Targeting Tumor Intrinsic and Extrinsic Survival Signaling to Overcome Resistance to Radiation Therapy in Pancreatic Cancer.

Abstract public domain (NIH RePORTER)

Project Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a 5-year survival rate of 13%. The only potential for curative treatment is surgical resection; however, only 10-15% of patients are diagnosed with resectable disease. Current radiation therapy (RT) strategies infrequently generate sufficient tumor regression to achieve resectability in locally advanced patients, and metastatic relapse is common. The resistance of PDAC to multiple therapies has been linked, in part, to its unique tumor microenvironment (TME), characterized by a dense, collagen-rich extracellular matrix (ECM), abundant and diverse populations of cancer-associated fibroblasts (CAFs), and resultant tumor cell hypoxia. PDAC’s fibrotic stroma has been associated with poor drug delivery and dysfunctional anti-tumor immunity. Research by multiple groups, including our own, has shown that downstream of this fibrotic ECM, the Focal Adhesion Kinase (FAK) pathway is chronically hyperactivated in human PDAC. In turn, FAK signaling regulates PDAC cell survival, cytokine production, and metastatic capacity. Additionally, studies have demonstrated that FAK inhibition decreases the tumor-supportive activity of CAFs. In preclinical models, FAK inhibition has improved responses to chemo- and immunotherapies, leading to several clinical trials, some of which have shown promising early results. Recently, we have discovered unique biology when FAK inhibition is combined with RT. The direct target of RT is DNA damage, which leads to cell death. In addition, RT can prime anti-tumor immunity by releasing tumor-derived antigens and danger signals, which likely plays a critical role in RT efficacy across multiple cancer types. It is unclear whether these immune-priming functions of RT are intact in cancers like PDAC. Further complicating this is the fact that RT-induced fibrosis in adjacent normal tissues is an established long-term treatment-related side effect. Thus, RT-induced fibrosis, either within the tumor or at tumor-normal borders, may also contribute to blunted anti-tumor immunity. Similarly, RAS/MAPK and FAK signaling have been implicated in RT resistance. Based on our data, simultaneously targeting both tumor and stromal FAK and Ras/MAPK pathways can overcome resistance to RT, enhance RT-induced tumor immunity, and prevent metastatic relapse. To test this, we will: Aim 1. Determine if the combination of FAK inhibition and SBRT can be further improved by addition of RAF- MEK inhibition in locally advanced PDAC patients. Aim 2: Determine the biomarkers of response and resistance to therapy. Aim 3: Determine the optimal FAK-RAS/MAPK-RT combination to stimulate lasting tumor immunity and prevent metastatic disease. Impact: These studies will build on strong early clinical data to use RAF-MEK and FAK inhibition to drive deeper responses to radiation therapy in human PDAC patients.

Public health relevance public domain (NIH RePORTER)

Project Narrative: This project seeks to use a combination of targeted therapy to shut down survival pathways in tumor cells and radiation therapy to treat pancreatic cancer patients. Targeted therapies will be employed to enhance initial tumor killing during radiation therapy and continued as maintenance therapy to prevent metastatic relapse in locally advanced pancreatic cancer patients.