Next-era targeted therapy overcoming Gleevec's shortcomings


Anaheim, Calif. -- Though Gleevec has shown "wonder drug" capabilities for treating chronic myelogenous leukemia and other cancers, experience in treating patients has revealed some shortcomings. In some cases, patients have undergone relapse after building a resistance to the drug. For others with advanced disease, the drug has failed to produce durable remissions.

However, a molecular understanding of resistance has rapidly led to a new generation of drugs that might prove more effective than Gleevec.

Two studies presented here at the 96th Annual Meeting of the American Association for Cancer Research report that a new compound, known as AMN107, may one day offer a more potent alternative for treating patients with acquired Gleevec resistance and others with advanced CML.

As originally conceived, Gleevec works in CML patients by selectively deactivating Bcr-Abl, the abnormal tyrosine kinase protein that triggers rapid growth of leukemic cells. Gleevec was hailed as the first approved drug to directly inhibit the activity of an enzyme known to cause uncontrolled cell growth, and it has been highly successful for many patients.

Scientists soon recognized, however, that some patients develop mutations in the Bcr-Abl protein that drastically reduce Gleevec's effectiveness.

AMN107 Holds Promise for Treating Gleevec-Resistant Leukemia According to Oregon Scientists: Abstract 5282

To overcome resistance to Gleevec, scientists are designing new compounds that bind tighter to the intended target, the Bcr-Abl protein. One such candidate drug is AMN107, synthesized by Novartis Pharmaceuticals in Basel, Switzerland, and characterized in collaboration with investigators at the Dana Farber Cancer Institute.

In essence, AMN107 retains half the chemical makeup of Gleevec, while the other half was engineered to assure a tighter link to Bcr-Abl, thus increasing potency and potentially overcoming resistance due to mutations in Bcr-Abl.

As a test, scientists at the Oregon Health and Science University in Portland compared the potency of the new compound against Gleevec using a panel of cell lines expressing 16 different Gleevec-resistant, mutant versions of Bcr-Abl.

Their results, reported during the AACR Annual Meeting, showed that AMN107 was at least 20 times more potent than Gleevec against most of the resistant mutants.

"Our findings show that 15 of the 16 mutants would be predicted to be sensitive to AMN107, while one mutant remains insensitive that would require a different, as yet undiscovered, inhibitor," said Thomas O'Hare, a research specialist in Gleevec pioneer Brian Druker's laboratory at the Oregon Health and Science University Cancer Institute.

"These data indicate that AMN107 is a highly active Bcr-Abl inhibitor that may have clinical utility in patients with Gleevec-refractory CML.

"In this study, we also investigated the other leading clinical candidate for treating Gleevec-refractory CML, a Bristol-Myers Squibb compound called BMS-354825. The results were equally impressive.

"This is great news for patients. We believe that having several safe and effective drugs available is the key to controlling acquired drug resistance in CML."

AMN107 Rescues Gleevec-Resistant Patients in Clinical Trial Conducted by Researchers at UT M. D. Anderson: Abstract 3971

AMN107 appears to effectively rescue patients with chronic myeloid leukemia (CML) who did not respond to targeted therapy with Gleevec, according to researchers from The University of Texas M. D. Anderson Cancer Center.

The researchers report that more than 70 percent of advanced CML patients in an international study have shown a response to the drug, AMN107, and that patients with the early form of the disease have responded at a rate of more than 90 percent.

"If you can take a pill and rescue people who failed the current standard of care, that is remarkable," says the study leader, Francis Giles, M.D., a professor of medicine in the Department of Leukemia at M. D. Anderson Cancer Center. The study, which includes researchers and patients at the University of Frankfurt in Germany, is still ongoing.

The researchers note that the response rate in over 100 patients enrolled in the clinical trial to date continues to improve, as doses are rapidly increased. The first patients began treatment at 50 milligrams, but now all are taking 400 milligrams twice a day "and we have certainly not reached a dose-limiting toxicity," Giles say. "The drug is very safe, and we are seeing a response that improves daily."

Giles stresses that the "vast majority" of CML patients do very well on Gleevec, and that AMN107 was designed to treat the 10 percent of patients who do not respond, either because of a known mutation that Gleevec does not treat, or because the cancer has advanced to the point where other mutations in the cancer arise.

He adds, however, that M. D. Anderson Cancer Center will soon launch a series of studies testing use of AMN107 as the first therapy used by CML patients, whether they have the early chronic stage, advanced "accelerated" and terminal "blast" stages of the disease.

"We are not looking to replace use of Gleevec, but to see how AMN107 can fit into the treatment picture," says Giles. "My guess is that patients will benefit from both agents." The study is being funded by Novartis, which manufacturers both AMN107 and Gleevec. Giles presented first results of the therapy in a fewer number of patients last December at the annual meeting of the American Society of Hematology.

AMN107 is a refinement of Gleevec because it binds more tightly on to the Bcr-Abl enzyme that pushes bone marrow stem cells to continually grow. The new agent also latches on to Gleevec-resistant, mutated versions of Bcr-Abl that cause resistance in some Gleevec users, Giles says. But the study also is demonstrating that not all patients, especially those in more advanced stages, benefit from AMN107, probably because they have developed new mutations, he says.

The high level of responses seen to date are classified as hematologic, which is defined as a return to normal blood counts, but increasing numbers of "cytogenetic" responses are also being seen, which is the elimination of cells with the so-called Philadelphia chromosome, which produces the cancer-causing Bcr-Abl kinase. Researchers also are monitoring the number of "molecular major responses," defined as a complete absence of all molecular abnormalities and a return to a normal status. "We now are beginning to see the number of cytogenetic responses climb, as well as molecular major responses," Giles says.

He added that the potential success of AMN107 represents a "phenomenal rate" of drug development since Gleevec was introduced in 1999. "We have been able to take the knowledge of how Gleevec works - where exactly it binds to Bcr-Abl - and tweak it to be as much as 30 to 100 times more potent."

It also represents a new era of medical treatment "in which the integration between preclinical researchers and clinical oncologists is seamless," Giles says. "I don't work in a lab. I spend all my time with patients. But clinicians are now using molecular endpoints every day and in every way to direct our therapy and to design protocols. It is incredibly exciting."

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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