Discovery of Novel Dopachrome Tautomerase (DCT) Functions Mediating Therapeutic Resistance in Melanoma
Abstract
Skin cancer is the most common form of cancer in the United States, affecting one in five Americans in their life time. Melanoma is a relatively rare type of skin cancer, but one that accounts for the majority of skin cancer deaths. Why is it that melanoma is so deadly? One possibility is that the cells that become melanomas, called melanocytes, already have characteristics that make for a deadly cancer. Whereas other types of skin cells need to evolve these characterizes after they become cancerous, melanocytes (and therefore melanomas) might start with a molecular deck of cards that is stacked against the patient. If true, it is very unlikely that the melanocytes hold that stacked deck for the purposes of generating deadly cancers. Rather, it is more likely that those characteristics evolved for healthy, everyday purposes, and they also happen to make melanomas disproportionally deadly. We recently identified characteristics of healthy melanocytes that are hidden in melanoma cells and discovered that patients with melanoma tumors that have these characteristics are more likely to die. Why these hidden characteristics are advantageous for melanoma tumors, and therefore detrimental for patient survival, is unknown. While one purpose of these characteristics is known – they help melanocytes make the pigment responsible for skin tone – not all melanocytes or melanoma cells with these characteristics make pigment, and pigment alone does not explain why these characteristics are important for melanoma tumors. It is remarkably difficult to identify other non-pigment related functions of these characteristics by traditional research methods and we suspect this is why generations of researchers have missed the contribution of key melanocyte characteristics to the deadliness of melanoma. We are proposing a series of carefully constructed experiments to discover the functions of one of these characteristics – a gene called dopachrome tautomerase (DCT) – specifically in melanoma. In addition to understanding this one gene, the proposed experiments will serve as a proof of principal workflow for how to uncover these hidden characteristics of melanocytes that contribute to melanoma. In seeking to unveil the melanoma-specific function of DCT, we will be discovering new candidate molecules for predicting how deadly a patient’s melanoma will be or how well that melanoma will respond to therapy. In addition, we will identify new candidate therapeutic targets for preventing melanoma formation, preventing and treating the advanced disease, or making the advanced disease more susceptible to current therapies. As this is a discovery focused proposal, we do not expect to have developed these biomarkers and small molecules by the end of the 2-year funding period, but rather we will have discovered completely new avenues to pursue these ends, in addition to inventing a strategy for further exploration of a whole class of potentially targetable, previously overlooked, genes important for melanoma progression. Thus, this work will set the foundation for research that will benefit patients at risk for recurrence, patients who do not respond to current treatments, and patients who eventually develop resistance to current treatments.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210495
Entities
People
- Rachel Belote
Organizations
- United States Army
- University of Utah