Purpose: Patients diagnosed with anaplastic thyroid (ATC) cancer display heterogeneous tumor responses to radiation therapy. It remains unclear how the molecular profiles of ATC subtypes mediate a radiosensitive or radioresistent phenotype. Furthermore, the optimal fractionation for ATC remains controversial. In this study, we sought to identify genetic determinants of tumor radioresistance in ATC subtypes. We further compared the role of hypofractionated radiotherapy to conventional fractionation in a novel orthotopic model of ATC.
Methods: Eight human ATC and PDTC cell lines (C643, SW1736, BCPAP, T238, CAL62, KHM-5M, 8505C, and KTC-2) were profiled using microarray analysis. Clonogenic survival assays were performed for each cell line. Irradiation (IR) was performed at 0, 2, 4, 6, and 8 Gy and cells were incubated for 8-10 days post-IR. Data were fitted to the linear quadratic model. Cell lines were classified as radioresistant (RR) or radiosensitive (RS) based on SF2 and SF4 values. Hierarchical clustering was performed to determine the genomic profile of RR and RS cell lines. For in vivo studies, mice were surgically implanted with the luciferase-tagged 8505C ATC cell line. Mice were randomized on the day of treatment initiation (day 14-15) based on BLI photon radiance signal to receive hypofractionated (HF), conventional fractionation (CF) or no irradiation. A total dose of 20Gy was delivered in 2 weekly doses for the HF group and daily 10 doses for the CF group.
Results: We identified five radioresistant cell lines and three radiosensitive cell lines. Microarray gene-expression analysis revealed an inflammatory gene signature associated with radioresistance. In particular, CXCR4 was increased by more than 2-fold in RR cell lines. CXCR4 has been shown to play a role in mediating tumor growth, metastasis and resistance to therapy and its targeting has shown efficacy in various tumor animal models. Longitudinal analysis of weekly BLI revealed significant differences in tumor growth in the HF group compared to the control and CF groups. On the last day in which all mice were alive (day 36), average photon radiance in the HF group was significantly lower compared to mice in the control group (125-fold decrease) and mice in the CF group (16-fold decrease). In addition to its effect on primary tumor growth, HF resulted in significantly improved survival compared to mice in the control and CF groups.
Conclusions: Our study provides evidence that hypofractionated radiotherapy is superior to conventional radiotherapy in a radioresistant model of ATC. Hypofractionated RT significantly retarded tumor growth and prolonged survival. Gene-expression analysis revealed targetable pathways that may be associated with radioresistance. These findings have direct clinical implications for enhancing treatment outcomes and survival in ATC patients.
Citation Format: Ayman J. Oweida, Andy Phan, Benjamin Vancourt, Tyler Robin, David Raben, Bryan Haugen, Nikita Pozdeyev, Rebecca Schweppe, Sana D. Karam. Radioresistant anaplastic thyroid cancers display a unique gene signature and respond to hypofractionated radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4168.