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Ryan Phillips, MD, PhD
Johns Hopkins University
RSNA Research Resident Grant
(2019 - 2020)
Inhibition of Centrosome Clustering to Enhance the Interplay Between Radiotherapy and Immunotherapy
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Abstract:
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Modern therapies for localized prostate cancer are highly effective, but metastatic disease remains an incurable, life-limiting condition despite numerous advances in systemic therapies. While mounting evidence suggests that the application of radiation therapy in the proper biological context may be capable of potentiating the effects of immunotherapy in prostate cancer, attempts have heretofore met with limited but promising success. Disruption of centrosome clustering increases micronuclei and decreases tumor DNA organization, both critical to immunogenic signaling through the cGAS/STING/interferon axis. Clinically relevant immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1 can potentiate the immune response to this signaling. I hypothesize that the co-administration of radiotherapy, immune checkpoint inhibition, and disruption of tumor-specific centrosome clustering will improve both local and abscopal responses to prostate cancer treatment and presents a unique, potentially curative paradigm for metastatic prostate cancer.
Prostate cancer cell lines and a prostate cancer mouse model will be treated with centrosomal clustering inhibitors, immune checkpoint inhibitors, and radiotherapy. In cultured cells, DNA damage and repair, inflammatory and immunogenic signaling, and viability will be quantified. Survival of tumor-bearing mice undergoing these treatment regimens will be compared using the Kaplan-Meier method and hazard ratios will be calculated. Tumor growth will be fit to a linear segmental model.
The experience gained by completing this project will improve the breadth of my scientific understanding and help cultivate the high-level skills necessary to lead a similar effort as an independently funded principal investigator within a research-oriented radiation oncology department. Most importantly, this work is aimed at directly improving our collective ability to assist in our patients' battles against cancer.
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