Modeling Virus-Associated Merkel Cell Carcinoma in Mice Using Viral DNA Regulatory Sequences
Abstract
Scientific Objective and Rationale The overall scientific objective of these studies is to produce a genetically engineered mouse model that will develop a very rare skin cancer called Merkel cell carcinoma (MCC), that is caused by a virus. A mouse model of MCC is needed to help us learn more about the detailed behavior of these tumors, including their rapid growth, invasion into surrounding tissues, and eventual spread to other organs. Understanding what controls these events could lead to new forms of treatment or prevention, and a mouse model of MCC is essential for testing new drugs, or drug combinations, before they can be used in MCC patients. We are proposing to create our mouse model by permanently inserting genetic material from the MCC-causing tumor virus into mouse tissues, because we have preliminary evidence that this can lead to MCC development in mice. One of the unique features of our mouse modeling strategy is to use specific genetic instructions taken from the MCC virus. These instructions should turn on the cancer-causing viral proteins in the right place, and at the right time, to produce MCC tumors in mice. The Fiscal Year 2021 Rare Cancers Research Program Idea Development Award Focus Areas: The Focus Areas we are addressing in our experiments, as explained in the preceding section, include Research Model, because we are planning to create a new mouse model, and Biology and Etiology, because our mouse model will help us better understand the behavior (biology) and cause (etiology) of MCC tumors. Ultimate Application of Our Research A mouse model of MCC will provide an important and much-needed tool for identifying and testing new ways to treat patients with MCC, and these studies could potentially also help patients with other related tumors called neuroendocrine cancers. Our mouse model will be especially useful for testing immunotherapy approaches to treatment, which rely on unleashing the killing potential of patients’ own immune cells against cancer. Pre-clinical immunotherapy trials, or combination trials using immunotherapy together with other treatments, require the use of animal models of cancer. Our studies are therefore likely to eventually have a major impact on cancer patients in many populations, including active-duty Service Members, Veterans, military beneficiaries, and the American public in general. Because MCC is much more common in older patients, our work may be especially relevant to older Veteran and public populations. Although our studies will not lead immediately to clinical trials, work with mouse models of cancer provides a critical pre-clinical testing phase for determining safety and possible effectiveness of new drugs before they are tried in patients. In the meantime, by studying our mouse model in detail we hope to learn more about the aggressive behavior of this cancer, and what factors are responsible. The amount of time needed for our work to make a direct impact on the care of MCC patients is difficult to predict, but I expect it would take somewhere between 5 and 10 years after we have successfully created our mouse model of MCC and confirmed that it is sufficiently similar to human MCC to be useful for pre-clinical studies. Although this proposal is centered specifically on MCC, our experiments may uncover new knowledge to better understand other types of neuroendocrine cancers, some of which are also rare. In addition, some of the innovative techniques that we are using to create our new mouse model of MCC may have applications that will help with the development of other mouse models of rare cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210980
Entities
People
- Andrzej Dlugosz
Organizations
- United States Army
- University of Michigan