Microsomal Glutathione Transferase as a New Target in Melanotic Melanoma
Abstract
One in five Americans will get skin cancer in their lifetimes. Skin cancers can affect your appearance as well as your health. Skin cancer is the most common form of cancer in the United States, with more than 3.5 million cases diagnosed yearly – more than all other cancers combined. Melanoma is the most deadly type of skin cancer. Despite some high-profile success stories using targeted and immunotherapy, it remains difficult to cure. Among cancers, melanoma is unique in its requirement for melanin, a pigment found in skin cells known as melanocytes. Melanin is a molecule that is created from amino acids through incompletely characterized pathways that produce both pheomelanin and eumelanin. Humans differ broadly in their capacities to generate melanin, and this creates a situation where certain individuals are more susceptible to melanoma initiation and progression. Our preliminary studies have shown that specific steps in melanin synthesis are catalyzed by enzymes that if knocked out, adversely alter melanin levels in melanoma cells and survival of melanoma-bearing mice. We hypothesize that one key step in melanin synthesis is altered in the absence of the enzyme (MGST1) and wish to examine this step, permitting a greater understanding of the missing link between this enzyme and melanoma. Moreover, humans are subject to genetic variation in GST enzymes, that is, some individuals do not have the types of enzymes that are integral to the melanin synthetic pathway. This may alter their susceptibility to ultraviolet-light induced conversion of melanocytes and other surrounding cells to a precancerous, and eventually cancer state. Our goal is to interrogate the melanin biosynthetic pathway, define the importance of an enzyme that we think influences melanin and pigmentation levels (also having antioxidant properties), relate this to alterations in immunity and determine whether new drugs that inhibit this enzyme can be developed as therapeutics. We have established evidence in preclinical models that depletion of the target enzyme significantly depletes pigmentation, delays cancer growth and metastases, and prolongs survival. Our short-term goals will include studies on how existing chemo-, targeted, and immunotherapies can be positively influenced by either genetic or pharmacologic inhibition of enzymatic catalysis. Results will prove the importance of MGST1 as a target and improve understanding of molecular pathways that influence metastatic spread, addressing fiscal year 2022 Melanoma Research Program Areas of Focus. If successful, a novel approach to the treatment of metastatic melanoma would improve survival of active-duty Service Members, Veterans, and the American public who suffer from this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310649
Entities
People
- Kenneth Tew
Organizations
- Medical University of South Carolina
- United States Army