A new drug to use in combination with IM for those of us developing resistance to IM

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Let's keep our eyes on this one!

New leukemia drug shows promise in overriding all Gleevec resistance

Temple University researchers have developed a new drug that could

potentially treat all forms of Gleevec-resistant chronic myelogenous

leukemia (CML). Their work is published in this week's early edition of

Proceedings of the National Academy of Sciences.

According to lead researcher, Prem Reddy, Ph.D., professor of biochemistry

and Director of the Fels Institute for Cancer Research at Temple University

School of Medicine, most patients with advanced CML, a rare but deadly form

of cancer, typically develop resistance to Gleevec, the most successful

treatment for CML to date, within a few years of starting the therapy.

CML is caused by the Philadelphia chromosome, an abnormality that produces a

cancer protein called BCR-ABL. Gleevec works by binding to BCR-ABL and

completely blocking its activity, thereby stopping cancer growth. When

Gleevec came to market about four years ago, it was widely hailed as a

miracle drug. For the first time, there was hope for this group of patients.

" Gleevec has been a remarkable success for the treatment of CML. However, a

significant number of patients eventually develop resistance to it because

their cancer cells are able to mutate and adapt, " said Reddy.

Since discovering this phenomenon, scientists have sought new ways to

prevent or overcome this resistance. Recently, two experimental drugs were

found to be effective in circumventing some but not all forms of Gleevec

resistance. Both, for instance, failed to block the activity of a mutant

BCR-ABL, called T315I, which is one of the more predominant mutations seen

in Gleevec-resistant patients.

Reddy and his research team sought instead to develop a drug that would

circumvent all of the mutations and therefore all forms of resistance. They

focused on other possible avenues to inhibit the actions of BCR-ABL. To do

so, they targeted parts of the BCR-ABL protein that didn't appear to be

mutating and adapting to Gleevec.

" We developed ON012380, a compound that specifically inhibits BCR-ABL by

blocking a different site in the protein, which is essential for its

activity. As a result, ON012380 was found to induce cell death of all of the

known Gleevec-resistant mutants and cause regression of leukemias in human

tumor cells and in animal models, " said Reddy, who is currently seeking FDA

approval to proceed with clinical trials. The drug is licensed to Onconova,

Inc.

" Our drug works just like Gleevec but by blocking another part of the

BCR-ABL protein. It can be combined with Gleevec to create synergy and when

patients become resistant to Gleevec, our drug kills 100 percent of the

cancer cells, " said Reddy.