Tumor Resistance to Fractionated Radiotherapy in Obese Mice

Abstract

Obesity has reached pandemic levels in the United States and will soon surpass smoking as the number one cause of preventable cancer. Clinical data demonstrate that obese cancer patients are more resistant to radiotherapy and have higher rates of recurrence. Although a growing number of cancer patients are obese, and obesity is linked to poor outcomes with radiotherapy, little is understood about how obesity impacts the efficacy of radiotherapy. Understanding if and how obesity induces radio-resistance and how to best treat obese cancer patients is a critical unmet need. In this study we test the hypothesis that tumors in obese mice have increased resistance to fractionated radiotherapy. Control and diet induce obese (DIO) mice were generated by feeding 4-6-week-old, genetically identical, inbred C57BL/6 mice with a high-fat diet consisting of 60% kcal from fat (DIO) or a control diet consisting of 10% fat (control) until 6 months of age. Mice were then implanted with syngeneic B16F0 tumors in the hind leg. When tumors reached 5mm in diameter mice were treated with fractionated radiotherapy (12 Gy delivered in daily 4 Gy fractions X 3 days) using a 2cm electron cutout to treat the tumor + margin only. DIO mice had significantly increased body weight (control 30-40 g; DIO 50-65 g), significantly increased visceral and subcutaneous fat deposits, and elevated leptin levels. Blood glucose levels and HgbA1c in DIO mice, although slighter higher than controls, were within normal limits and did not indicate insulin resistance. Mice were divided into four groups of 8 mice (control, control + RT, DIO, DIO + RT). Fractionated radiotherapy (4 Gy x 3) significantly reduced the growth of B16F0 tumors by about three-fold in control mice compared to untreated controls. Radiotherapy failed to significantly reduce tumor size in DIO mice (compared to unirradiated DIO), although the treated tumors trended towards being modestly smaller. Additionally, tumors in the DIO + RT group were significantly larger than the tumors in the control + RT group. Initial mechanistic studies suggest increased tumor proliferation and immune dysfunction in DIO mice may induce the observed radio-resistance. Using genetically identical mice with genetically identical tumors we demonstrate, for the first time, that diet and obesity can drastically alter the anti-tumor effects of radiotherapy. Mechanistic studies and studies in other tumor models are underway. Understanding how obesity impacts radiotherapy response and developing strategies to address these issues will improve outcomes in obese patients. Thus, these studies can have a major clinical impact and represent a step towards personalized medicine by tailoring radiotherapy treatment strategies to a patient's metabolic parameters.