Harnessing the Circadian Clock to Alleviate Ionizing Radiation-Induced Toxicity During Melanoma Therapy

Melanoma is the most lethal form of skin cancer, due to its predilection for early metastasis, and is often associated with a poor prognosis due to resistance to therapy. Despite the promise of immunotherapy, less than 50% of melanoma patients respond to monotherapy or combination therapy with targeted therapy. Although, radiation therapy (RT) plays a small role in the traditional management of metastatic melanoma for palliation, recent experimental and clinical evidence suggests a broader involvement of RT in enhancing tumor cell killing in immunotherapy by augmenting the patient's immune system. According to ClinicalTrials.gov, there are currently 109 active clinical trials underway for treatment of melanoma patients with RT, mostly in combination with targeted/immunotherapy. However, the majority of patients that receive RT suffer skin inflammation ranging from mild erythema to ulceration. This side effect limits the dosages of radiation that can be administered, often to the point of terminating therapy early in order to prevent patient discomfort, which in turn increases the risk of redeveloping tumors and those tumors being resistant to further treatment.

Understanding the circadian clock in healthy skin and melanoma may lead to prevention of these outcomes by minimizing skin toxicity and by improving tumor cell killing from RT in combination with immunotherapy. The circadian clock maintains daily rhythms in an organism, and the expression levels of many genes are controlled by oscillations of the circadian clock. The objective of this proposal is to translate our findings on the circadian clock control of RT-mediated cellular toxicity and the immune system to patient benefit by minimizing skin toxicity and improving treatment efficacy in melanoma patients. Our hypothesis is that the circadian clock influences both tumor shrinkage and healthy tissue toxicity resulting from RT in combination with immunotherapy. We specifically seek to determine: how circadian rhythms impact RT-mediated tissue toxicity and immune response in healthy tissues and melanoma tumors in genetic mouse models, and the impact of the circadian clock on efficacy of RT in combination with immunotherapy in melanoma-prone genetic mouse models.

This funding will help improve our mechanistic understanding of melanoma treatment. The successful completion of this study will lay a solid foundation for the next phase of the project, which will involve identifying how the circadian clock can be harnessed to improve efficacy and minimize toxicity of radiotherapy followed by immunotherapy. My career development plan facilitates these goals by focusing on interacting and collaborating with experts in cancer, immunotherapy, and radiation biology; forging new connections at conferences and workshops; and continuing to propose projects for extramural funding.

In the long term, our research has the potential to benefit not only melanoma patients, but any cancer patient receiving RT as well as immunotherapy, by reducing the toxic side effects and improving efficacy of their treatment. The end results of our research will lead to improved efficacy of radiation treatment through resetting of the patient circadian rhythm. Although this is not a clinical trial that will lead to immediate patient outcomes, this study will lay the groundwork for clinical trials that could be rapidly implemented, allowing us to understand the influence of the circadian rhythm on skin toxicity, especially radiodermatitis, and the immune system at the molecular level. This knowledge will help medical professionals better tailor their treatments to their patients' biological rhythms. This research is particularly relevant to military personnel because the incidence of melanoma in active duty personnel has been increasing and is now higher than in the general population.