Intratumoral hypoxia is an important predictor of tumor response to radiation therapy (RT). Not only does intratumoral hypoxia reduce the amount of molecular oxygen available for radiation-induced DNA damage, but hypoxia also alters a variety of cellular signaling pathways by stabilizing hypoxia- inducible factors HIF-1? and HIF-2?. Elegant in vitro studies have shown that HIF-1? and HIF-2? play opposing roles in tumor cell response to RT. To study the role of HIFs in tumor response to RT in vivo, I have deleted HIFs in a novel primary mouse model of soft tissue sarcoma with conditional activation of oncogenic RAS and deletion of p53. In this proposal, I will determine how deletions of HIF-1? and/or HIF-2? in primary sarcomas affect RT response. Furthermore, by performing metabolomic-profiling on non-irradiated and irradiated tumors, I will determine how HIF-deficiency mediates changes in tumor response to RT via alterations in tumor metabolism. My long-term goal is to use this knowledge to develop novel therapies that may be administered with RT to improve tumor cure.
Soft tissue sarcoma (STS) affects approximately 11,280 new patients, and will cause 3,900 deaths in 2012 in the US. The majority of STS occur in the extremities, where they are treated with a combination of limb-sparing surgery and radiation therapy (RT). In these patients, RT improves local control by 60%. For patients with surgically unresectable tumors, RT alone results in a local control rate of 20-45%. To improve local control for the patients with local recurrence, it is crucial to understand the mechanisms behind tumor cell survival post-RT. Clinical data have shown that intratumoral hypoxia is highly correlated to tumor resistance to radiation;however, the mechanisms behind hypoxia-induced tumor resistance to radiation remain unclear. One mechanism by which intratumoral hypoxia might modulate tumor radiation response is through the stabilization of hypoxia-inducible factors (HIFs) in hypoxic tumor cells, leading to tumor metabolic reprogramming. The goal of this proposed work is to determine the role of HIFs on tumor cell metabolic adaptations and survival after RT in a primary model of soft tissue sarcoma, so that novel therapies can then be generated to improve tumor radiation response in human patients. This work is important because recent studies have shown that the response of primary cancer models to therapies closely mimic the response of the same therapies applied to human cancers in clinical trials.