David J. Robbins, Ph.D.
Professor of Surgery
Description of Research
The Hedgehog (Hh) signal transduction pathway plays a critical role in both early development and in cancer. Underscoring these observations, individuals with the developmental disorder known as Gorlin's syndrome, in which the Hh receptor is mutated, also exhibit an inherited predisposition to a variety of tumor types. Components of the Hh signaling pathway are also found mutated in sporadic forms of these same tumors. More recently, constitutive activation of the Hh pathway has also been implicated as a survival factor for a different subset of human tumors, including those derived from the lung, breast, prostate or pancreas. No mutations of Hh signaling components were found in these latter tumors. Rather, increased production of Hh was implicated as a key factor in tumor maintenance. Additionally, hyperactivation of the Hh signaling pathway was found to act as a marker of more aggressive tumors. Thus, the Hh pathway appears to play a crucial role in the progression and maintenance of many common tumors.
Consistent with the important role Hh plays in human cancer, recent results from the first clinical trial of a Hh small-molecule inhibitor showed a dramatic reduction in the tumor burden of patients who received this drug. The cellular target of this small-molecule is the G-protein coupled transmembrane protein Smoothened. While Smoothened plays a pivotal and rate limiting step in Hh signal transduction, the mechanism by which it acts remains largely unknown. Dr. Robbins’ research program is focused on elucidating the role Hh plays in cancer, and toward this goal he has identified the only two known Smoothened effectors. His team’s future work is focused on: 1) dissecting the signaling pathway downstream of Smoothened, and 2) elucidating the production and presentation of the Hh ligand. He is studying this pathway in both developmental and pathological settings, making his research highly complementary and mutually supporting. Such an approach will more rapidly decipher the mechanism by which the Hh pathway contributes to human oncogenesis, as well as facilitate the rational design of additional Hh inhibitors.
Highlights
- Identified and cloned various components of the MAP kinase signaling pathway
- Demonstrated that the oncogene Ras regulates MAP kinase activity
- Identified the first kinesin related protein implicated in a signal transduction pathway
- Identified a novel multimeric form of Hh
- Demonstrated that the G-protein Gi plays a pivotal role in Hh signaling
- Demonstrated the importance of Hh signaling in non-small cell lung cancer
- Identified novel small-chemical modulators of Hh signaling
Selected Cancer-Related Publications
Programs
Collaborating in the Multidisciplinary Research Program(s):