Targeting Focal Adhesion Kinase to Improve RT-inducted Tumor Immunity

靶向粘着斑激酶以改善 RT 诱导的肿瘤免疫

• 批准号: 10428469
• 负责人: David G DeNardo
• 金额: $ 55.73万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-14 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10428469
• 关键词: 3-Dimensional; Adjuvant; Antigens; Breast Cancer therapy; Cell Death; Cell Hypoxia; Cells; Clinical; Clinical Data; Clinical Trials; Collagen; DNA Double Strand Break; Data; Desmoplastic; Diagnosis; Disease; Dose; Drug Delivery Systems; Excision; Extracellular Matrix; Fibroblasts; Fibrosis; Focal Adhesion Kinase 1; Genetically Engineered Mouse; Goals; Image Analysis; Immune; Immunologic Monitoring; Immunotherapy; Impairment; Infiltration; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Neoadjuvant Therapy; Normal tissue morphology; Operative Surgical Procedures; Organoids; Pancreatic Ductal Adenocarcinoma; Pathologic; Patients; Phase I/II Clinical Trial; Play; Population Heterogeneity; Proliferating; Property; Radiation therapy; Regimen; Resectable; Resistance; Role; Shapes; Side; Signal Transduction; Stromal Neoplasm; Survival Rate; System; T-Lymphocyte; Testing; Therapeutic; Treatment Efficacy; Tumor Immunity; Tumor-Derived; Tumor-infiltrating immune cells; Work; base; cancer type; checkpoint therapy; curative treatments; density; disorder control; efficacy study; improved; ineffective therapies; lung cancer cell; malignant breast neoplasm; neoplastic cell; non-invasive imaging; novel; novel strategies; pancreatic ductal adenocarcinoma cell; pre-clinical; response; safety study; safety testing; targeted agent; tissue culture; treatment optimization; tumor; tumor microenvironment

PROJECT SUMMARY The resistance of PDAC to multiple agents, has been linked in part to its unique tumor microenvironment (TME), which is characterized by a desmoplastic stroma composed of dense collagen-rich extracellular matrix (ECM), abundant and diverse populations of cancer associated fibroblasts (CAFs), and resultant tumor cell hypoxia. PDAC’s fibrotic stroma contributes to poor drug delivery, and deprived infiltration and function of anti- tumor immune cells. These three aspects have been linked to PDAC resistance to both chemo- and immunotherapy. However, it is not clear how the PDAC-associated desmoplasia and fibrosis might impact resistance to RT. Historical studies have focused on radation therapy (RT) as a direct mechanism to damage proliferating tumor cells leading to the accumulation of double-strand DNA breaks and cell death. It is also appreciated that RT can prime anti-tumor immunity by releasing tumor-derived antigens and danger signals, and that this likely plays a critical role in RT efficacy in multiple cancer types. However, it is unclear if these immune priming functions of RT are intact in a highly fibrotic and immunosupressive cancers like PDAC. Previous work from our lab demonstrated that inhibition of Focal Adhesion Kinase (FAK), which is hyper activated in PDAC, reduced tumor-associated fibrosis and thus improves responses to chemo- and checkpoint immunotherapies14,15. These studies have moved to clinical trials with promising early results. However, our recent data suggest FAK can synergize even more effectively with RT plus T cell checkpoint combinations. Based on these data, we hypothesize that fibrotic stroma contributes to PDAC resistance to RT and RT- induction of tumor immunity. To test this we will: Aim 1. Determine the mechanism(s) by which fibrosis impairs RT efficacy and how FAK inhibition overcomes this. Aim 2: Determine if FAK inhibition enhances RT-induced anti-tumor immunity and disease control in locally advanced PDAC patients. Aim 3: Determine the mechanism(s) by which inhibition of FAK signaling improves RT-induced checkpoint immunotherapy response. Impact: Studying how fibrosis negatively impacts RT efficacy in PDAC will further our understanding of how to integrate a stromal targeted agents into current RT regimens with the ultimate goal of improving efficacy of RT.

项目总结