Novel Intracellular Oncogenic Functions of CTLA4 in Melanoma
Abstract
An important feature of the Principal Investigator’s (PI’s) (Zaidi) research is that he has been venturing into uncharted territories of melanoma research. Although the major risk factor for melanoma is long known to be the exposure to ultraviolet radiation (UV), the molecular underpinning of the causal relationship remains largely elusive. Despite UV being a mutagen and strong evidence linking UV signature mutations to melanoma, several lines of evidence suggest that there is no straight line between UV-induced DNA mutations and melanoma, and that non-mutational mechanisms play important roles in melanomagenesis. The overall goal of the PI’s research program is to elucidate and delineate these UV-mediated non-mutational mechanisms. In this regard, the PI has already made significant contributions to the melanoma field. He reported a paradoxical pro-melanomagenic role of a conventionally anti-tumor cytokine pathway. He has also made contributions to the understanding of the differences between the melanomagenic effects of UVA and UVB wavebands. The PI has also published the regulation of the expression of the gene (CTLA4), which is the subject of this proposal, in melanoma. The latest research from his lab is studying novel molecular mechanisms in melanoma progression, metastasis, and drug resistance, which have great potential to be leveraged in the clinic against melanoma. This proposal addresses the FY21 MRP Challenge Statement and FY21 MRP Focus Areas in the following manner: Our preliminary studies identified melanoma as one of the highest expressers of intracellular CTLA4 and found that high expression of CTLA4 facilitates melanoma tumorigenicity and drug resistance. Thus, the new paradigm of prevention investigated here is that CTLA4 overexpression is a common molecular node upstream of melanoma metastasis and drug resistance, making it an attractive intracellular therapeutic target to prevent melanoma progression, metastasis, drug resistance, and recurrence. This is in contrast to the current anti-CTLA4 immunotherapy, which only targets the CTLA4 extracellular function and shows only modest response rates. Thus, this proposal addresses the Fiscal Year 2021 Melanoma Research Program Focus Areas of understanding mechanisms of metastatic spread and delineating the molecular pathways that influence metastatic spread and recurrence. CTLA4 is a protein that we have discovered to be highly expressed in melanoma cells, but it is not known whether this overexpression of the CTLA4 has a role in the disease etiology of melanoma. Our preliminary studies have shown that overexpression of CTLA4 in mouse melanoma cells enhances their aggressiveness, including metastatic capability and drug resistance. We propose that CTLA4 protein plays important roles in multiple yet unknown functions with melanoma cells. This proposal will elucidate and delineate these roles in molecular detail utilizing a variety of methodologies. This proposal is novel and innovative because currently nothing is known about the functions of CTLA4 inside melanoma cells and how it may be involved in melanoma progression and drug resistance. Experimental evidence supporting novel pro-progression, pro-metastasis, and pro-drug resistance functions of CTLA4 expression in melanoma cells will not only significantly advance our understanding of a protein whose entire known biology relates to its function as a cell surface receptor, but also provide a rationale for targeting the intracellular CTLA4 with small-molecule drugs as a novel therapeutic option to prevent the progression, metastasis, and drug resistance of the most common type of melanoma, which is mutant for the BRAF or NRAS genes and exhibits high CTLA4 expression (approximately 60% of melanoma cases). Such targeting would be especially useful in patients whose melanomas are resistant to BRAF and MEK inhibitors. Thus, this proposal will have specific actionable outcomes that will h
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210442
Entities
People
- M. Raza Zaidi
Organizations
- Temple University
- United States Army