Credentialing a Mouse Model for Merkel Cell Carcinoma
Abstract
Background: Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma with an estimated incidence of 0.2 to 0.7 per 100,000 annually in the United States, with high mortality. There are two established causes: the more common one is due to a viral infection by Merkel cell polyomavirus and the second due to high levels of DNA damage caused by excessive sun exposure. Immunotherapy has proven effective; yet there are no targeted approaches, and no strategies for immunotherapy-reesistant disease. Importantly, evidence suggests that virus positive and virus negative MCC are biologically distinct despite largely indistinguishable diagnostic and clinical features. An important resource for addressing these pressing unmet needs and to make needed translational progress, is the availability of an appropriately-credentialed animal model of MCC. Several laboratories have been involved in sustained efforts to generate a faithful mouse model of MCC. However, it has not been definitively established which normal cells give rise to MCC. With this in mind, we removed the two most highly mutated tumor suppressors in MCC, RB1 and TP53, in mice, in skin cells called keratinocytes. The mice develop cutaneous tumors within 6 months of age and recapitulate microscopic features of human MCC. Focus Area(s): This project significantly leads to promising outcomes in all three Focus Areas. First, the main Focus Area is production of a new research model. Second, this model allows us to test how skin cells can give rise to MCC. This contributes to our understanding of MCC biology and etiology and allows us to understand how keratinocytes can give rise to MCC. Third, this model allows us to directly test novel therapies, including immunotherapy. Applicability: We expect that our work will be directly applicable to MCC patients, but also more generally to patients with neuroendocrine carcinomas such as small cell lung cancer and neuroendocrine variants of bladder and prostate cancer. There is a significant unmet medical need to address gaps in our ability to treat these cancers effectively. We expect that our findings will be applicable to other related cancers because they also seem to suffer from the same genetic defects that non-virus MCC does. The ability to work with an animal model of MCC allows us to test new therapies and validate their use in the context of clinical trials in humans. We anticipate clinically relevant outcomes from this work to result within the next 2-3 years. Our plan is to generate necessary preclinical data to justify practice-changing clinical trials and to also understand mechanisms by which MCC can be sensitized to immunotherapy. More generally, the development of this model allows us to leverage data from models of related neuroendocrine cancers, probe the relatedness of this group of aggressive cancers, and look for common and distinct vulnerabilities which can be used to treat them more effectively.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211084
Entities
People
- Kenneth Y. Tsai
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army