Leukemia drug shows promise
in overriding all Gleevec resistance
Temple researchers have developed a new drug that could potentially treat all forms of Gleevec-resistant chronic myelogenous leukemia (CML). Their work was recently published in Proceedings of the National Academy of Sciences.
According to lead researcher Prem Reddy, professor of biochemistry and director of the Fels Institute for Cancer Research at the 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,” Reddy said.
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,” Reddy said.
Other Temple researchers on the team are Kiranmai Gumireddy, Stacey J. Baker, Stephen C. Cosenza, Premila John, Anthony D. Kang, Kimberly A. Robell and M.V. Ramana Reddy.
To access this study, “A novel non-ATP competitive inhibitor of BCR-ABL overrides imatinib-resistance,” go to www.pnas.org/cgi/doi/10.1073/pnas.0408283102.
- By Eryn Jelesiewicz