Targeting Focal Adhesion Kinase to Improve RT-inducted Tumor Immunity

项目概要 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），其特征是由致密的富含胶原蛋白的细胞外基质组成的促纤维增生基质 (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输送不良，并剥夺抗肿瘤药物的浸润和功能。 肿瘤免疫细胞。这三个方面与 PDAC 对化疗和化疗的耐药性有关。 免疫疗法。然而，尚不清楚 PDAC 相关的结缔组织增生和纤维化如何影响 对 RT 的抵抗。历史研究重点关注放射治疗（RT）作为损伤的直接机制 增殖的肿瘤细胞导致双链DNA断裂的积累和细胞死亡。这也是 认识到 RT 可以通过释放肿瘤源性抗原和危险信号来启动抗肿瘤免疫， 这可能对多种癌症类型的放疗疗效发挥着关键作用。然而，尚不清楚这些是否 RT 的免疫启动功能在 PDAC 等高度纤维化和免疫抑制的癌症中完好无损。 我们实验室之前的工作表明，对粘着斑激酶 (FAK) 的抑制作用非常强。 在 PDAC 中激活，减少肿瘤相关纤维化，从而改善对化疗和检查点的反应 免疫疗法14,15。这些研究已进入临床试验，并取得了有希望的早期结果。然而，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，我们假设纤维化基质导致 PDAC 对 RT 的抵抗和 RT- 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。 目标 2：确定 FAK 抑制是否能增强 RT 诱导的局部抗肿瘤免疫和疾病控制 晚期 PDAC 患者。 目标 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 中的 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当前的 RT 治疗方案中，最终目标是提高 RT 的疗效。

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.