Pharmacologic Inhibition of B-Raf-driven growth signaling in malignant melanoma

The major focus of our laboratory is the study of the biochemical and biologic consequences of oncogene activation in human tumors and the use of this information to develop novel, mechanism-based treatment strategies. In this effort, we use both genetic and pharmacologic techniques. In normal cells, growth is often regulated by stimulation of the so-called 'Ras-signaling pathway.' This pathway constitutes a `circuit' in which the Ras protein activates the Raf protein which in turn activates the MEK and then the MAPK protein. Activation of this pathway leads to the proliferation of melanocytes. The genes encoding either of two elements of this circuit, the N-Ras and B-Raf genes, are mutated in the great majority of melanomas. These mutations lead to hyperactivation of this pathway and cause the unregulated growth of these tumors.

We have used drugs that inhibit the B-Raf and MEK proteins to understand the role of this pathway in melanoma and show that it is essential to their growth. We have demonstrated that the protein Hsp90 is required for the stability of the B-RAF protein. An inhibitor of Hsp90, 17-AAG, causes the destruction of B-Raf and inhibits the growth of melanomas in mouse models. Based on these data, we and others have initiated Phase 1 clinical trials of 17-AAG in patients with metastatic melanoma. Antitumor activity has been observed in these trials. Based on these data, phase 1 and phase 2 trials of new, improved Hsp90 inhibitors are in progress and in the planning stage.

In parallel work, we have used a potent and very selective inhibitor of the MEK protein to investigate the role of activation of the Ras signaling circuit in human cancer. We have shown that melanomas, especially those with B-Raf mutations are especially sensitive to this inhibitor. Blocking the circuit causes the growth of the melanomas to completely arrest at an early stage of the proliferation cycle. Our studies are beginning to unravel the molecular mechanisms for this growth arrest. We have gone on to show that this drug works extremely well in animals and that its effects can be imaged with PET scanning. These discoveries led us to suggest the use of the MEK inhibitor in patients with melanoma. Exciting clinical results have now been obtained; in early trials this drug causes objective antitumor responses in many patients with advanced metastatic melanoma refractory to other treatments. We are now planning a phase 2 trial of this therapeutic strategy.

This work has been presented at several national meetings and is the subject of two recent publications:
Solit DB et al. B-Raf mutation predicts sensitivity to MEK inhibition. Nature 439:358-362, 2006.
Grbovic et al. V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc. Natl Acad. Sci. 103:57-62. 2006.

We are quite excited about the rapid clinical translation of our work. This year we plan to aggressively pursue these clinical trials and to study ways to improve antitumor activity. We have now discovered that inhibition of another signaling circuit together with inhibition of the Raf circuit leads to profound death of the tumor cell, not just growth arrest. We plan to investigate why this is so and to develop combination therapy strategies for melanoma and other tumors that are based on these findings.

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