Chromosomal Instability as a Marker and Mechanism of Radiation Response

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ABSTRACT Human Papilloma Virus (HPV) causes nearly 5% of all cancers worldwide and is implicated in 95% of cervical and 70% of oropharyngeal cancers (OPC). Curative platinum-based chemoradiation is the standard of care for patients with locally advanced cervical and OPC but patients with cervical cancer have significantly worse survival despite sharing the same viral etiology. Thus, there are significant differences in the radiation response between, and within, these two HPV+ cancers yet we continue to treat all patients similarly without consideration of individual tumor biology. Patients with HPV+ and HPV- cancers are also treated identically despite the significantly worse outcome of HPV- cancers in both sites. It is therefore imperative to gain a better understanding of tumor biology in order to tailor radiotherapy to improve patient outcomes and minimize toxicity. Chromosomal instability (CIN) is an ongoing rate of chromosome missegregation events over the course of multiple cell divisions, and when increased beyond a certain threshold can lead to cell death due to loss of both copies of one or more essential chromosomes. We, and others, have shown that very high levels of CIN are associated with cell death, tumor suppression, and improved prognosis in certain cancers. Moreover, combining two sources of CIN can increase it beyond the viable threshold resulting in cell death. Because both HPV and radiation induce certain types of CIN, I hypothesize that cells with pre-existing CIN will be more sensitive to radiation. Additionally, both CIN and radiation can induce innate and adaptive immune responses which are expected to affect overall treatment response, but predictive markers and mechanistic insights are lacking. This proposal aims to 1) define the types and extent of CIN caused by different HPV genotypes and viral oncogene levels, 2) determine if pre- existing CIN sensitizes HPV+ and HPV- cells to radiation in vitro, in vivo, and in patient tumors, and 3) determine how CIN affects innate and adaptive immunity in the context of radiation. Together, this proposal aims to determine HPV+ and HPV- tumor intrinsic and extrinsic factors that affect radiation response such that tumor and host biology can be incorporated into radiation treatment paradigms to decrease toxicity and increase cure. Dr. Cosper is a post-doctoral fellow in Radiation Oncology and will use this award to gain expertise in virology, chromosomal instability and immunology, in order to determine biomarkers that allow for personalization of radiotherapy. Dr. Cosper’s mentorship team consists of world-renowned experts in HPV virology (Dr. Paul Lambert), CIN (Dr. Beth Weaver), head and neck cancer radiobiology (Dr. Randall Kimple), and tumor immunology (Dr. Doug McNeel). The academic environment at the University of Wisconsin is superb, with abundant resources and collaborative opportunities. Further mentorship and training afforded by this award will provide Dr. Cosper a unique set of skills that will enable novel translational research to personalize radiation treatment for head and neck and cervical cancer patients and result in transition to a successful independent investigator.