This research proposal, prepared by Dr. Florian Karreth, describes a three-year training program for the development of an academic career in cancer research. Dr. Karreth has several years of experience in mouse modeling and cancer biology and has recently begun to study the role of BACH2 in melanoma progression and drug resistance in Dr. Lewis Cantley's laboratory. He identified BACH2 in two independent forward genetic screens that were aimed at discovering mutations that either accelerate oncogenic BRAF-driven melanoma development or confer resistance of melanoma to the BRAFV600E-specific small molecule inhibitor vemurafenib. Dr. Karreth now proposes a detailed molecular and cell biological characterization of BACH2. BACH2 is a transcription factor that has mainly been studied in B-cells where it regulates germinal center formation and plasma cell differentiation. Genomic deletion of BACH2 is observed in a considerable portion of leukemias and lymphomas, suggesting a tumor suppressive role. Dr. Karreth proposes to characterize the effect of BACH2 loss on oncogenic transformation of murine and human melanocytes and melanoma cells. Moreover, Dr. Karreth will utilize novel tools to study the effect of BACH2 loss on tumor progression in a BRAFV600E-driven mouse model of melanoma. BACH2 regulates the expression or activity of proteins that play central roles in cancer such as p19ARF, p53, and the master regulator of the antioxidant program, NRF2. The contribution of these factors and other BACH2 targets to the tumor suppressive function of BACH2 will be studied. Moreover, Dr. Karreth will examine how BACH2 confers resistance of BRAFV600E-driven melanoma to vemurafenib in vitro and in vivo. To this end, he will analyze NRF2-regulated drug detoxification upon loss of BACH2 and investigate whether other NRF2-depedent and -independent transcriptional targets are involved. These analyses will shed light on the tumor suppressive function of BACH2 in melanoma and provide novel approaches for therapy. Evaluation of such approaches will be a focus of Dr. Karreth's future research. Prior to the Award, Dr. Karreth will receive further training at Weill Cornell Medical College (WCMC) in the laboratory of Dr. Lewis Cantley, a renowned expert in signaling and metabolism. Dr. Cantley's laboratory will provide Dr. Karreth with the opportunity to gain additional expertise to become a well-rounded scientist. Dr. Karreth will benefit from WCMC's stimulating environment that is created by close interactions with outstanding faculty and by multiple core facilities that provide excellent research support. Dr. Karreth is committed to a career in biomedical research and has outlined a comprehensive Career Development program to achieve his goal of independence. This program includes lectures and seminar series, scientific conferences, and educational workshops and courses at WCMC. In addition, the guidance and advice from Dr. Karreth's advisory committee and his collaborators - all experts in their respective fields - will greatly facilitate his transition to an independent investigator position.
Despite the recent development of targeted therapy metastatic melanoma remains an almost uniformly fatal form of cancer due to the eventual emergence of drug resistance. Thus, there is an urgent need to devise novel treatment strategies that target the molecular and genetic aberrations driving melanoma progression and resistance. This proposal focuses on the characterization of BACH2 as a mediator of progression and resistance and its suitability as a novel therapeutic target.