAFs during the 4-6 weeks window period between completion of induction FOLFIRINOX chemoradiotherapy and surgery. In aim 2, we will determine if PHL therapy is sufficient to reduce the percentage of chemoresistant EMT PDAC cells and suppress activated CAFs. To determine these biological features, we will deploy single-cell RNA sequencing linked to orthogonal in situ biomarkers established in our hands for activated CAFs in PDAC. To conduct this work, we assembled a team of experts in clinical and basic science of pancreatic cancer with a strong track record of collaborations in innovative therapies for PDAC. Since we anticipate PHL to be well tolerated, our study will pave the way for larger phase II-III trials in order to evaluate the PHL for clinical endpoints of efficacy such as R0 resection rate, time to relapse, and overall survival.