Oregon Health & Science University Cancer Institute researchers have found that an experimental drug known as SGX393 is effective against Gleevec-resistant chronic myeloid leukemia (CML).
Gleevec, the targeted therapy identified by OHSU Cancer Institute Director Brian Druker, M.D., is the current first line therapy for CML. Gleevec works by inhibiting the activity of Bcr-Abl, an enzyme that is present only in CML cells and upon which these cells depend for survival. Although most patients with CML respond dramatically to Gleevec, some patients develop resistance to the drug. Most Gleevec-resistant CML cells carry a mutated form of Bcr-Abl, which prevents Gleevec from functioning properly. The second-generation drugs Sprycel and Tasigna have been developed as largely successful treatments for Gleevec-resistant patients. However, one mutated form of Bcr-Abl, called T315I, is resistant to all three clinical CML drugs and is a frequent cause of relapse.
Michael Deininger, M.D., Ph.D., head of the Hematologic Malignancies Section, and his research team in the OHSU Cancer Institute have shown that SGX393, developed by SGX Pharmaceuticals, Inc., San Diego, Calif., inhibits the T315I mutant and most, but not all, other Gleevec-resistant mutants. This was shown to be true using laboratory models as well as leukemia cells from patients with CML.
Researchers then took this success a step further. Using a method developed in their laboratory to rapidly and accurately forecast drug-resistant Bcr-Abl mutations, Deininger and colleagues established a resistance 'profile' for SGX393. Though SGX393 showed a handful of mutation weak spots, the T315I mutation was absent among thousands of samples surveyed in the laboratory. In contrast, T315I was frequently recovered when running the screen with any of the other drugs.
"Because the resistance profile of SGX393 nicely complemented those of the other drugs and none of the drugs individually controlled all of the mutations, we extended our study to look at using a combination of the drugs. Remarkably, we found that the combination of SGX393 with either Sprycel or Tasigna completely suppressed resistance," said Christopher Eide, research technician. He is a co-author with fellow OHSU Cancer Institute researchers Thomas O'Hare, Ph.D., Jeffrey Tyner, Ph.D., Amie Corbin, and Matthew Wong.
"Our pre-clinical study suggests that rationally combining two Bcr-Abl inhibitors with different resistance profiles could provide a dragnet to protect against resistance," O'Hare said. "The idea is that each drug is especially adept at handling certain Bcr-Abl mutants and that the drugs can team up to eliminate cells carrying mutants that neither drug could eliminate on its own."
"The effectiveness and safety of Gleevec for most patients remains remarkable," said Deininger. "However, it is important for patients to know that, with the addition of a drug such as SGX393 to the set of current approved CML drugs, we may have the therapeutic tools to achieve and maintain even more effective and longer control of their cancer. This is not equivalent to a cure, but it could potentially represent an important advance in the management of CML."
The results of this study will be published the week of March 24th in the Proceedings of the National Academy of Sciences.
This research was supported in part by the National Heart, Lung, and Blood Institute Grant HL082978-01 and the Leukemia and Lymphoma Society.
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