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.

项目摘要 PDAC对多种代理的阻力已与其独特的肿瘤微环境联系在一起 （TME），其特征是由富含胶原蛋白的细胞外基质组成的脱肿瘤基质 （ECM），癌症相关的成纤维细胞（CAF）的丰富和大型种群以及由此产生的肿瘤细胞 缺氧。 PDAC的纤维化基质有助于药物递送不良，并且抗渗透和抗抗药性功能 肿瘤免疫细胞。这三个方面与PDAC对化学和化学的抗性有关 免疫疗法。但是，尚不清楚如何影响与PDAC相关的脱木质和纤维化影响 对RT的阻力。历史研究集中于放射疗法（RT）作为损害的直接机制 增殖的肿瘤细胞导致双链DNA断裂和细胞死亡的积累。也是 赞赏RT可以通过释放肿瘤衍生的抗原和危险信号来启用抗肿瘤免疫力， 而且，这可能在多种癌症类型的RT效率中起着至关重要的作用。但是，目前尚不清楚这些是否 RT的免疫启动功能在高度纤维化和免疫性癌症（如PDAC）中是完整的。 我们实验室的先前工作表明，抑制焦点粘附激酶（FAK），这是超级 在PDAC中激活，减少肿瘤相关的纤维化，从而改善对化学和检查点的反应 免疫疗法14,15。这些研究已转向临床试验，并有希望的早期结果。但是，我们的 最近的数据表明，FAK可以与RT加上T细胞检查点组合更有效地协同作用。 基于这些数据，我们假设纤维化基质有助于PDAC对RT和RT-的抗性 诱导肿瘤免疫力。为了测试这一点，我们将： 目标1。确定纤维化损害RT效率以及FAK抑制如何克服的机制 这。 目标2：确定FAK抑制是否增强了RT诱导的局部抗肿瘤免疫学和疾病控制 晚期PDAC患者。 AIM 3：确定抑制FAK信号的机制可改善RT诱导的检查点 免疫疗法反应。 影响：研究纤维化如何对PDAC的RT效率产生负面影响将进一步了解我们如何理解 将基质靶向剂整合到当前的RT方案中，以提高RT效率的最终目标。