Novel Combination Therapies for Anaplastic Thyroid Cancer
Abstract
Background and Objectives: Anaplastic thyroid cancer (ATC) is a rare form of thyroid cancer and is one of the most aggressive tumors known, with an annual incidence rate of 0.18/100,000 and a survival rate of about 3-6 months after diagnosis. ATC happens when cells in the thyroid develop DNA mutations that make the cells multiply very rapidly. The cells form a tumor that grows to invade nearby tissue and can spread (metastasize) to the lymph nodes in the neck. ATC cells do not respond well to radiotherapy or chemotherapy. However, recent therapies with drugs called kinase inhibitors have been very successful to make tumors shrink and easier to remove surgically. Unfortunately, responses to the drugs are short-lived due to the emergence of additional DNA mutations during treatment. There is, therefore, the need to identify novel molecules produced by the resistant cells that we could target with different drugs. We have found a new molecule called p38/MAPK14 in resistant cells and a drug that can possibly inhibit it, called ralimetinib. This project will evaluate if p38/MAPK14 is truly responsible for resistance and test the efficacy of ralimetinib in combination with other drugs in cultured ATC cells and in mice developing ATC. If successful, these results will justify future clinical trials. We believe that our study has the potential to create new treatment options for patients with ATC or other aggressive tumors. Focus Area: This proposal addresses the vision and mission statements of the fiscal year 2022 Rare Cancers Research Program, which are (1) to improve outcomes for patients with rare cancers through discovery, (2) to expand knowledge across the cancer landscape, and (3) to enable clinically impactful discoveries for the benefit of Service Members, Veterans, and/or the American public. Patient Population: ATC affects patients of both sexes. In one of our recent studies investigating 87 ATC patients, the median age was 65 years (range 35-88 years). The clinical course of ATC is characterized by rapid and invasive local tumor growth, frequent distant metastases, and fatal outcomes. Therefore, ATC requires rapid diagnosis and prompt treatment. Potential Clinical Application: Ralimetinib is currently in clinical trials for glioblastoma. As mentioned above, if treatments of our ATC mouse models are conclusive, the data will justify a future phase 1 trial with ATC patients. Adverse reactions to ralimetinib exist such as hepatitis, rash, and nausea. However, because we are testing synergistic interactions between ralimetinib and other Food and Drug Administration-approved drugs, we will use lower doses of the combination constituents, which will hopefully reduce adverse reactions. Time Until Clinically Relevant Outcome: We expect to present the complete set of data within 3 years. Contributions for Rare Cancer Research: Mutations found in ATC are very similar to those found in melanoma, which accounts for only 1% of all skin cancers diagnosed in the United States but causes most of the deaths from skin cancer. We therefore believe that our study has the potential to create new treatment options not only for ATC patients, but also for patients affected by aggressive tumors such as melanoma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310675
Entities
People
- Marie-claude Hofmann
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army