Abstract 3307: Chemopotentiation by low dose fractionated radiation therapy in colon cancer cells

Abstract

Abstract Response rates for patients with primary and metastatic colorectal cancer treated with modern chemotherapy regimens such as 5-FU, leucovorin, oxaliplatin (FOLFOX) have routinely exceeded 50% and are frequently as high as 60-70%. However, as in most chemotherapy regimens, toxicity to normal cells is often a significant limitation. Tumors of the gastrointestinal (GI) track are also sensitive to radiation but the inability to combine radiation therapy (RT) with full-dose chemotherapy can be detrimental to patients, particularly those that may have disseminated micrometastatic disease. Therefore, new treatment strategies that incorporate chemotherapy that could increase tumor response without increasing toxicity are highly desirable. Laboratory and clinical data suggest that using low-dose fractionated radiation therapy (LDFRT) as a chemopotentiator may allow for full-dose chemotherapy with improved efficacy without adding to the toxicity of the systemic treatment. Here we show that twice daily radiation doses as low as 0.15 Gy for three consecutive days can significantly increase FOLFOX killing efficiency in human colon cancer RKO cells. In addition, our data indicate that the chemopotentiation by LDFRT may be mediated by the stress inducible hnRNP A18 protein. Down regulation of hnRNP A18 sensitizes RKO cells to LDFRT and FOLFOX independently and increases further the chemopotentiation by LDFRT. Moreover, overexpression of hnRNP A18 increases radio-resistance and chemo-resistance to FOLFOX. hnRNP A18 is a new regulator of protein translation in cancer cells that specifically targets transcripts devoted to confer growth advantages. This data suggest that hnRNP A18 could be targeted to increase further the systemic effect of chemopotentation by LDFRT. The identification of hnNRP A18 as a new cellular pathway responsive to low dose radiation and its contribution to chemopotentiation provide a novel opportunity for better measurement of the therapeutic response and could contribute to the rationale designs of new mechanism based clinical trials. Citation Format: Teresa Smith, Palak R. Parekh, Elizabeth T. Chang, Michael Chuong, France Carrier. Chemopotentiation by low dose fractionated radiation therapy in colon cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3307. doi:10.1158/1538-7445.AM2015-3307