The AACR-The ASCO Cancer Foundation Young Investigator Translational Cancer Research Award provides funding to promising investigators to encourage and promote quality research in clinical oncology. The purpose of this award is to fund physician-scientists during the transition from a fellowship program to a faculty appointment. The award is open to physicians (M.D., D.O. or international equivalent) or physicians holding a combined M.D./Ph.D. Applicants must be working in an oncology laboratory or clinical research setting in an academic medical institution. Research projects are restricted to translational cancer research.
2012 GRANTEE
Richard M. White, M.D., Ph.D.Attending Oncologist, Sloan Kettering Institute for Cancer Research, New York, NY
BRAFV600E as a Regulator of Transcriptional Elongation
"Recent advances in targeting BRAFV600E have led to unprecedented clinical responses in melanoma. Despite this, the majority of patients become resistant to BRAF inhibition, necessitating novel mechanistic and therapeutic insights into the process. In previous work, we have utilized a transgenic zebrafish model of melanoma to identify initiating events in BRAFV600E induced melanoma. This demonstrated that, in vivo, the majority of melanomas express early neural crest lineage markers such as sox10, ednrb and foxd3. In a zebrafish chemical screen, we identified several small molecules that suppressed the expression of these lineage markers. One class, inhibitors of the DHODH enzyme such as leflunomide, completely suppresses neural crest development and neural crest stem cell self-renewal. Leflunomide acts to inhibit the transcription elongation step of early neural crest genes, without affecting genes in differentiated progeny. Because DHODH is downstream of MAP kinase signaling, we found that the combination of leflunomide and PLX4032 led to synergistic abrogation of tumor growth in vitro and in mouse xenograft studies. This indicates that targeting of a developmental pathway, along with an oncogenic pathway, offers a unique method of treating melanoma. We now aim to understand whether BRAFV600E directly regulates transcriptional elongation of lineage specific neural crest genes. This will be done using zebrafish and human systems, with measurement of transcriptional elongation carried out via chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq). Because DHODH is downstream of BRAF, we hypothesize that it is an excellent candidate for circumventing either de novo or acquired resistance to BRAF inhibitors such as PLX4032. We will test whether leflunomide can prevent or treat BRAF resistance in human tissues. Taken together, our comprehensive approach utilizing zebrafish, mouse and human systems offers an unprecedented opportunity to understand the biological and clinical implications of transcriptional regulation by BRAFV600E."
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