Beyond Gleevec: The next-era drugs for GIST
AMN107 could prove to be the next bullet in the Novartis cancer arsenal
(Editor’s note: The first part of this article was adapted from an April 19 press release from the American Association of Cancer Research.)
By Jerry Call Life Raft science coordinator
Patients with chronic myelogenous leukemia (CML) typically respond very well to Gleevec. However, for a small number, their disease eventually becomes resistant to Gleevec. The primary mechanism of resistance identified in these patients is the acquisition of a new secondary mutation in bcr/abl, the oncogene that causes CML. At least 16 secondary mutations have been identified in CML.
In GIST patients,
secondary mutations in the target gene,
c-kit, are the largest known mechanism
of resistance. Secondary mutations in
GIST patients also occur in an
alternative receptor, PDGFRA.
Structural studies have identified the crystal structure of both bcr/abl and KIT. Using this enhanced understanding of the exact shape/structure of the intended target, researchers from the Dana-Farber Cancer Institute in Boston and Novartis Pharmaceuticals have developed a new drug, AMN107, that binds tighter to the bcr/abl target (the kinase domain of the bcr/abl protein).
In an abstract presented April 19 at the 96th annual meeting of the American Association of Cancer Research AACR in Anaheim, Calif., scientists at Oregon Health and Science University (OHSU) in Portland compared AMN107 against Gleevec using a panel of cell lines expressing 16 different mutant, Gleevec-resistant versions of bcr/abl.
The OHSU researchers found that 15 of the 16 mutants are predicted to be sensitive to AMN107, while one mutation remains insensitive and will require a different, as yet undiscovered, inhibitor. In the same study, the investigators also tested BMS-354825, the new drug from Bristol-Myers Squibb. This drug was equally impressive, according to Dr. Thomas O’Hare, a research specialist in the lab of Dr. Brian Druker, OHSU’s CML pioneer.
Researchers presented preliminary results of the phase I trial for AMN107 in CML patients. They reported that more than 70 percent of advanced CML patients have responded to the drug — and early CML patients have responded at a rate of more than 90 percent. The researchers noted that the response rate in more than 100 patients enrolled in the clinical trial to date continues to improve, as doses are rapidly increased. The first patients began treatment at 50 mg., but now all are taking 400 mg. twice a day and have not reached a dose-limiting toxicity.
According to Dr. Francis Giles, leader of the AMN107 study at M.D. Anderson Cancer Center in Houston, the potential success of AMN107 represents a “phenomenal rate” of drug development since Gleevec was introduced in 1999.
“We have been able to take the knowledge of how Gleevec works — where, exactly, it binds to bcr/abl — and tweak it to be as much as 30 to 100 times more potent.”
DISCUSSION
CML and GIST occur with very similar frequencies, 10 to 20 people per million per year for CML and 14.5 people per million per year in GIST. Relapse rates to Gleevec are higher in GIST than in early stage CML, and relapse rates in advanced CML are probably higher than in GIST. AMN107 was designed for Gleevec-resistant CML patients. BMS-354825 was designed as a Src inhibitor. Its excellent efficacy in CML is perhaps just a fortunate coincidence. While the Pfizer drug SU11248 has shown some efficacy in Gleevec-resistant GIST patients, there is still an unmet need for a new KIT/PDGFRA inhibitor that, using currently available structural data of the KIT/Gleevec interaction, has been engineered to overcome secondary mutations in KIT/PDGFRA.
A phase I clinical trial to include Gleevec-resistant GIST patients is underway for BMS-354825. Trials with AMN107 are planned. It remains to be seen whether either of these drugs, which were not optimized for KIT or PDGFRA mutations, will prove to be more effective than currently available therapies. Phase II trials are underway for the Amgen drug AMG706, but it is too early to speculate on the response of Gleevec-resistant GIST patients.
So the question becomes, “Where’s the optimized drug for GIST?” Perhaps a half-dozen or more new drugs that inhibit either KIT or PDGFRA were reported in abstracts at the AACR meeting. Most of these drugs also inhibit various forms of VEGF. Thus, their primary target indications may be based upon their ability to inhibit angiogenesis. As such, it is unlikely that they have been specifically engineered to overcome the secondary KIT/PDGFRA mutations that cause GIST to resist Gleevec. It’s possible that one or more of these drugs will be effective in resistant GIST due to chance. Another possibility might be attacking KIT/PDGFRA using a different or perhaps complementary method, such as anti-sense therapy or HSP-90 inhibitors.
GIST seems to be a more complex disease than CML. It is possible that the response rate to more effective optimized KIT/PDGFRA inhibitors still might not be as high as in CML, and that combinations of drugs might be more effective than single agents.
