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Cancer pill targets previously impenetrable disease-causing gene mutation in leukemia patients

Ponatinib, developed through a research collaboration between the Knight Cancer Institute and ARIAD, promises to be an option for treating drug-resistant CML and ALL, according to Phase I study results published in the New England Journal of Medicine

A promising cancer pill could provide a treatment option for leukemia patients whose disease no longer responds to currently available drugs.

Ponatinib, which was developed by ARIAD Pharmaceuticals Inc. in a research collaboration with the Knight Cancer Institute at Oregon Health & Science University (OHSU), circumvents a common gene mutation that causes resistance to currently available treatments, such as Gleevec®. This mutation prevents drugs like Gleevec from shutting down the rogue enzyme that triggers a patient’s bone marrow to produce an excess of white blood cells.

Results of a Phase I clinical trial to determine if the drug was safe for treating patients with this troublesome gene mutation are published in the Nov. 29 edition of the New England Journal of Medicine. The results indicate that ponatinib successfully bypassed this so-called gatekeeper mutation in patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). This mutation, named T315I, and other similar mutations cause about 10 to 20 percent of all CML patients to become drug-resistant in five years of starting treatment, and it causes drug resistance in about 50 to 60 percent of ALL patients within one to two years.

“This is another tool to fight this disease, but it’s the tool we’ve been waiting for,” said Brian Druker, M.D., director of the OHSU Knight Cancer Institute. Druker is a co-author on the Phase I clinical trial and his laboratory collaborated with ARIAD on the testing of compounds to inhibit Gleevec-resistant mutations. In this collaboration, which began in 2003, ARIAD designed compounds that were tested in the Druker laboratory against an extensive collection of Gleevec-resistant mutations. This collaborative work, which led to the identification of ponatinib, was published in the prominent journal Cancer Cell in 2009. The clinical trials, in which OHSU participated, confirmed the laboratory findings of significant activity against Gleevec-resistant mutations, including T315I.

Druker, said, “From the beginning, ARIAD was committed to finding a drug to shut down this one last mutation and we are grateful for the opportunity to work closely with ARIAD to bring this badly needed new medication to our patients.”

The Phase I study — which was led by Jorge Cortes, M.D., of MD Anderson Cancer Center, and also included Knight Cancer Institute physician Michael Mauro, M.D., as one of the study co-authors - involved 81 CML and ALL patients who had become drug-resistant on existing therapies. Of the 43 patients with chronic phase CML, 98 percent had their blood counts return to normal (a complete hematologic response). It also eradicated abnormal cells in 72 percent of these patients (known as a major cytogenetic response). Finally, 44 percent became free of detectable diseased genes (a major molecular response).

All 12 of the patients in the study with chronic phase CML, who also had detectible T315I mutations, had a complete hematologic response and 92 percent had a major cytogenetic response. Further, 100 percent of 13 chronic phase CML patients without detectable mutations had a complete hematologic response and 62 percent had a major cytogenetic response.

Results were also encouraging for those with advanced forms of leukemia. Of the 22 patients in the trial with accelerated phase or blast phase CML, or Philadelphia chromosome-positive ALL, 36 percent had a major hematologic response and 32 percent had a major cytogenetic response.

The drug’s side effects included pancreatitis, minor skin problems such as rashes, as well as constitutional issues, including nausea.

Arsenal of therapies

ARIAD last month filed for an accelerated review for its new drug application by the U.S. Food and Drug Administration. If approved, ponatinib would become one of an arsenal of therapies for cancer caused by an abnormality called the Philadelphia chromosome. This defect creates a malfunctioning gene called BCR-ABL, which produces the tyrosine kinase enzyme that signals bone marrow to overproduce white blood cells.

Druker said the Phase I trial results for ponatinib are similar to how patients responded during clinical trials of Gleevec, which had one of the fastest FDA approvals in history after proving it could successfully stop the rogue tyrosine kinase enzyme.

Gleevec was the first of what is now a growing class of targeted cancer therapies that work by manipulating specific molecules inside a cell. Druker and his colleagues revolutionized cancer treatment and research by proving with Gleevec that it was possible for a compound to zero in on only the molecules that are malfunctioning inside a patient’s cells without harming healthy cells. This work ushered in the era of truly personalized cancer medicine.

ARIAD Pharmaceuticals, which funded the Phase I study of ponatinib, used a computational model to eventually develop a compound capable of stopping the T315I mutation. It enlisted the Knight Cancer Institute to test the compound. The Knight Cancer Institute has one of the largest collections of cells with BCR-ABL mutations, which includes T315I.

OHSU and Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential individual and institutional conflict of interest has been reviewed and managed by OHSU.

Along with Cortes and Druker, co-authors on the study were: Hagop Kantarjian, M.D., of MD Anderson; Neil P. Shah, M.D., Ph.D., of the University of California San Francisco; Dale Bixby, M.D., Ph.D., and Moshe Talpaz, M.D., of the University of Michigan Comprehensive Cancer Center; Ian Flinn, M.D., Ph.D., of the Sarah Cannon Research Institute; and Thomas O’Hare, Ph.D., and Michael W.N. Deininger, M.D., Ph.D., of Huntsman Cancer Institute, University of Utah. They were joined by Simin Hu, Ph.D.; Narayana I. Narasimhan, Ph.D.; Victor M. Rivera, Ph.D.; Tim Clackson, Ph.D.; Christopher D. Turner, M.D.; Frank G. Haluska, M.D., Ph.D., of ARIAD Pharmaceuticals.


Brian Druker, M.D., is director of the Oregon Health & Science University Knight Cancer Institute, associate dean for oncology in the OHSU School of Medicine, JELD-WEN Chair of Leukemia Research at OHSU, and a Howard Hughes Medical Institute investigator.

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