Targeting the Stroma for Pancreatic Cancer Treatment

靶向间质治疗胰腺癌

基本信息

批准号：
10605351
负责人：
Arsen Osipov
金额：
$ 24.42万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
2021-05-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605351
关键词：
Address Adjuvant Chemotherapy Biology Biopsy CD8-Positive T-Lymphocytes CXCR4 gene Carcinoma Cementation Clinical Clinical Trials Coculture Techniques Combination immunotherapy Combined Modality Therapy Complex Comprehensive Cancer Center Coupled Culture Techniques Cytotoxic Chemotherapy Desmoplastic Development Plans Disease Environment Excision Fibroblasts Focal Adhesion Kinase 1 Future Gene Expression Profile Generations Genes Goals Growth Human Hyaluronic Acid Immune Immunohistochemistry Immunologic Surveillance Immunotherapeutic agent Immunotherapy In complete remission Inflammatory International Investigation K-Series Research Career Programs KPC model Laboratory Research Learning Lymphoid Macrophage Malignant Neoplasms Malignant neoplasm of pancreas Mentors Mentorship Myelogenous Myeloid Cells Neoadjuvant Therapy Oncologist Operative Surgical Procedures Outcome PD-1 inhibitors Pancreatic Ductal Adenocarcinoma Pathologic Patient-Focused Outcomes Patients Phase II Clinical Trials Phenotype Phosphorylation Population Production Randomized Reactive Oxygen Species Recurrence Recurrent disease Refractory Regulatory T-Lymphocyte Relapse Research Research Personnel Resectable Resistance Role Safety Science Signal Transduction Sorting Source Specimen Stains Stromal Cells Systemic disease T cell infiltration T cell response T-Lymphocyte Techniques Testing Therapeutic Intervention Tissue Model Tissues Training Translating Translational Research Translations Work anti-PD-1 anti-PD1 antibodies anti-PD1 therapy anti-tumor immune response antibody conjugate anticancer research arm bench to bedside biomarker panel cancer immunotherapy cancer therapy career career development checkpoint inhibition chemotherapy clinical translation density design disorder control effector T cell experience genetic signature high risk human tissue immunoregulation improved innovation kinase inhibitor mouse model neoplastic neoplastic cell neutrophil novel open label pancreatic ductal adenocarcinoma model pembrolizumab pre-clinical precision oncology response success transcriptome sequencing translational approach treatment response tumor tumor microenvironment tumor-immune system interactions

项目摘要

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.

项目摘要胰腺导管腺癌（PDAC）仍然是最致命的Malignancys目的地之一在许多其他肿瘤类型中注意到的免疫疗法成功的范式转移了成功。 PDAC中的新辅助策略为热干预提供了独特的机会来减少全身性复发，但这仍然是接受治愈性手术的患者的重大问题。显着的去胶质基质，免疫抑制和T细胞贫瘠的肿瘤微环境（TME）是免疫治疗的障碍 PDAC的功效。然而，新辅助方法为全面而稳健提供了独特的优势 TME和基质的分析。该建议描述了一项职业发展计划，并相交通过新辅助翻译方法精心设计的研究策略。这种方法是专门的提议为了巩固自己的独立职业，成为翻译基质和TME的小说发现的领导者生物学进入PDAC的未来科学驱动的临床试验。作为一名肿瘤学家，专注于胰腺癌，申请人的长期目标是成为胰腺癌领域的领导者，并具有翻译方面的专业知识协作实验室研究和患者生物循环分析的发现。这很重要开发奖提案基于以前广泛的临床前和临床工作的持续重点由申请人围绕TME的主调节器，称为焦点粘合剂激酶（FAK）。这提案还基于高度焦点，这是更深入的临床翻译实验学习的机会，专家精神和密集的教学能力将为未来的床头至卧铺调查提供信息翻译。拟议的工作将在Lei Zheng博士和博士的特殊心理下进行。胰腺癌研究国际领导人Stephen J Pandol。约翰·霍普金斯的环境 Sidney Kimmel综合癌症中心，彭博金梅尔癌症免疫疗法研究所胰腺癌精密医学卓越中心是一个最佳环境研究可以起源新发现并发展独立的研究者。这个五年的提案包括：（1）进行临床试验，以评估肿瘤内T细胞浸润，临床反应和抗PD-1抗体Pembrolizumab的免疫疗法的安全性，有或没有FAK抑制剂（FAKI）， Defactinib，在具有高危PDAC受试者的新辅助化学疗法之后，（2）采用A 新型多重免疫组织化学技术，用于检查反应背后的TME免疫机制 pembrolizumab和defactinib的耐药性，以及（3）pembrolizumab与并且在成纤维细胞表型上没有去毒性和与活性氧相关的免疫调节在使用RNASEQ和肿瘤/成纤维细胞共培养的TME中。该提议的最终目标是能够生成新的假设并为PDAC患者开发创新的治疗方法。