New drug candidate knocks out resistant form of chronic myeloid leukemia

Oregon Health & Science University Cancer Institute researchers have found a new, experimental drug candidate it to be effective against a highly resistant mutation in chronic myeloid leukemia (CML).

This drug candidate could build on the legacy of Gleevec, which has been the gold standard for treating this leukemia and was developed by Brian Druker, M.D., director of the OHSU Cancer Institute. Despite Gleevec's success, some CML patients develop resistance to Gleevec, often due to mutations that interfere with drug binding. The second-generation drugs Sprycel and Tasigna have been developed as largely successful treatments for Gleevec-resistant patients. However, one mutation, termed T315I, is completely resistant to all three clinical CML drugs and is a frequent cause of relapse.

Now, however, a new drug candidate, SGX393, has been found to inhibit most resistant mutations, including T315I, both in mouse models and in patient cells in laboratory studies. SGX393 was identified by SGX Pharmaceuticals Inc., a biotechnology company focusing on cancer therapeutics.

The OHSU Cancer Institute researchers took this a step further.

“Because none of the drugs controlled all of the known mutations, we extended our study to look at using combinations of the drugs,” said Christopher Eide, research technician, hematology/medical oncology, OHSU School of Medicine.

“Remarkably, we found that the combination of SGX393 with either Sprycel or Tasigna completely suppressed resistant growth. Our findings raise the exciting possibility that inhibitor ‘cocktails' may be sufficient to completely pre-empt drug resistance in CML,” Eide said.

He is a co-author with OHSU Cancer Institute research scientist Thomas O'Hare, Ph.D., research specialist, hematology/medical oncology, OHSU School of Medicine.

The study was performed in the laboratory of Michael Deininger, M.D., Ph.D., associate professor of medicine, hematology/medical oncology, OHSU School of Medicine.

“What patients should know is that, with the addition of this drug candidate to the currently available set of clinical CML drugs, we may have the therapeutic tools to achieve and maintain even more effective and longer control of their disease,” Bumm said.

Gleevec continues to be remarkably successful in the vast majority of patients. However, for those patients who develop resistance, incorporating a targeted T315I inhibitor such as SGX393 into the suite of available CML drugs in the clinic is urgently needed. This is not equivalent to cure, but it could potentially represent an important advance in disease management with CML inhibitor therapy.

SGX Pharmaceuticals, Inc. is targeting submitting an Investigational New Drug application for SGX393 in the first half of 2008.

OHSU has licensed some of the underlying technology used in this research to MolecularMD.

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