Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Novel drugs help solve Gleevec resistance

06.12.2004


Two different novel targeted therapies can produce strong responses in patients who have become resistant to Gleevec(tm), the standard therapy for chronic myeloid leukemia (CML), researchers at The University of Texas M. D. Anderson Cancer Center are reporting.



Researchers say the benefits offered by these drugs, BMS-354825 and AMN107, appear to be promising for treatment of relapsed CML and offer an immediate effective option for the minority of patients who do not achieve an optimal response to Gleevec therapy.

M. D. Anderson Cancer Center, the only institution to have tested both of these novel compounds, undertook independent Phase I clinical trials of both agents. It conducted the study of BMS-354825 in conjunction with the University of California, Los Angeles, and the study of AMN107 with the University of Frankfurt, in Germany. The M. D. Anderson researchers will discuss their experiences using these agents in patients with leukemia at the American Society of Hematology (ASH) meeting.


BMS-354825 "shows remarkable activity"

In the study conducted at M. D. Anderson and at UCLA School of Medicine, the majority of patients with advanced, Gleevec-resistant CML have responded to the drug BMS-354825, says Moshe Talpaz, M.D., a professor in the Department of Experimental Therapeutics at M. D. Anderson.

Of 11 patients with advanced "blast phase" CML, seven have had a hematologic response from the drug (defined as control of white blood cell counts). Of these, three patients experienced a complete hematologic response (disappearance of all findings consistent with advanced stage CML, and return of blood counts to normal), while two patients showed no evidence of leukemia. Two other patients had their CML downgraded to "chronic." Additionally, of the 11 patients, four have had a major "cytogenetic response" (defined as elimination of cells with the cancer-causing defect), and two had minor cytogenetic responses.

Of six patients with advanced accelerated phase of the disease, three had a hematologic response: two were complete, and one patient showed no remaining evidence of leukemia. One patient demonstrated resistance to BMS-354825, Talpaz reports. Side effects, which included reduced red and white blood cells and platelets, have been well tolerated, he says. Talpaz expects the efficacy of BMS-354825 to increase as more patients are enrolled and tested. "We haven’t reached anything close to the maximum tolerated dose, yet we still are showing some remarkable activity," he says. "Very encouraging responses continue to be seen in the new cohort of patients recently enrolled."

Talpaz is co-principal investigator with Charles Sawyers, M.D., professor of medicine at UCLA, of a study that tested 29 patients with early-stage CML who are either resistant to Gleevec or who could not tolerate the drug’s side effects. Their study is being presented by Dr. Sawyers in the first presentation at the meeting’s plenary session.

The investigators found that in these patients, 73 percent experienced a complete hematologic response "and they have shown that the drug is capable of overcoming Gleevec resistance in the vast majority of cases which resistance is caused by a mutation in the BCR-ABL gene," Talpaz says. "This is a remarkably high response rate," he says. "Also exciting is the fact that clinical responses matched very well to preclinical testing in animal models. A specific mutation that was resistant to BMS-354825 in the test tube and the animal model was associated with resistance in patients, whereas the other mutations did not induce resistance in the test tube or the patient.

This suggests that we may be able to ’tailor’ therapy according to the molecular profile of the disease," Talpaz says. "That means different treatments may be proposed for different patient subsets based on molecular and biochemical screening." Bristol-Myers Squibb, which manufactures BMS-354825, paid for this study.

AMN107 is effective in patients with Gleevec-resistant ALL and CML

Francis Giles, M.D., professor of medicine in the Department of Leukemia, presented results of the second study, which found that the novel oral targeted therapy, AMN107, can produce responses not only in advanced and Gleevec-resistant CML patients, but also in patients with acute lymphocytic leukemia (ALL) associated with the "Philadelphia chromosome."

The AMN107 Phase I study has accrued 65 patients since opening in May 2004. Even though an optimal dose has yet to be established as no significant toxicities have yet been encountered, more than 50 percent of patients with Gleevec-resistant CML have responded, including cytogenetic and molecular responses in some patients so far, Giles says.

"While more study needs to be done to define a reasonable regimen for this drug, it has, so far, produced very important responses in patients who were desperately ill," he says. "Despite the response rate, we still have not seen any consistent severe side effects, so clearly AMN107 will have a different tolerability profile than Gleevec, a drug which is, in general, very well tolerated," he adds.

"Gleevec changed everything in CML. It has led to marked improvement in survival in all three phases of the disease, and it also has shown benefit in treating the 20 percent of ALL that shares the same genetic abnormality as CML, the Philadelphia chromosome," Giles says. "But a drug that can cope with resistance to Gleevec might do even better across the board, although it must be remembered that we are still learning how to optimally use Gleevec itself, a drug which we have only had available for a few years."

The clinical trial reported by Giles is unusual in that it allows for a rapid "intrapatient" dose escalation. Within the trial, patients are allowed to move to higher doses as they prove to be safe, and the study can move seamlessly from Phase I into Phase II. "No patient is ever ’stuck’ at a lower, potentially ineffective dose," says Giles, who helped design the protocol. "Everyone keeps moving up until we find the best dose that is both safe and active." Doses from 50 milligrams to 1,200 milligrams have been tested so far. "This kind of study is in the best interest of patients because it gives us the power and the numbers to quickly find the dose that can work best," he says. The study is funded by Novartis, which manufacturers both AMN107 and Gleevec.

Both drugs have "tight" mechanism of action

Gleevec, as well as its two new companions, reduces the activity of an abnormal tyrosine kinase enzyme that leads to uncontrolled cell growth. Both CML and Philadelphia-positive ALL is caused by the swapping of genetic material in bone marrow stem cells between chromosome 9 and 22, producing an abnormality called the Philadelphia chromosome (named for the city from where the first patient in whom it was seen resided).

Specifically, a fusing of a piece of chromosome 9 that contains part of the ABL gene with a piece of chromosome 22 that contains part of the BCR gene forms the new cancer causing gene, BCR-ABL. This oncogene produces a tyrosine kinase that turns on multiple signals that tell the cells to grow and divide in an uncontrolled manner leading to overt leukemia. Gleevec binds to the abnormal enzyme (Bcr-Abl) and shuts down its activity, often leading to the death of the leukemia cell.

AMN107 is up to 30 times more potent than Gleevec because it was designed to more efficiently bind to the enzyme, Giles says. "Through molecular, chemical and crystallography studies, we now know the detailed structure of the enzyme, which allowed the development of the better-fitting drug AMN107," he says. "This both increases the effectiveness of the agent and perhaps reduces the potential of developing resistance."

BMS-354825 has a dual mechanism of action, which gives it a 100-fold greater potency to inhibit BCR-ABL, based on preclinical tests that compared it to Gleevec, Talpaz says. Such experiments also have shown that it can treat 14 of 15 mutations that arise in Gleevec-resistant tumors, he says. Giles adds that this appears to be similar to the activity profile of AMN107.

Like AMN107, BMS-354825 binds to the active form of Bcr-Abl. It is less specific than AMN107, however, and therefore has a broader spectrum of action because it inhibits a family of tyrosine kinases known as Src, Talpaz says.

"This is an engineered drug so we know exactly how it works, but we cannot say at this point whether there are clinically meaningful differences between BMS-354825 and AMN107," he says. "Many more studies are needed to see how these drugs will perform."

The bottom line, says Giles, is that "rational drug design is a reality and effective targeted therapies will rapidly increase in number, which means that options for patients are expanding," he says. "Prognosis of diseases that were, until very recently, rapidly fatal is getting better at an unprecedented rate. Science works."

Nancy Jensen | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Health and Medicine:

nachricht Second cause of hidden hearing loss identified
20.02.2017 | Michigan Medicine - University of Michigan

nachricht Prospect for more effective treatment of nerve pain
20.02.2017 | Universität Zürich

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Switched-on DNA

20.02.2017 | Materials Sciences

Second cause of hidden hearing loss identified

20.02.2017 | Health and Medicine

Prospect for more effective treatment of nerve pain

20.02.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>