RAS mutations occur in one-third of all human cancers and confer a poor prognosis with a high risk of recurrence. Oncogenic KRAS mutations are particularly common among non-small cell lung cancer and pancreatic cancer, which are frequently treated with radiation therapy. These genetic alterations have been associated with radiation resistance, which often contributes to therapy failure for these common malignancies. The underlying mechanism by which KRAS-mediated resistance to ionizing radiation occurs is poorly understood, but has been proposed to be mediated via a cell-autonomous signaling mechanism. Using genetically engineered mouse models of primary soft tissue sarcomas, my preliminary data demonstrate that Kras-mutant tumors respond poorly to radiation compared to Kras wild-type tumors in an immune system- dependent manner. To understand the role of myeloid cells in the radiation response of Kras-mutant tumors, I will apply Cre-LoxP technology to generate Kras-mutant and Kras-wild type tumors while manipulating specific subsets of myeloid cells. The long-term goal of this project is to elucidate and harness mechanisms of radiation resistance to enhance the efficacy of radiation therapy in the clinic. The primary objective of this project is to dissect the role of immune cells in the radiation response of Kras-driven tumors by genetically manipulating myeloid cells. By improving our understanding of the role of Kras mutations in the immune response to radiation therapy, a critical mechanism of radiation resistance will be defined. Evaluating the role of the immune system in the radiation response of primary cancers will help determine the viability of targeting the immune system to improve the efficacy of radiation therapy in the clinic.
Radiation therapy is used in the treatment or care of nearly 2/3 of all cancer patients, but the mechanisms behind tumor resistance to radiation remain unclear. This proposal is relevant to public health because it will identify pathways that confer radiation resistance across multiple cancer types. Knowledge gained from this project may reveal novel targets for improving the efficacy of radiotherapy in many tumor types, and thus contributes to the NCI?s mission to alleviate the burden of cancer on patients.
| Wisdom, Amy J; Mowery, Yvonne M; Riedel, Richard F et al. (2018) Rationale and emerging strategies for immune checkpoint blockade in soft tissue sarcoma. Cancer 124:3819-3829 |
