"Cancer Chemotherapy: An Unfolding Story"

Luke Whitesell, 2005–2006 Grass Fellow at the Radcliffe Institute, Whitehead Institute for Biomedical Research

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Video (1:21 minutes)

Treatment of cancer in the modern era has evolved dramatically, driven by empirical clinical research, fundamental new molecular genetic insights, and powerful technological advances. Unfortunately, drugs designed to target specific cancer-causing genetic defects discovered through decades of intense basic research have proven far less efficacious than expected in the clinic. The problem has not been the ability to generate potent and selective compounds, but rather the networked complexity of human cancers at the molecular level. Luke Whitesell’s research is directed at surmounting this barrier through the discovery and development of anticancer drugs that alter the global cellular context in which cancer-causing mutant genes operate rather than attacking them directly. In this lecture, he will describe work on modulators of protein folding in the cell as an example of new therapeutic strategies aimed not at oncogenes but at exploiting the unique demands imposed on cellular physiology by the malignant lifestyle.
 
Luke Whitesell is a pediatric oncologist and senior research scientist at the Whitehead Institute. His clinical interests lie in the treatment of children with recurrent, refractory solid tumors. His laboratory efforts focus on the discovery and pre-clinical development of new anticancer drugs that target heat shock proteins and the cellular heat shock response. These ancient adaptive mechanisms act genome-wide to restore the normal protein folding environment within cells and enhance the survival of organisms under stress. In contrast to such well-recognized beneficial effects, however, they also enable cells to accommodate the drastic imbalances in signaling and profound alterations in DNA, protein, and energy metabolism that occur in cancers. In essence, the malignant lifestyle confers a profound dependence on these “non-oncogenes,” strongly supporting the feasibility of targeting them to more effectively treat cancers.

Whitesell pursued graduate work in pharmacology at Cambridge University prior to completing medical training at Johns Hopkins University and residency at Boston Children’s Hospital. After fellowship training at the National Cancer Institute, he joined the University of Arizona where he was a professor of pediatric oncology in the College of Medicine. Studies from his group helped launch the numerous clinical trials of experimental heat shock protein-targeted anticancer drugs that are ongoing. A fellowship year at the Radcliffe Institute for Advanced Study encouraged transition to his current position, which provides an unparalleled environment for biology-driven drug discovery efforts.

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