Date of Award

12-2007

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Dr. Bruce Bejcek

Second Advisor

Dr. George Vande Woude

Third Advisor

Dr. John Geiser

Fourth Advisor

Dr. Pamela Hoppe

Abstract

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 Doctoral Thesis 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.

Access Setting

Dissertation-Open Access

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