The efficacy of radiotherapy is limited by the adverse effects caused by damage to healthy tissues adjacent to the tumor. Tumor radiosensitivity is determined by intrinsic sensitivity, the inherent sensitivity of the tumor cells, and extrinsic sensitivity, resistance to killing that is imparted through the tumor environment. One key factor determining extrinsic radiosensitivity is tumor hypoxia. A possible strategy to reduce tumor hypoxia is to decrease the oxygen consumption rate in the normoxic tumor cells thereby increasing the availability of oxygen to the hypoxic areas. In order to identify compounds that can alleviate tumor hypoxia, we conducted a high throughput screen to measure oxygen consumption in cancer cells and screened a library of 1,697 FDA-approved compounds. One of the potential compounds we identified was the antimalarial drug atovaquone as a potent reducer of oxygen consumption. Atovaquone was subsequently demonstrated to reduce hypoxia in spheroids and xenograft tumors and caused significant tumor growth delay in combination with radiation in these models. The aim of this project is to further investigate the mechanism of action of atovaquone and other compounds identified in the screen or their derivatives in vitro and in vivo in combination with radiation and other anti-cancer therapeutics.
Our research will identify new drug therapies to selectively render tumors more sensitive to radiation without exacerbating effects in normal tissues.