Chemotherapy boosts small molecules' success

Vienna, Austria - Among the most promising avenues in melanoma treatment are approaches that combine small molecule therapies with more traditional treatments.

The genesis for many new approaches stems from the discovery of a mutation found more often in melanoma than in other tumors. It occurs within the BRAF gene, which plays a part in governing tumor cell growth.

"That discovery has electrified the field because this mutation leads to a continuous activation of the MAP kinase (MAPK) pathway," Meenhard Herlyn, D.V.M., says. "In other words, the tumor cells are no longer that dependent on being fired from the outside - they do their own firing and stimulation, constantly (Davies H et al. Nature. 2002 Jun 27;417(6892):949-954. Epub 2002 Jun 9.)." Professor and chairman of the Wistar Institute's Molecular and Cellular Oncogenesis Program, he also holds adjunct appointments in the University of Pennsylvania's departments of pathology and dermatology.

What makes the mutation a fruitful target for melanoma treatment is the fact that it occurs in 60 percent to 70 percent of melanoma tumors.

"Within the gene," Dr. Herlyn adds, "it's a remarkably small change in amino acids that accounts for the activation. Because the gene is an enzyme, one can develop inhibitors to it. It is a bonanza to the melanoma field that we now can develop a new generation of inhibitors, which are specific to the tumor. That's very exciting because we expect this approach to produce activity with few if any side effects."

While such projects remain largely on the drawing board, Bayer/Onyx has begun testing the RAF kinase inhibitor BAY 43-9006 (recently renamed sorafenib). Though it's not specific to the BRAF mutation, it binds to the BRAF gene and other enzymes in tumor cells.

'Interesting' data

Clinical trials of the drug produced "interesting initial data, but nothing spectacular," Dr. Herlyn says. "However, through chance circumstances this drug has been combined with conventional chemotherapeutic drugs (cisplatin and Taxol/paclitaxel, Bristol-Myers Squibb). The results of this combination trial are very promising."

Researchers testing the combination in an ongoing trial with patients who had pancreatic cancer and leukemia decided to test the approach in melanoma at the same time, although there was no indication then that it would work for this illness. However, in a cohort of 54 patients, the combination of BAY 43-9006 and chemotherapy achieved a partial response rate of 37 percent and stable disease in 48 percent of patients. In only 9 percent of patients did disease progress (unpublished - Flaherty K. results presented at 2004 American Society of Clinical Oncology/ASCO annual meeting, June 5-8, 2004, New Orleans; also at ASCO 2005 annual meeting.)

Since that study was completed, the National Cancer Institute has instituted a larger phase 3 trial of 800 patients using the same regimen. Slated to be under way this summer, the trial will compare chemotherapy alone against the combination of chemotherapy and BAY 43-9006.

"This is the first generation of specific inhibitors that we expect to see in the treatment of melanoma," Dr. Herlyn says. "In the next five years, we expect to see that many other specific genes will be targeted, either alone or in combination."

The main challenge facing researchers involves finding the optimal and most efficient combinations of drugs to target critical pathways.

He says, "The downside at the moment is that some of these kinase inhibitors bind not just to one kinase, but to several. That would decrease their efficiency or may give rise to some side effects such that high enough doses cannot be given. The race is on, by many companies, as well as by academic researchers, to find specific combinations and to determine exactly which of the signaling pathways in melanoma need to be targeted with this new type of therapy."