Investigating the contribution of cellular senescence to the efficacy of radiation therapy.

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PROJECT SUMMARY/ ABSTRACT Ionizing radiation (IR), a highly effective cancer therapy, is known to induce cellular senescence, a cell cycle arrest program triggered by the DNA damage response. Cellular senescence results in upregulation of mRNAs encoding secreted factors (including inflammatory cytokines and chemokines), a program referred to as the senescence-associated secretory phenotype (SASP). The SASP modulates the tumor microenvironment, and it has pleiotropic immune-modulatory effects. Although IR sensitivity is known to depend upon host immunity, the contribution of senescence and the resultant SASP is unknown. Our preliminary data suggest that the SASP contributes to both localized and systemic anti-tumor effects of IR in immunocompetent, but not immunodeficient, mouse models. Thus, we hypothesize that the anti-tumor effects of IR, both local and systemic, are mediated in part by the SASP through an immune effector. This project will use a combination of mouse and human models to test this hypothesis and to define the mechanisms through which the radiation- induced SASP alters both local and distant tumor microenvironments. In addition, it will use patient tumor samples to establish clinical relevance in patients with rectal cancer treated with radiation therapy or with radiation combined with immune checkpoint blockade. While this proposal focuses on rectal cancer, it has broad clinical implications, as radiation therapy is a widely used treatment modality for cancer. Dr. Paul Romesser has outlined a 5-year career plan that builds upon his clinical training in radiation oncology and on his research background in cancer biology, radiation biology, genetically engineered mouse models, and patient-derived models. Dr. Romesser will be mentored by Dr. Scott Lowe, an internationally renowned expert in senescence, p53 biology, and mouse modeling with a strong track record of training physician-scientists. Dr. Romesser’s career development plan includes research experience, course work, workshops, and mentoring from an interdisciplinary advisory committee comprising distinguished basic scientists, physician-scientists, and radiation oncologists. He will have the support and infrastructure of Memorial Sloan Kettering Cancer Center, a center of excellence in basic, translational, and clinical cancer research. Successful completion of the research project will lead to new approaches for treating patients with radiation therapy and will provide the foundation for Dr. Romesser to transition to a position as an independent investigator with his own laboratory and R01 funding.