Abstract 2402: Fractionated dosing: A more clinically relevant approach to radiotherapy in preclinical tumor models

Abstract

Abstract Genomic assault in the form of DNA double-strand breaks represents the most efficient mechanism by which radiotherapy mediates killing of cancer cells. In order to preserve cellular integrity and mitigate the adverse effects and complications arising from insult to healthy tissues, a fractionated dosing regimen, where low doses of ionizing radiation are administered over a course of several days, is the principal mode of radiation therapy in clinical settings. Additionally, it has been demonstrated that fractionated dosing has a greater capacity to elicit anti-tumor activity and immune mediated abscopal response, compared to bolus delivery. However, in most preclinical animal models of cancer that employ the use of focal beam radiation, administration of a single bolus dose is the standard practice. To establish a more translationally relevant approach to radiation therapy, we utilized computerized tomography (CT) guided Small Animal Radiation Research Platform (SARRP) in three murine subcutaneous tumor models, MB-49 (bladder), B16F10 (melanoma) and MC38 (colon). Each treatment cohort was subjected to a fractionated dosing regimen, and response was assessed by caliper measurements of tumor volume. Therapy was well tolerated across all models and dosing regimens, as evidenced by no significant body weight loss or presentation of adverse clinical symptoms compared to controls. Fractionated focal radiation at 2Gy delivered over a course of five consecutive days (QDx5) induced a modest anti-tumor response in the MB-49 model, resulting in a 66.7% increase in time to progression (ITP) and a 64.1% median ΔT/ΔC on day 16 post implant. Mice bearing MC38 tumors exhibited meaningful response with incidences of 55% ITIP and a median ΔT/ΔC of 29% on day 26, following treatment with radiation at 2Gy, QDx5. Additionally, fractionated doses at 10Gy and 5Gy both delivered Q5Dx2 produced robust anti-tumor response in the B16F10 model, with incidences of 5% and 21% median ΔT/ΔC on Day 15, respectively. Though notable responses were observed across all treatment cohorts, there were no incidences of tumor free survivors or complete regressions, thus allowing for additional therapeutic intervention and synergistic approaches. Further assessment of fractionated dosing regimens in additional mouse models, as well as potential impact on immunomodulation, are ongoing. Over 50% of cancer patients are treated with radiotherapy, with a significant portion requiring integration with other therapeutic modalities to enhance survival and curative benefits. It is therefore imperative to identify appropriate fractionated dose levels and schedules across preclinical cancer models, in order to more accurately reflect the clinical landscape and provide a more viable framework for interrogating rational combination strategies. Citation Format: Kerry-Ann Bright, Derrik Germain, Erin Trachet, Sheri Barnes. Fractionated dosing: A more clinically relevant approach to radiotherapy in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2402.