Neoadjuvant Stroma Modification in Pancreatic Cancer

胰腺癌的新辅助基质修饰

• 批准号: 10199321
• 负责人: Igor Astsaturov
• 金额: $ 21.05万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199321
• 关键词: Ablation; Admission activity; Autophagocytosis; Basic Science; Biochemical; Biological; Biological Assay; Biological Markers; Biology; Cancer Etiology; Cell Compartmentation; Cell membrane; Cells; Cessation of life; Chemoresistance; Cicatrix; Clinical; Clinical Sciences; Collaborations; Conflict (Psychology); Dangerousness; Desmoplastic; Disease; Epigenetic Process; Epithelial; Excision; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Fostering; Future; Gene Expression; Genomics; Hand; Human; Hydroxychloroquine; Immunofluorescence Immunologic; In Situ; Individual; Inflammatory; Informatics; Innovative Therapy; Institutes; Institution; Integrin alpha5beta1; Integrins; Intervention; Label; Link; Losartan; MADH2 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modification; Morphology; Nature; Neoadjuvant Therapy; Operative Surgical Procedures; Pancreatectomy; Pancreatic Ductal Adenocarcinoma; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II/III Trial; Pilot Projects; Population; Protocols documentation; Radiation therapy; Recurrence; Recycling; Refractory; Regimen; Relapse; Research; Resectable; Resistance; Role; Sonic Hedgehog Pathway; Stromal Cells; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transforming Growth Factor beta; Treatment Efficacy; Vitamin D Analog; Vitamin D3 Receptor; Work; base; cancer cell; cancer survival; chemoradiation; chemotherapy; clinical care; design; feasibility trial; improved; inhibitor/antagonist; neoplastic cell; novel therapeutic intervention; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; paricalcitol; predictive marker; prevent; prognostic of survival; resistance mechanism; safety and feasibility; single cell sequencing; single-cell RNA sequencing; survival prediction; tumor; tumor growth; tumor heterogeneity; tumor microenvironment; tumorigenic

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.

项目摘要 名为“胰腺癌新辅助基质修饰”的项目正在寻求进展， 了解胰腺导管腺癌（PDAC），这是一种致命的疾病， 早期转移性播散。因此，单纯手术很少能治愈，而术前化疗和化疗则不能治愈。 放射治疗有可能增加长期生存和最终治愈的可能性。广泛的既往 我们小组在过去二十年的工作已经确定， 促结缔组织增生性瘢痕组织是生存的预后。这种特殊的形态模式最近被 由Cukierman实验室进行表征，以证明活化的β5整合素在癌症相关性中的表达 成纤维细胞（CAF）作为生存预测生物标志物（eLife，2017）。PDAC细胞之间的相互作用 周围间质通过基因的表观遗传改变促进肿瘤生长和抵抗化疗 表情因此，有效的PDAC治疗必须包括旨在使基质“正常化”的干预（再治疗）。 建立物理和/或生物化学肿瘤抑制性基质），而不是基质破坏。在此， 我们建议确定暴露于新辅助化疗的PDAC肿瘤产生耐药的机制， 放化疗和测试策略旨在破坏PDAC-基质相互作用。 在目标1中，我们将进行3种基质修饰药物（PHL：维生素D类似物）的I期可行性试验 帕立骨化醇、羟氯喹和洛沙坦）用于在4-6周内灭活PDAC CAF 完成诱导FOLFIRINOX放化疗和手术之间的窗口期。 在目标2中，我们将确定PHL治疗是否足以降低化疗耐药EMT PDAC的百分比。 细胞并抑制激活的CAFs。为了确定这些生物学特征，我们将部署单细胞RNA， 与我们手中建立的PDAC中激活CAF的正交原位生物标志物相关的测序。 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创新疗法方面的合作记录良好。因为我们预计PHL会很好， 我们的研究将为更大规模的II-III期试验铺平道路，以评估PHL的临床终点 如R 0切除率、复发时间和总生存率。