Targeted Degradation of Mutant GNAQ/11 in Uveal Melanoma Cells
Abstract
This Idea Award project addresses inhibition of mutant forms of GNAQ and GNA11, early drivers of oncogenesis in more than 90% of uveal melanomas, rare melanomas that occur in the eye and frequently metastasize to the liver. This project will apply targeted degradation technology to examine the feasibility of this approach for inhibiting mutant GNAQ and GNA11 and use this technology to identify novel regulators of mutant GNAQ/GNA11 signaling pathways. Thus, this project strongly addresses two of the fiscal year 2022 (FY22) Melanoma Research Program (MRP) Focus Areas: (1) Investigate topics relevant to rare melanomas (e.g., uveal, acral, mucosal melanoma, etc.) that cover the entire research spectrum, from risk factors and initiation to distant macro-metastases, in model organisms and/or patients; and (2) Delineate the molecular pathways that influence metastatic spread, recurrence, and/or dormancy. Similarly, this project is responsive to the FY22 MRP Challenge Statement by focusing on mutant GNAQ/GNA11, the key drivers of initiation and metastasis in uveal melanoma, which causes alterations of signaling pathways in uveal melanoma. GNAQ and GNA11 are genes coding for highly similar proteins termed G protein alpha q and alpha 11. These G proteins are important regulators of cellular pathways that regulate the proliferation of melanocytes. Their activity is normally tightly controlled by switching between an inactive GDP-bound state and an active GTP-bound state. However, in uveal melanoma GNAQ or GNA11 is frequently mutated at the amino acid glutamine 209 (Q209) with the result that mutant GNAQ or GNA11 is locked in the active GTP-bound state, thus driving uncontrolled cell proliferation. A great deal of research has focused on using known drugs to inhibit cell proliferation pathways that are overactivated by mutant GNAQ or GNA11. However, these targeted therapy approaches have met with little success. A likely reason why these targeted therapies have not been useful is that mutant GNAQ/GNA11 is well known to activate multiple signaling pathways, and therefore blocking only one, or even two, pathways is not sufficient to fully disrupt oncogenic signaling by mutant GNAQ/GNA11. On the other hand, if one could directly inhibit mutant GNAQ/GNA11 – (i.e., the initiator of aberrant signaling – all signaling pathways that are activated by mutant GNAQ/GNA11 would likewise be blocked). The objective of this project is to examine and implement a technology for inducing the destruction of GNAQ/GNA11 in uveal melanoma cells. A key aspect of this approach is that mutant GNAQ/GNA11 will be specifically destroyed in the cell, but the normal, non-mutant forms of GNAQ/GNA11 in other cells will remain intact, thereby preventing toxicity due to disruption of the normal physiological functions of GNAQ/GNA11. Currently, there is a lack of effective therapies for metastatic uveal melanoma, and it is crucial to develop novel ways to inhibit mutant GNAQ/GNA11. In the short term, this basic science research project will demonstrate that regulated degradation, i.e., destruction, of mutant GNAQ/GNA11 is a viable approach for disrupting aberrant proliferation of uveal melanoma cells. Moreover, it is anticipated that this research will prompt the research field to maximize efforts for developing clinically useful small molecule drugs that promote the degradation of mutant GNAQ/GNA11; such drugs are termed PROTACS, for proteolysis targeting chimeras. The longer-term successful development of these drugs, spurred by the results of this Idea Award project, will have a major impact in prolonging the life of uveal melanoma patients by blocking the growth of metastatic uveal melanoma tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310950
Entities
People
- Philip Wedegaertner
Organizations
- Thomas Jefferson University
- United States Army