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: 10616539
• 负责人: David G DeNardo
• 金额: $ 54.96万
• 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/10616539
• 关键词: 3-Dimensional; Adjuvant; Antigens; Breast Cancer therapy; Cell Death; Cell Hypoxia; 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; Immuno-Chemotherapy; Immunologic Monitoring; Immunotherapy; Impairment; Infiltration; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; 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; Signal Transduction; Stromal Neoplasm; Survival Rate; System; T-Lymphocyte; Testing; Therapeutic; Treatment Efficacy; Tumor Immunity; Tumor-Derived; Tumor-infiltrating immune cells; Work; 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; side effect; synergism; 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对多种药物的耐药性部分与其独特的肿瘤微环境有关 (TME)，其特征在于由致密的富含胶原的细胞外基质组成的促结缔组织增生基质 (ECM)丰富多样的癌症相关成纤维细胞（CAF）群体，以及由此产生的肿瘤细胞 缺氧PDAC的纤维化基质导致药物递送不良，并且剥夺了抗-PDAC的浸润和功能。 肿瘤免疫细胞这三个方面与PDAC对化疗和化疗药物的耐药性有关。 免疫疗法然而，目前尚不清楚PDAC相关的结缔组织增生和纤维化如何影响 历史研究集中在放射治疗（RT）作为损伤的直接机制 增殖肿瘤细胞，导致双链DNA断裂的积累和细胞死亡。也是 认识到RT可以通过释放肿瘤源性抗原和危险信号引发抗肿瘤免疫， 并且这可能在多种癌症类型的RT疗效中起关键作用。然而，目前尚不清楚这些 RT的免疫引发功能在高度纤维化和免疫抑制的癌症如PDAC中是完整的。 我们实验室以前的工作表明，抑制粘着斑激酶（FAK）， 在PDAC中激活，减少肿瘤相关的纤维化，从而改善对化疗和检查点的反应 免疫疗法14，15.这些研究已经进入临床试验阶段，并取得了有希望的早期结果。但我们的 最近的数据表明FAK可以与RT加T细胞检查点组合更有效地协同作用。 基于这些数据，我们假设纤维化间质有助于PDAC对RT和RT-1的抵抗。 诱导肿瘤免疫。为了测试这一点，我们将： 目标1。确定纤维化损害RT疗效的机制以及FAK抑制如何克服 这个 目的2：确定FAK抑制是否增强局部中RT诱导的抗肿瘤免疫和疾病控制。 晚期PDAC患者 目的3：确定抑制FAK信号传导改善RT诱导的检查点的机制 免疫治疗反应。 影响：研究纤维化如何对PDAC的RT疗效产生负面影响将进一步了解如何 将基质靶向药物整合到目前的RT方案中，最终目标是提高RT的疗效。