Deploying a Novel Model of Merkel Cell Carcinoma for Development of Novel Therapeutic Approaches
Abstract
Merkel cell carcinoma (MCC) is a rare skin cancer with an estimated incidence of 0.2 to 0.7 per 100,000 people annually in the United States. However, although it is not as common as the better-known skin cancer, melanoma, MCC has a lethality which is comparable. There are two established causes: the more common one is due to infection by the Merkel cell polyomavirus in skin cells; the other cause is due to DNA damage from excessive sun exposure. Immunotherapy has proven very effective; yet only half of all patients treated will respond. In addition, there are no drugs which directly molecular defects in the cancer cells of MCC. An important resource for addressing these pressing unmet needs and to make needed translational progress, is the availability of an appropriately credentialed animal model. In cancer research, the development of new therapies is often greatly aided by the availability of animal models. These models are designed to mimic human disease in their essential features and to therefore allow for the testing of new therapies before they can be safely tested in humans. Merkel cell carcinoma has never had a fully accurate or faithful model. This has been a major impediment to generating the next generation of therapies for MCC. This project significantly leads to promising outcomes in all three Focus Areas. First, this is the first in vivo model of non-virus associated MCC we are aware of and the primary Focus Area is research model. We will freely disseminate this model widely in the community as quickly as possible and this will immediately impact our ability to study the pathogenesis of this cancer and test therapies in vivo, a major block for translational studies in this disease. Second, this model allows us to test how neuroendocrine differentiation may be driven in keratinocytes. We have used lessons from other cancers which are related to MCC but which occur in other organs such as lung. Based upon our analysis of data from our laboratory and those of others, we designed a model to mimic MCC in the mouse. This allows us to better understand the biology and etiology of MCC to better design therapies. Third, this model allows us to directly test novel therapeutic approaches, including immunotherapy. This allows us to immediately advance preclinical data to justify testing novel therapies in MCC. Key questions of how the tumor immune microenvironment can be modeled, and more importantly, related to existing human data from clinical trials and standard of care therapy we already have. The most immediate benefit is to people who have Merkel cell carcinoma or who are at risk of developing it. Our model will enable the greater cancer research community to immediately better understand how MCC develops in a live model and test new therapies quickly. This specific capability can be deployed immediately. Therefore, a clinically relevant outcome can be realized within the frame of the grant period and a clinical trial concept advanced within that timeline.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210921
Entities
People
- Kenneth Y. Tsai
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army