Neoadjuvant Stroma Modification in Pancreatic Cancer

胰腺癌的新辅助基质修饰

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该项目名为“胰腺癌新辅助基质修饰”，正在寻求以下方面的进展：了解胰腺导管腺癌（PDAC），这是一种具有高度倾向性的致命疾病因此，单纯手术很少能治愈，而术前化疗和联合治疗则可能会导致早期转移扩散。放射治疗有可能增加长期生存和最终治愈的可能性。我们小组在过去二十年的工作已经确定，肿瘤替代的程度这种特定的形态学模式最近已被证实是促纤维增生性疤痕组织的生存预后。由 Cukierman 实验室鉴定，证明激活的 β5 整合素在癌症相关中的表达成纤维细胞（CAF）作为生存预测生物标志物（eLife，2017）。和周围的基质通过基因的表观遗传变化促进肿瘤生长并抵抗化疗因此，有效的 PDAC 治疗必须包括旨在基质“正常化”（重新表达）的干预措施。在本文中，物理和/或生化肿瘤抑制基质的建立，而不是基质破坏。我们建议确定暴露于新辅助治疗的 PDAC 肿瘤中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，我们将对 3 种基质修饰药物（PHL：维生素 D 类似物）进行 I 期可行性试验帕立骨化醇、羟氯喹和氯沙坦）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 中激活的 CAF 正交原位生物标志物相关的测序。为了开展这项工作，我们组建了一支由胰腺癌临床和基础科学专家组成的团队， PDAC 创新疗法方面的合作记录良好，因为我们预计 PHL 会表现良好。如果能够耐受，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 的临床终点疗效，如 R0 切除率、复发时间和总生存期。