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Doctoral Dissertation Announcement
Candidate: Matthew W. VanBrocklin
Doctor of Philosophy
Department: Biological Sciences
Title: Mitogen Activated Protein Kinase Signaling Promotes Survival in Melanoma
Dr. Bruce Bejcek, Chair
Dr. John Geiser
Dr. Pamela Hoppe
Dr. George Vande Woude
Date: Monday, October 29, 2007 2:00 p.m. – 4:00 p.m.
2734 Wood Hall
Extracellular signals activate mitogen-activated protein kinase (MAPK) cascades potentiating biological activities such as cell proliferation, differentiation, and survival. Constitutive activation of MAPK signaling pathways is implicated in the development and progression of many human cancers, including melanoma. Mutually exclusive activating mutations in NRAS or BRAF are found in ~85% of all melanomas resulting in constitutive activation of the MAPK pathway (RAS-BRAF-MEK-ERK-RSK). We have previously demonstrated that inhibition of this pathway with small molecule MEK inhibitors selectively induces apoptosis in human melanoma cells both in vitro and in vivo, but not in normal melanocytes. These results support the notion that the MAPK pathway represents a tumor-specific survival signaling pathway in melanoma, and that targeting members of this pathway may be an effective therapeutic intervention strategy for treating melanoma. Understanding the mechanisms by which constitutive MAPK activation promotes survival and defining the minimal vital MAPK pathway components required for the development and progression of melanoma may have direct translational implications.
The overall objective of this dissertation was to define the molecular mechanism(s) by which the MAPK pathway mediates melanoma-specific survival signals. In doing so, several new promising therapeutic targets (Bcl-2, Bcl-xL and Mcl-1) have emerged and a novel small molecule inhibitor (TW37) of these has been developed. Combined targeting of MAPK and these Bcl-2 pro-survival members was synergetic in vitro and in vivo. Additionally, the ability of RAS, BRAF and RSK to transform normal mouse melanocytes was evaluated revealing that NRAS and BRAF are very efficient while RSK required secondary genetic events for progression. Upon investigation, high level intrachromosomal gene amplification of Met, a growth factor receptor tyrosine kinase implicated in melanoma progression. MET expression is rarely detected in primary human melanoma, but is frequently observed in advanced metastatic disease and therefore may be an additional attractive therapeutic target to prevent disease progression.