Metastatic Progression in Medullary Thyroid Cancer
Abstract
Medullary thyroid cancer (MTC) is an aggressive thyroid cancer (a Peer Reviewed Cancer Research Program PRCRP Topic Area) of thyroid neuroendocrine cells. Patients with advanced MTC have a poor 10-year survival rate of 21%. Thyroid nodules are associated with increased risk for MTC. Thus, military Service Members exposed to ionizing radiation from nuclear accidents or military test sites or other toxic agents, which have been shown to cause thyroid nodules, are at increased risk for MTC. Because of the disproportionate thyroid cancer-related mortality caused by MTC and the unique exposures for military personnel, improving MTC-related outcomes for Soldiers, Veterans, and their Family Members is the focus of this proposal. Effective treatment for this appalling cancer does not exist because of an extremely limited number of research models, which do not accurately represent the complexity of the original tumor. Cell lines made from patient-derived MTC tissue only have one type of cancer cell, while the original cancer has many types of cancer cells. Furthermore, although mouse models have many types of cancer cells, the mouse cancer is too different from the human version. As a result, treatments developed using existing research models do not improve survival. Organoids or mini-organs, are 3-dimensional research models that incorporate features of the represented organ. For example, organoids derived from thyroid tissue will maintain features of the thyroid gland. Because organoids contain many cell types and can be made from human tissues, these models better represent the original human tissue compared to cell culture or mouse models. Organoids have been successfully used to study cancers that were previously difficult to study and treat, such as esophageal cancer, pancreatic cancer, and colon cancer. We developed the first MTC organoids, which proliferated and produced hormones similar to the original tumor. The overall goal of this application is to support my training and development as a leader in thyroid cancer research. The career development plan includes structured mentorship and development of expertise in MTC biology, advanced stage cancer, and cancer genomics through completion of the aims. In this proposal, we use patient MTC tissues and our novel MTC organoids to understand the features of cells that lead to advanced disease. In our first aim, we implement new techniques to understand the genetics of cells that lead to advanced MTC. In our second aim, we employ a 3-dimensional organ-on-a-chip platform, which represents the human body, to study cells that escape from the MTC organoids and invade other normal tissue organoids. Using these strategies, we intend to identify the features of cells that cause advanced disease and ultimately reveal vulnerabilities that can be targeted clinically. We expect that our new techniques can be used by scientists studying other cancers, so that patients with other cancers can also benefit from this research. As a result of this work and aligning with the PRCRP Overarching Challenges of Diagnostics/Prognostics and Therapeutics, we will be able to identify patients who are risk for advanced disease and target vulnerabilities in the most dangerous cancer cells, which cause advanced disease. After validating our findings, we are poised to develop a clinical trial to target these pathways in the next 10 years. Thus, this proposal has the potential not only to advance my scientific career, but also treatment of MTC and other cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310503
Entities
People
- Priya Dedhia
Organizations
- Ohio State University
- United States Army