New Drug Battles Gleevec Resistance

Posted by rob on July 15, 2004 under Uncategorized | Be the First to Comment

New Drug Battles Gleevec Resistance

It may help some of the 20 percent of chronic myeloid leukemia patients who don’t respond to the breakthrough drug.

By Ed Edelson
HealthDay Reporter

THURSDAY, July 15 (HealthDayNews) — A new compound appears to help patients with chronic myeloid leukemia (CML) who do not respond to Gleevec, the drug widely hailed as one of the major success stories in cancer treatment, researchers report.

Gleevec can halt the progression of CML in most patients. However, as many as 20 percent of those patients either have or develop resistance to the drug. The new drug has been successful against a mouse model of leukemia, says a report in the July 16 issue of Science, and now is in early trials in human patients who have not benefited from Gleevec.

“We are certainly excited by what we are seeing, but the actual clinical data will be presented in December,” said study author Dr. Neil P. Shah, an assistant professor of hematology and oncology at the University of California, Los Angeles, Jonsson Cancer Center.

Detailed knowledge of the way Gleevec works on the molecular level led to development of the new drug, Shah said.

CML, which strikes about 4,500 Americans each year, causes overproduction of white blood cells, which in turn is caused by overactivity of an enzyme designated BCR-ABL. Gleevec binds to BCR-ABL, stopping its cell-producing activity.

But there are many mutations of BCR-ABL, some of which have shapes different enough so that Gleevec cannot bind to them. Some CML patients have this type of mutated form of the enzyme at the time of diagnosis, while mutations can develop in other patients during the course of treatment. In either case, Gleevec is ineffective.

The development of the new drug began with a report in 2000 by John Kuriyan, a researcher at Rockefeller University whose work is funded by the Howard Hughes Medical Institute, detailing the way in which Gleevec binds to BCR-ABL. A precise match of the Gleevec molecule to the enzyme shape is needed, Kuriyan found.

That report prompted Dr. Charles L. Sawyers, another professor of hematology and oncology at UCLA, to speculate that a molecule that bound in a different way to BCR-ABL could be effective against the various mutated forms of the enzyme.

Sawyers and Kuriyan began a collaboration that resulted in a report in 2002 about 15 mutations of BCR-ABL that caused resistance to Gleevec. In each case, the mutation changed the shape of the enzyme just enough to prevent Gleevec from forming the precise link that turned it off.

ABL is a member of a broader family of enzymes called Src proteins, which are involved in many forms of cancer.

“I was giving scientific talks on the structural implications of Gleevec mutations, and stating that I thought that an Src inhibitor would be a good thing,” Sawyers said.

It happened that the drug company Bristol-Myers Squibb was developing an ABL-Src inhibitor. Bristol-Myers Squibb got in touch with Sawyers, and the result was a research program that resulted in the journal report and the clinical trials of BMS-354825, as the molecule is now designated.

The ultimate use of that molecule in CML treatment must still be determined by the human trials that are just beginning, Shah said.

“It depends on what the weaknesses of this compound are,” he said. “There is one mutation we would predict would make CML resistant not only to Gleevec but to this compound. Whether it can replace Gleevec depends on what other mutations render it ineffective. It is possible that it will be a smaller circle in the large circle of Gleevec.”

More information

Read about CML and its treatment at the National Library of Medicine (www.nlm.nih.gov ).

Copyright © 2004 ScoutNews LLC. All rights reserved.

 

Gleevec-Like Drug Shows Promise in Beating Cancer Resistance

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Gleevec-Like Drug Shows Promise in Beating Cancer Resistance

By Kevin Davies
Bio-IT World (online)

(07/15/04)â??The remarkable success of Novartis’ anti-cancer drug Gleevec, approved by the FDA in 2001, has been tempered somewhat by the frequent onset of resistance in leukemia patients taking the drug. But in new findings reported this week in Science magazine, researchers describe a new compound that shows immense promise in overcoming this resistance â?? at least in mice.

The research was led by Charles Sawyers, a UCLA physician-scientist who conducted some of the key clinical trials that resulted in Gleevec’s record approval, along with scientists from Bristol-Myers Squibb (BMS). The goal was to find a drug that could overcome a key limitation in Gleevec’s efficacy. Many cancer patients develop mutations in the target protein, BCR-ABL, that prevent the drug from binding.

Studies over the past two years have mapped the location of these resistance-inducing mutations on the BCR-ABL protein. Many of them reside in the active site of the protein, and apparently impair the kinase’s flexibility, preventing it from shuttling from the ‘on’ conformation to the ‘off’ conformation, which is the state of the molecule to which Gleevec binds.

Sawyers and his colleagues conducted experiments with a compound called BMS-354825. The research shows that the BMS drug improves survival of mice with CML (chronic myelogenous leukemia). “The bottom line, according to Sawyers, is that his “data indicate that this drug is active against all of the [resistance] mutations except for one” â?? a total of 14 out of 15.

Sawyers, who is also an investigator with the Howard Hughes Medical Institute, figured that a “sloppier inhibitor” than Gleevec might grasp the kinase less tightly, thereby allowing it to bind in both the ‘on’ as well as the ‘off’ position. “I thought that a SRC inhibitor would be a good idea,” says Sawyers, referring to SRC, another key oncoprotein. “This was an informed guess based on what we were seeing in the crystallography data.”

Indeed, BMS-354825 is an orally available dual ABL/SRC inhibitor. “If this drug should prove to be safe and effective in the clinic, one can envision using this in a combination kinase inhibitor therapy for CML,” says Sawyers.

http://www.bio-itworld.com/news/071504_report5608.html

New Drug Shows Promise Against Gleevec Resistance in Mice

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Thu Jul 15 12:33:12 2004 Pacific Time

      New Drug Shows Promise Against Gleevec Resistance in Mice

       CHEVY CHASE, Md., July 15 (AScribe Newswire) — One of the truly spectacular success stories in modern oncology is the development and implementation of Gleevec, a drug that virtually halts the progress of chronic myeloid leukemia. Yet for some patients who harbor particularly stubborn genetic mutations, Gleevec fails miserably.

       Now, Howard Hughes Medical Institute (HHMI) researchers at the University of California, Los Angeles, and colleagues at Bristol-Myers Squibb Oncology in Princeton, NJ, are reporting the first description of a new compound that is designed to overcome Gleevec resistance in some of these individuals.

       In an article published in the July 16, 2004, issue of the journal Science, HHMI investigator Charles L. Sawyers, Neil P. Shah and colleagues at UCLA’s Jonsson Comprehensive Cancer Center, report that the compound BMS-354825, which is under development by Bristol-Myers Squibb, successfully sidesteps the vexing problem of Gleevec (imatinib) resistance. “The identification of this compound as a drug candidate is a direct byproduct of understanding why patients develop resistance to Gleevec,” said Sawyers. He notes that just as Gleevec was developed as a “molecularly targeted” inhibitor, the next generations of Gleevec, of which is BMS-354825 is one, will be refined and improved by structural biology studies that show how the drugs “fit” with their target, and how mutations alter the shape of that target.

       The all-important drug target in chronic myeloid leukemia (CML) is an enzyme called Abelson tyrosine kinase (ABL), which becomes overactivated by a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR, which are located on different chromosomes, become fused and express a hybrid BCR-ABL enzyme that is always active. The hyperactive BCR-ABL, in turn, drives the overproliferation of white blood cells that is the hallmark of CML.

       In the studies published in Science, Sawyers and his colleagues demonstrated that BMS-354825 prolongs survival of mice with CML. In tests with cultured human bone marrow cells, the researchers showed that the drug inhibits the proliferation of bone marrow progenitor cells that are positive for BCR-ABL in patients who are resistant to Gleevec. “The bottom line is that our in vitro data indicate that this drug is active against all of the mutations except for one,” Sawyers said.

       At the time Sawyers and his colleagues were writing their Science article, there were 17 reported Gleevec-resistance mutations. There are more known now. Each mutation hampers Gleevec’s ability to bind to its target, the ABL kinase.

       Sawyers, who in addition to being a researcher, also sees cancer patients at UCLA, has long been hunting for an explanation of Gleevec resistance. Deftly moving between the clinic and the research lab, Sawyers has been at the center of understanding why Gleevec works for some patients, but stops working for others.

       In September 2000, HHMI investigator John Kuriyan, a structural biologist then at The Rockefeller University, who had studied the regulation of Abl kinases for many years, made the seminal discovery that Gleevec, or STI-571, worked by binding to Abl when the enzyme was in its “off” position. If Abl was in the “on” position, the drug would not work.

       In the arcane worlds of cellular signaling and structural biology, it was well known that Abl looks structurally quite similar to the Src family of oncogenes that also produce kinases. Yet, as Kuriyan’s work demonstrated, STI-571 does not inhibit the Src proteins because they maintain a different shape when in their inactivated, or “off,” position. As Kuriyan prophetically stated at the time, “The puzzle of STI-571′s extreme affinity and specificity is of broader interest because protein kinases are crucial elements in signal transduction pathways that control cell growth, cell death and other processes. Thus, understanding how kinases are turned on and off is a matter of extreme interest.”

       Kuriyan’s work caught the attention of Sawyers, who was examining how mutations in the ABL kinase could blunt the effect of Gleevec. Sawyers and Kuriyan began a collaboration to probe the problem, which culminated in a publication in the August 2002 issue of the journal Cancer Cell, reporting the identification of 15 mutations in the BCR-ABL gene that caused resistance to Gleevec.

       In that paper, Kuriyan’s structural studies revealed that only a subset of patients bore a mutation right at the point where Gleevec would bind to BCR-ABL to inhibit it. Instead, most patients had mutations that impaired the flexibility of the kinase, preventing it from assuming the “off” position. To Sawyers and others, this raised the possibility that a second drug — a “sloppier inhibitor” than Gleevec that didn’t hold the target to such tight structural constraints — might work against the mutations. In short, Sawyers wondered whether a drug that bound Abl in the “on” position, like a Src inhibitor, would be the model for Gleevec’s second coming.

       Over time, Sawyers’s musings became more public. “I was giving scientific talks on the structural implications of Gleevec mutations and stating that I thought that a Src inhibitor would be a good idea,” said Sawyers. “This was an informed guess based on what we were seeing in the crystallography data.” As fate would have it, Bristol-Myers Squibb had a dual Abl/Src inhibitor under development. Sawyers received a phone call from Bristol-Myers Squibb – and BMS-354825′s reincarnation as a cancer drug was under way.

       As Sawyers is quick to point out, only time – and further research – will tell whether the drug makes it into the clinic. Early signs are good. “This could be the first drug to get around kinase resistance, and that has broad implications,” Sawyers said. “If this drug should prove to be safe and effective in the clinic, one can envision using this in a combination kinase inhibitor therapy for CML.”

       BMS-354825 is currently being evaluated at UCLA and MD Anderson Cancer Center in Houston in phase I clinical trials in CML patients with Gleevec resistance.

       CONTACT: Jim Keeley, Howard Hughes Medical Institute, 301-215-8858, keeleyj@hhmi.org

       —

       The Howard Hughes Medical Institute was established in 1953 by the aviator-industrialist. HHMI’s principal mission is conducting basic biomedical research, which it carries out in collaboration with more than 66 universities, medical centers and other research institutions throughout the United States. Its more than 300 investigators, along with a scientific staff of more than 3,000, work at these institutions in Hughes laboratories. The Institute also has a philanthropic grants program that is strengthening science education and training, from elementary school through graduate and medical school. It also supports the work of biomedical researchers in many countries around the globe.

       HHMI is one of the largest philanthropies in the world, with an endowment of more than $12 billion. Its headquarters are located in Chevy Chase, Maryland, just outside Washington, D.C.

http://www.ascribe.org/cgi-bin/spew4th.pl?ascribeid=20040715.113200&time=12%2033%20PDT&year=2004&public=1

Experimental Compound Battles Gleevec Resistance

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Source: University of California, Los Angeles (UCLA), Jonsson Comprehensive Cancer Center    
Released: Tue 13-Jul-2004, 07:20 ET
Embargo expired: Thu 15-Jul-2004, 14:00 ET 

Experimental Compound Battles Gleevec Resistance

An experimental therapy that may battle resistance to the drug Gleevec in patients with chronic myeloid leukemia (CML) has shown promising results in a study at UCLAâ??s Jonsson Cancer center, increasing survival in animal models and perhaps paving the way for a second generation targeted therapy.

The results of the study appear in the July 16, 2004 issue of the peer-reviewed journal Science, published by the American Association for the Advancement of Science, the worldâ??s largest general scientific organization. Early phase human studies of the experimental therapy, taken in pill form like Gleevec, already are underway at the Jonsson Cancer Center in patients who have developed a resistance to Gleevec.

About 15 to 20 percent of CML patients who take Gleevec become resistant to the drug and suffer a relapse, leaving them with few effective treatment options, said Dr. Neil Shah, an oncologist and researcher, an assistant professor of hematology/oncology and the studyâ??s first author. In patients with resistant disease, secondary mutations in the gene linked to CML allow the cancer to evade therapy. It is those mutations that are targeted by the new compound, BMS-354825, being developed by Bristol-Myers Squibb.

â??Learning from what happens when a drug fails in some patients can lead to a new treatment paradigm,â? Shah said. â??In the future, we may be combining therapies that can, amongst them, override all the resistance mechanisms that allow cancer to evade individual therapies. In the future, cancer may be treated similarly to HIV, with a cocktail of drugs.â?

Gleevec targets a mutant cancer-causing protein linked to CML, which each year strikes more than 10,000 adults worldwide. Specifically, Gleevec is a tyrosine kinase inhibitor, one of a new class of drugs that can interfere with cell signaling pathways implicated in tumor development. Much of the pioneering work done to link the gene and its mutant protein to CML was performed at UCLAâ??s Jonsson Cancer Center.

In some patients, secondary mutations in the CML-linked gene arise that prevent Gleevec from binding to its intended target. These mutations, because they then operate unchecked, cause the leukemia to recur.

Dr. Charles Sawyers, a professor of hematology/oncology, an investigator with the
Howard Hughes Medical Institute and the senior author of the study, said this work could represent a major advance for the patients who suffer a relapse on Gleevec.

â??Gleevec remains a spectacular step forward in the application of targeted therapy to CML specifically, and serves as a model for how to do this more generally in cancer,â? Sawyers said. â??However, some CML patients develop resistance to Gleevec after several years of therapy. Structural modeling studies predicted that other inhibitors that bind to the target protein differently from Gleevec should work against these mutants. This paper reports the effectiveness of such an inhibitor in Gleevec resistant cells in tissue culture and in mice.â?

Shah and Sawyers are hopeful that the experimental inhibitor will prove effective in human patients as well. Future studies may eventually pair Gleevec with this new inhibitor, if it proves to be safe and effective in clinical trials.

â??We hope this represents another viable treatment option for patients with this disease,â? Shah said. â??There may now be hope beyond Gleevec should their disease relapse.â?

Shah said the drug also may be useful for treating other diseases that respond to Gleevec initially, such as gastrointestinal stromal tumors.

The research, conducted at UCLAâ??s Jonsson Cancer Center, was funded in part by the Howard Hughes Medical Institute and the Leukemia & Lymphoma Society of America.

UCLA’s Jonsson Comprehensive Cancer Center is made up of more than 240 cancer researchers and clinicians engaged in cancer research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, is dedicated to promoting cancer research and applying the results to clinical situations. In 2004, the Jonsson Cancer Center was named the best cancer center in the western United States by U.S. News & World Report, a ranking it has held for five consecutive years.

For more information on the Jonsson Cancer Center, visit our web site at http://www.cancer.mednet.ucla.edu.

http://www.newswise.com/articles/view/506005/

Bristol’s Heir To Gleevec

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A powerful new leukemia drug from Bristol-Myers Squibb can kill off mutant leukemia cells that are resistant to the most powerful drug on the market, UCLA and Bristol-Myers researchers are reporting.

In lab experiments, the new drug called BMS-354825 eliminated virtually all signs of leukemia in mice whose disease was resistant to Gleevec, the breakthrough drug from Swiss drugmaker Novartis (nyse: NVS – news – people ). Untreated, the mice all died within weeks.

The finding, reported in today’s issue of the journal Science, is important because it could pave the way for a new generation of leukemia drug cocktails that could hold the disease in check for many years. Gleevec, approved in 2001, has prolonged the lives of thousands of patients with chronic myeloid leukemia, or CML, by blocking a bad gene called ABL that causes certain white blood cells to proliferate like mad. But already, 10% of CML patients are showing signs of resistance to Gleevec after several years of treatment. Researchers are finding new mutations that cause resistance all the time.

http://www.forbes.com/technology/sciences/2004/07/15/cz_rl_0715bmy.html

Revised drug battles leukaemia

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Published online: 15 July 2004; | doi:10.1038/news040712-13

Revised drug battles leukaemia
Helen Pilcher
Gleevec-resistant patients given fresh hope. 
 
Targeted drugs have revolutionised the treatment of leukaemia.

Cancer treatment’s ‘magic bullet’ has had a makeover. Researchers have developed and tested a second-generation version of the leukaemia drug, Gleevec. It is hoped that the newcomer will offer relief to those who have developed resistance to the original drug.

Gleevec was the first cancer drug of its kind – designed specifically to target the molecules that cause chronic myeloid leukaemia (CML), a deadly form of cancer that affects 1 in 100,000 people. Since its approval by the US Food and Drug Administration in 2001, it has become the front-line therapy for CML. But around 20% of patients become resistant to the drug in the early stages of the disease, so other treatments are needed.

The new drug, called BMS-354825, shrinks tumours and prolongs life in mice with a Gleevec-resistant form of CML, researchers report in Science1. Around 80% of treated rodents were still alive one month after their cancer started to develop. Without treatment, all animals died within two weeks.

BMS-354825 also slows the proliferation of cultured bone marrow cells taken from CML patients, regardless of whether they have developed resistance to Gleevec or not.

In theory this means that the drug could work against both drug-resistant and Gleevec-treatable forms of human CML, says Neil Shah from the University of California, Los Angeles, who co-authored the study. But the best treatment regime may involve prescribing Gleevec and BMS-354825 together, he says.

Designer drugs

Gleevec, also known as imatinib, works by binding to and blocking an enzyme that drives the growth of leukaemia cells. Because it targets only the cancer cells, it leaves neighbouring healthy cells unharmed.

The problem is that sometimes genetic mutations occur that cause the enzyme to change shape and prevent the drug from latching on. BMS-354825 is less selective about how it binds to the enzyme, so it can attach even to mutated forms of the protein.

Up to now, 17 resistance-causing mutations have been spotted. The new drug works against 14 of the 15 tested so far. “We’re optimistic that the other untested mutations will also be sensitive to the compound,” says Shah.

At present, when Gleevec fails, patients hold out for a bone-marrow transplant. But less than a third of patients are eligible, discounted by their age and a lack of tissue-matched donors. Without treatment, the cancer is invariably fatal.

So BMS-354825 is a welcome addition to the CML armoury. Last November, the first human patient began taking the drug as part of a phase I clinical trial. Around 30 CML patients are taking the drug to help assess its safety.

“It’s good news for the CML community,” says Junia Melo who studies haematology at London’s Hammersmith Hospital. But she says it is disappointing that one of the tested mutations is immune. The mutation, known as T315I, is responsible for around one fifth of all drug-resistant CML cases.

References
Shah N. P., et al. Science, 305. 399 – 401 (2004).

http://www.nature.com/news/2004/040712/full/040712-13.html#B1

New drug shows promise against Gleevec resistance

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Public release date: 15-Jul-2004




Charles L. Sawyers, M.D.

Full size image available
here.

One of the truly spectacular success stories in modern oncology is the development and implementation of Gleevec, a drug that virtually halts the progress of chronic myeloid leukemia. Yet for some patients who harbor particularly stubborn genetic mutations, Gleevec fails miserably.

Now, Howard Hughes Medical Institute (HHMI) researchers at the University of California, Los Angeles, and colleagues at Bristol-Myers Squibb Oncology in Princeton, NJ, are reporting the first description of a new compound that is designed to overcome Gleevec resistance in some of these individuals.

In an article published in the July 16, 2004, issue of the journal Science, HHMI investigator Charles L. Sawyers, Neil P. Shah and colleagues at UCLA’s Jonsson Comprehensive Cancer Center, report that the compound BMS-354825, which is under development by Bristol-Myers Squibb, successfully sidesteps the vexing problem of Gleevec (imatinib) resistance.

“The identification of this compound as a drug candidate is a direct byproduct of understanding why patients develop resistance to Gleevec,” said Sawyers. He notes that just as Gleevec was developed as a “molecularly targeted” inhibitor, the next generations of Gleevec, of which is BMS-354825 is one, will be refined and improved by structural biology studies that show how the drugs “fit” with their target, and how mutations alter the shape of that target.

The all-important drug target in chronic myeloid leukemia (CML) is an enzyme called Abelson tyrosine kinase (ABL), which becomes overactivated by a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR, which are located on different chromosomes, become fused and express a hybrid BCR-ABL enzyme that is always active. The hyperactive BCR-ABL, in turn, drives the overproliferation of white blood cells that is the hallmark of CML.

In the studies published in Science, Sawyers and his colleagues demonstrated that BMS-354825 prolongs survival of mice with CML. In tests with cultured human bone marrow cells, the researchers showed that the drug inhibits the proliferation of bone marrow progenitor cells that are positive for BCR-ABL in patients who are resistant to Gleevec. “The bottom line is that our in vitro data indicate that this drug is active against all of the mutations except for one,” Sawyers said.

At the time Sawyers and his colleagues were writing their Science article, there were 17 reported Gleevec-resistance mutations. There are more known now. Each mutation hampers Gleevec’s ability to bind to its target, the ABL kinase.

Sawyers, who in addition to being a researcher, also sees cancer patients at UCLA, has long been hunting for an explanation of Gleevec resistance. Deftly moving between the clinic and the research lab, Sawyers has been at the center of understanding why Gleevec works for some patients, but stops working for others.

In September 2000, HHMI investigator John Kuriyan, a structural biologist then at The Rockefeller University, who had studied the regulation of Abl kinases for many years, made the seminal discovery that Gleevec, or STI-571, worked by binding to Abl when the enzyme was in its “off” position. If Abl was in the “on” position, the drug would not work.

In the arcane worlds of cellular signaling and structural biology, it was well known that Abl looks structurally quite similar to the Src family of oncogenes that also produce kinases. Yet, as Kuriyan’s work demonstrated, STI-571 does not inhibit the Src proteins because they maintain a different shape when in their inactivated, or “off,” position. As Kuriyan prophetically stated at the time, “The puzzle of STI-571′s extreme affinity and specificity is of broader interest because protein kinases are crucial elements in signal transduction pathways that control cell growth, cell death and other processes. Thus, understanding how kinases are turned on and off is a matter of extreme interest.”

Kuriyan’s work caught the attention of Sawyers, who was examining how mutations in the ABL kinase could blunt the effect of Gleevec. Sawyers and Kuriyan began a collaboration to probe the problem, which culminated in a publication in the August 2002 issue of the journal Cancer Cell, reporting the identification of 15 mutations in the BCR-ABL gene that caused resistance to Gleevec.

In that paper, Kuriyan’s structural studies revealed that only a subset of patients bore a mutation right at the point where Gleevec would bind to BCR-ABL to inhibit it. Instead, most patients had mutations that impaired the flexibility of the kinase, preventing it from assuming the “off” position. To Sawyers and others, this raised the possibility that a second drug — a “sloppier inhibitor” than Gleevec that didn’t hold the target to such tight structural constraints — might work against the mutations. In short, Sawyers wondered whether a drug that bound Abl in the “on” position, like a Src inhibitor, would be the model for Gleevec’s second coming.

Over time, Sawyers’s musings became more public. “I was giving scientific talks on the structural implications of Gleevec mutations and stating that I thought that a Src inhibitor would be a good idea,” said Sawyers. “This was an informed guess based on what we were seeing in the crystallography data.”

As fate would have it, Bristol-Myers Squibb had a dual Abl/Src inhibitor under development. Sawyers received a phone call from Bristol-Myers Squibb â?? and BMS-354825′s reincarnation as a cancer drug was under way.

As Sawyers is quick to point out, only time â?? and further research â?? will tell whether the drug makes it into the clinic. Early signs are good. “This could be the first drug to get around kinase resistance, and that has broad implications,” Sawyers said. “If this drug should prove to be safe and effective in the clinic, one can envision using this in a combination kinase inhibitor therapy for CML.”

###

BMS-354825 is currently being evaluated at UCLA and MD Anderson Cancer Center in Houston in phase I clinical trials in CML patients with Gleevec resistance.

 

http://www.eurekalert.org/pub_releases/2004-07/hhmi-nds071304.php

New Drug May Offer New Hope for Leukemia Patients

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By Maggie Fox, Health and Science Correspondent

WASHINGTON (Reuters) – A second-generation cancer drug offers one last shot at life for leukemia patients who have not been helped by the “miracle” drug Gleevec, doctors reported on Thursday.

Tests on mice show the experimental drug overcomes virtually all of the genetic mutations that cause some cancers to resist treatment with Gleevec, the researchers report. Gleevec, made by Swiss drug company Novartis AG and sold in Europe under the name Glivec, was the first “targeted” cancer drug.

The findings, published in Friday’s issue of the journal Science, add to evidence that precisely targeted cancer drugs can be designed quickly and rushed into testing for the most desperate cancer patients.

Unpublished findings, which the researchers may not discuss, suggest the new drug is working safely and in some cases dramatically in some chronic myeloid leukemia patients who had run out of options.

“We hope this represents another viable treatment option for patients with this disease,” said Dr. Neil Shah of the University of California Los Angeles, who worked on the study. “There may now be hope beyond Gleevec should their disease relapse.”

Taken as a pill, the drug produced remarkable results in patients with advanced chronic myeloid leukemia, an immune-system cancer that kills about half the 4,000 or so people affected in the United States each year.

But about 15 percent of patients are not helped by Gleevec. Researchers discovered a series of genetic mutations in their tumors that helped the cancer cells evade its effects.

TARGETED THERAPY

Gleevec, known chemically as imatinib, works by attaching to and blocking an enzyme called BCR-ABL that helps leukemia cells grow. Mutations in this enzyme change its shape enough so that Gleevec cannot attach itself.

“We realized if we want to develop drugs that inhibit the mutants, they need to be a little sloppier, less demanding in their binding rules,” said Dr. Charles Sawyers, a Howard Hughes Medical Institute researcher at UCLA.

Members of a closely related class of drugs called SRC inhibitors also sometimes attach to and block ABL, he discovered. “Bristol Myers Squibb had a SRC inhibitor program and they called me,” added Sawyer, who worked on the development of Gleevec and led this week’s study.

One drug, BMS-354825 being developed by Bristol-Myers Squibb, looked like it would work perfectly against the mutated versions of CML cells.

Shah said it took only three years to develop the new drug — light-speed in terms of cancer therapy. And the science has advanced to where a curious doctor can tell a patient with CML why he is or is not being helped by a drug.

“I can tell them why they are resistant. I can tell them whether they are likely to respond to this new agent,” Shah said. “We hope that this is the first of many diseases that are being treated this way.”

Sawyers and colleagues reported on mice and tests in lab dishes of human cancer cells. They said the new drug is active against 14 out of 15 different Gleevec-resistant tumors.

The drug is in Phase I safety trials in CML patients in Los Angeles and Houston and at least one patient says he is seeing clear results among others.

Shah said the Phase I trial is still in the dose-escalating phase, meaning they are raising doses of the new drug to the highest levels they can without seeing serious side-effects.

http://news.yahoo.com/news?tmpl=story&cid=571&u=/nm/20040715/hl_nm/health_cancer_drug_dc&printer=1

Revised drug battles leukaemia

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Published online: 15 July 2004; | doi:10.1038/news040712-13

Revised drug battles leukaemia

Helen Pilcher

Gleevec-resistant patients given fresh hope.


Targeted drugs have revolutionised the treatment of leukaemia.

© Digital Vision

Cancer treatment’s ‘magic bullet’ has had a makeover. Researchers have developed and tested a second-generation version of the leukaemia drug, Gleevec. It is hoped that the newcomer will offer relief to those who have developed resistance to the original drug.

Gleevec was the first cancer drug of its kind – designed specifically to target the molecules that cause chronic myeloid leukaemia (CML), a deadly form of cancer that affects 1 in 100,000 people. Since its approval by the US Food and Drug Administration in 2001, it has become the front-line therapy for CML. But around 20% of patients become resistant to the drug in the early stages of the disease, so other treatments are needed.

The new drug, called BMS-354825, shrinks tumours and prolongs life in mice with a Gleevec-resistant form of CML, researchers report in Science1. Around 80% of treated rodents were still alive one month after their cancer started to develop. Without treatment, all animals died within two weeks.

BMS-354825 also slows the proliferation of cultured bone marrow cells taken from CML patients, regardless of whether they have developed resistance to Gleevec or not.

In theory this means that the drug could work against both drug-resistant and Gleevec-treatable forms of human CML, says Neil Shah from the University of California, Los Angeles, who co-authored the study. But the best treatment regime may involve prescribing Gleevec and BMS-354825 together, he says.

Designer drugs

Gleevec, also known as imatinib, works by binding to and blocking an enzyme that drives the growth of leukaemia cells. Because it targets only the cancer cells, it leaves neighbouring healthy cells unharmed.

The problem is that sometimes genetic mutations occur that cause the enzyme to change shape and prevent the drug from latching on. BMS-354825 is less selective about how it binds to the enzyme, so it can attach even to mutated forms of the protein.

Up to now, 17 resistance-causing mutations have been spotted. The new drug works against 14 of the 15 tested so far. “We’re optimistic that the other untested mutations will also be sensitive to the compound,” says Shah.

At present, when Gleevec fails, patients hold out for a bone-marrow transplant. But less than a third of patients are eligible, discounted by their age and a lack of tissue-matched donors. Without treatment, the cancer is invariably fatal.

So BMS-354825 is a welcome addition to the CML armoury. Last November, the first human patient began taking the drug as part of a phase I clinical trial. Around 30 CML patients are taking the drug to help assess its safety.

“It’s good news for the CML community,” says Junia Melo who studies haematology at London’s Hammersmith Hospital. But she says it is disappointing that one of the tested mutations is immune. The mutation, known as T315I, is responsible for around one fifth of all drug-resistant CML cases.

http://www.nature.com/news/2004/040712/full/040712-13.html

Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein

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Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP) / ABCG2 drug pump.
Blood. 2004 Jul 13; ():
Imatinib mesylate, a potent tyrosine kinase inhibitor, is successfully used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. However, the intended chronic oral administration of imatinib may lead to development of cellular resistance and subsequent treatment failure. Indeed, several molecular mechanisms leading to imatinib resistance have already been reported, including overexpression of the MDR1/ABCB1 drug pump. We examined whether imatinib is a substrate for the BCRP/ABCG2 drug pump that is frequently overexpressed in human tumors. Using a panel of well-defined BCRP-overexpressing cell lines we provide the first evidence that imatinib is a substrate for BCRP, that it competes with mitoxantrone for drug export, and that BCRP-mediated efflux can be reversed by the fumitremorgin C analog Ko-143. Since BCRP is highly expressed in the gastrointestinal tract, BCRP might not only play a role in cellular resistance of tumor cells but also influence the oral bioavailability of imatinib.

http://www.pmbrowser.info/pmdisplay.cgi?issn=00064971&uids=15251980

Suppression of bcr-abl synthesis by siRNAs or tyrosine kinase activity by Glivec

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Suppression of bcr-abl synthesis by siRNAs or tyrosine kinase activity by Glivec alters different oncogenes, apoptotic/antiapoptotic genes and cell proliferation factors (microarray study).
FEBS Lett. 2004 Jul 16; 570(1-3): 195-204
Short 21-mer double-stranded/small-interfering RNAs (ds/siRNAs) were designed to target bcr-abl mRNA in chronic myelogenous leukemia. The ds/siRNAs were transfected into bcr-abl-positive K-562 (derived from blast crisis chronic myelogenous leukemia), using lipofectamine. Penetrating of ds/siRNAs into the cells was detected by fluorescent confocal microscopy, using fluorescein-labeled ds/siRNAs. The cells were treated with mix of three siRNA sequences (3×60 nM) during 6 days with three repetitive transfections. The siRNA-treatment was accompanied with significant reduction of bcr-abl mRNA, p210, protein tyrosine kinase activity and cell proliferation index. Treatment of cells with Glivec (during 8 days with four repetitive doses, 180 nM single dose) resulted in analogous reduction of cell proliferation activity, stronger suppression of protein tyrosine kinase activity, and very low reduction of p210. siRNA-mix and Glivec did not affect significantly the viability of normal lymphocytes. Microarray analysis of siRNA- and Glivec-treated K-562 cells demonstrated that both pathways of bcr-abl suppression were accompanied with overexpression and suppression of many different oncogenes, apoptotic/antiapoptotic and cell proliferation factors. The following genes of interest were found to decrease in relatively equal degree in both siRNA- and Glivec-treated cells: Bcd orf1 and orf2 proto-oncogene, chromatin-specific transcription elongation factor FACT 140-kDa subunit mRNA, gene encoding splicing factor SF1, and mRNA for Tec protein tyrosine kinase. siRNA-mix and Glivec provoked overexpression of the following common genes: c-jun proto-oncogene, protein kinase C-alpha, pvt-1 oncogene homologue (myc activator), interleukin-6, 1-8D gene from interferon-inducible gene family, tumor necrosis factor receptor superfamily (10b), and STAT-induced STAT inhibitor.

http://www.pmbrowser.info/pmdisplay.cgi?issn=00145793&uids=15251464

CML Support News Feed

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To access our news feed, simply link your script or program to the following address:

http://cmlsupport.blogspot.com/atom.xml

Telomere Shortening Correlates with Prognostic Score at Diagnosis

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Telomere Shortening Correlates with Prognostic Score at Diagnosis and Proceeds Rapidly during Progression of Chronic Myeloid Leukemia.

Drummond M, Lennard A, Brummendorf T, Holyoake T.

HOS, Division of Cancer Sciences and Molecular Pathology, Glasgow Royal Infirmary University of Glasgow Glasgow G31 2ER UK.

Chronic myeloid leukemia (CML) is associated increased stem cell turnover. We have previously shown that short telomeres in chronic phase (CP) predict for early progression to blast phase (BP). Poor prognostic score patients may therefore exhibit increased telomere loss at diagnosis and/or a greater than normal rate of loss during the disease course. We prospectively studied newly diagnosed CML patients for degree of telomere loss; measured telomere length in CML patients at all stages of disease; and performed follow-up sampling according to cytogenetic response to imatinib mesylate. Using flow-FISH, telomere length in peripheral blood leucocytes (PBL) from 32 consecutive newly diagnosed patients was measured (with ex-vivo expanded T-cells as an internal BCR-ABL negative control), in addition to 65 samples from all CML stages and 7 paired CP/BP samples. Fifty-five normal individuals served as a control population. Patients who attained either a complete cytogenetic response (CCR, 0% Ph( + ), n = 10) or no CR (100% Ph( + ), n = 11) underwent follow-up measurement. All statistical tests were two sided. Telomeres in accelerated phase (AP) and BP patients were significantly shorter than in CP, and mean telomere shortening was significantly greater in high-risk score than low-risk patients (P < 0.05) at diagnosis. The rate of shortening during disease progression was 10 – 20 times the rate observed in normal granulocytes. BP samples had undergone at least 30 – 60 additional divisions from baseline Ph( – ) telomere length. Our findings show that telomere shortening in CML is greatest in high-risk score patients at diagnosis, and occurs rapidly during disease progression.

PMID: 15223635 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15223635&dopt=Abstract