Posted by rob on June 27, 2006 under Uncategorized | 
From wweeggee
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From jazzyboy1
Posted by rob on June 19, 2006 under Uncategorized |
From Wilfried Joh
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Olabisi OO, Mahon GM, Kostenko EV, Liu Z, Ozer HL, Whitehead IP.
Department of Microbiology and Molecular Genetics and University Hospital Cancer Center, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey.
Virtually all patients with chronic myelogenous leukemia (CML) express an aberrant protein (p210 Bcr-Abl) that contains NH(2)-terminal sequences from Bcr fused to COOH-terminal sequences from Abl. In a yeast two-hybrid screen, we have identified TSG101 as a binding partner for Bcr. Because TSG101 is a subunit of the mammalian endosomal sorting complex required for transport (ESCRT), which regulates protein sorting during endosomal trafficking, this association suggests that Bcr may have a related cellular function. The docking site for TSG101 has been mapped to the COOH terminus of Bcr, indicating that this interaction may be disrupted in CML. Overexpression studies with full-length TSG101 and Bcr reveal that this interaction can be recapitulated in mammalian cells. The association can also be observed between natively expressed proteins in a panel of hematopoietic and nonhematopoietic cell lines, where a second subunit of the ESCRT complex, vacuolar sorting protein 28 (Vps28), was also found to interact with Bcr. Both Bcr and TSG101 exhibit a punctate cytoplasmic distribution and seem to colocalize in HeLa cells, which would be consistent with an in vivo association. Bacterially purified Bcr and TSG101 also bind, suggesting that the interaction is direct and is not dependent on ubiquitination. Disruption of the endosomal pathway with an ATPase-defective Vps4 mutant results in the cellular redistribution of Bcr, and suppression of Bcr in HeLa cells by small interfering RNA impairs epidermal growth factor receptor turnover. Taken together, these observations suggest that Bcr is a component of the mammalian ESCRT complexes and plays an important role in cellular trafficking of growth factor receptors. (Cancer Res 2006; 66(12): 6250-7).
PMID: 16778200 [PubMed - in process]
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Assouline S, Laneuville P, Gambacorti-Passerini C.
Publication Types:
PMID: 16775249 [PubMed - in process]
Link
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Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG.
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1402, USA. hkantarj@mdanderson.org
BACKGROUND: Resistance to imatinib mesylate can occur in chronic myelogenous leukemia (CML). Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50. METHODS: In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily. RESULTS: Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes. Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response; of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response; 11 of 12 patients with the chronic phase had a complete hematologic remission. CONCLUSIONS: Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML. (ClinicalTrials.gov number, NCT00109707 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
PMID: 16775235 [PubMed - in process]
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Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL.
Department of Leukemia, M.D. Anderson Cancer Center, Houston, USA.
BACKGROUND: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). METHODS: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. RESULTS: A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. CONCLUSIONS: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
PMID: 16775234 [PubMed - in process]
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Buijs A, Terhal PA, Thunnissen PL.
Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center, Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands.
Publication Types:
PMID: 16772126 [PubMed - in process]
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Zhu T, Chen R, Li A, Liu J, Gu D, Liu Q, C Chang H, Zhou J.
Department of Molecular Cell Biology and Toxicology, Jiangsu Provincial Key Laboratories of Human Functional Genomics and of Applied Toxicology, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China.
Previous data showed that JWA might be a novel environmental responsive gene regulated by environmental stressors such as heat shock and oxidative stress. However, the molecular mechanism underlying JWA gene function involved in oxidative stress is still unknown. In this study, the potential role of JWA was further investigated in hydrogen peroxide (H2O2) induced DNA damage and cell apoptosis in K562 cells. Series of the oxidative stress models were established to observe if JWA was involved in DNA damage or cell apoptosis induced by H2O2 exposure. These results indicated that the inhibitory effect on K562 cells’ viability induced by H2O2 was concentration and time dependent. JWA was more sensitive to H2O2 (0.01 mmol/L) than the heat-shock proteins (hsp70 and hsp27), and its expression pattern was similar to that of hsp70. In addition, JWA, hsp70, hsp27, and p53 were overexpressed and the expression patterns of JWA, hsp70, and p53 were similar during cell apoptosis. H2O2 led to the cleavage and activation of procaspase-3. In conclusion, these results suggested that JWA might be an effective environmental responsive gene that functions as a parallel with hsp70 in oxidative stress-responsive pathways in K562 cells. Like hsp70, JWA might enhance intracellular defenses and function against H2O2-induced oxidative stress in leukemia cells. At the same time, JWA was involved in the p53-associated signal pathways of oxidative stress-induced apoptosis, which is also caspase-3 dependent.
PMID: 16766476 [PubMed - as supplied by publisher]
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[Article in German]
Strobel E, Schoniger M.
Institut fur Medizinische Mikrobiologie, Immunologie und Krankenhaushygiene.
HISTORY: A 17-year-old boy with chronic myelogenous leukemia received a bone marrow transplantation (BMT) from an unrelated donor. 22 days before BMT he had been HBs antigen and anti-HBc negative. 68 days after BMT he was tested again and showed a “seroconversion” for hepatitis B (anti-HBc positive, anti-HBs 59 IU/l), raising the suspicion of a posttransfusion hepatitis. The patient had not received any blood transfusion in the 6 months before BMT. From day 0 to day + 68 he received four red blood cell concentrates and 18 platelet concentrates. The bone marrow donor had been HBs ag and anti-HBc negative. INVESTIGATIONS: A stored serum sample of the recipient obtained on day -8 was available and proved to be negative for HBsAg and Anti-HBc IgM, but positive for anti-HBc and anti-HBs. A serum sample from day -22 was negative for all these parameters. DIAGNOSIS: These results can be explained by the administration of 17.5 g of a polyvalent immunoglobulin (Ig) concentrate for CMV prophylaxis on day -9: anti-HBc and anti-HBs (1814 IU/l) were found in the lot that the patient had received. Nine further doses of immunoglobulin concentrates were given up to day + 68. COURSE: Four months after the last administration of Ig concentrates, the patient was negative for HBs ag, anti-HBc and anti-HBs. CONCLUSION: Ig concentrates contain not only those antibodies, which are given to a patient for treatment, but also all other antibodies contained in the donor plasma pool. Thus administration of Ig concentrates can cause a “false-positive” hepatitis B serology by passive transfer of these antibodies. Such an artificial seroconversion may also lead to a false suspicion of a transfusion transmitted hepatitis B infection.
PMID: 16761202 [PubMed - in process]
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Guerzoni C, Ferrari-Amorotti G, Bardini M, Mariani SA, Calabretta B.
Department of Biomedical Sciences, Universita di Modena e Reggio Emilia, Modena, Italy.
C/EBPalpha and C/EBPbeta, two transcription factors of the C/EBP family play important roles in the proliferation and differentiation of various cell types including myeloid progenitors. Expression of C/EBPalpha and C/EBPbeta is repressed in myeloid blast crisis of Chronic Myelogenous Leukemia by mechanisms that involve translation repression which depends on the interaction of RNA-binding proteins with conserved binding sites in the 5′UTR of c/ebpalpha and c/ebpbeta mRNA. Ectopic expression of C/EBPalpha and C/EBPbeta in myeloid progenitors expressing the BCR/ABL oncogene inhibits proliferation, induces differentiation and suppresses leukemogenesis in mice, but C/EBPalpha is markedly more effective than C/EBPbeta. The more potent effects of C/EBPalpha probably depends on protein-protein interaction with cell-cycle regulatory proteins, but the pattern of genes modulated by C/EBPalpha and C/EBPbeta is not completely overlapping. This suggests that transcription-dependent and -independent effects are both involved and support the therapeutic potential of reactivating C/EBPalpha and C/EBPbeta expression in leukemic cells.
PMID: 16760662 [PubMed - as supplied by publisher]
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Azam M, Nardi V, Shakespeare WC, Metcalf CA 3rd, Bohacek RS, Wang Y, Sundaramoorthi R, Sliz P, Veach DR, Bornmann WG, Clarkson B, Dalgarno DC, Sawyer TK, Daley GQ.
*Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Division of Hematology/Oncology, The Children’s Hospital, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA 02115.
Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IM(R)) BCR/ABL kinase variants. Both compounds potently inhibit most IM(R) variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IM(R)-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance.
PMID: 16754879 [PubMed - in process]
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Pichiorri F, Trapasso F, Palumbo T, Aqeilan RI, Drusco A, Blaser BW, Iliopoulos D, Caligiuri MA, Huebner K, Croce CM.
Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA. pichiorri.1@osu.edu
PURPOSE: Expression of the FHIT protein is lost or reduced in most solid tumors and a significant fraction of hematopoietic malignancies. Adenovirus 5 (Ad5) virus or adeno-associated viral vectors have been used to study the tumor suppressor function of FHIT in solid tumors, but these tools have not been effective in leukemias. We have generated a chimeric FHIT-containing adenovirus composed of Ad5 and the group B adenovirus called F35 with which we have been able to efficiently infect hematopoietic cells. EXPERIMENTAL DESIGN: Infection efficiency of Ad5/F35-FHIT and Ad5/F35-GFP viruses was tested in leukemia cell lines that lacked FHIT expression, and biological effects of successful infection were assessed. An acute myelogenous leukemia, a chronic myelogenous leukemia, and four acute lymphoblastic leukemia human cell lines were examined as well as two EBV-transformed B lymphoblastoid cell lines that expressed endogenous FHIT. RESULTS: Two of four acute lymphoblastic leukemia cell lines, Jurkat and MV4;11, which were efficiently infected with Ad5/F35-FHIT, underwent growth suppression and massive induction of apoptosis without apparent activation of caspase-8 or caspase-2 and late activation of caspase-3. Treatment of infected cells with caspase-9 and caspase-3 inhibitors partially blocked FHIT-induced apoptosis. The two remaining infected acute lymphoblastic leukemia cell lines, Molt-3 and RS4;11, were apparently unaffected. Restoration of FHIT expression in the chronic myelogenous leukemia K562 cell line and the acute myelogenous leukemia KG1a cell line also induced apoptosis but at later time points than seen in the acute lymphoblastic leukemia Jurkat and MV4;11 cell lines. I.v. injection of Ad5/F35-FHIT-infected Jurkat cells resulted in abrogation of tumorigenicity in the NOD/SCID xenogeneic engraftment model. CONCLUSION: FHIT restoration in some FHIT-deficient leukemia cells induces both antiproliferative and proapoptotic effects involving the intrinsic caspase apoptotic pathway.
PMID: 16740775 [PubMed - in process]
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Five years ago, the drug Gleevec changed the lives of patients with leukemia. But some patients become resistant to Gleevec over time. Now, doctors are studying two new treatments that are even more potent.
This is more than a visit to a botanical garden for Amy Baker. It’s part of what she calls her “leukemic” adventure. Baker was diagnosed with chronic myelogenous leukemia or CML. She first took the drug Gleevec (imatinib).
“[Gleevec] is a pill you take once a day and actually produces complete remission of this disease,” says Kapil Bhalla, M.D., a hematologist/oncologist at Moffitt Cancer Center and Research Institute in Tampa, Fla.
But Baker became resistant to Gleevec. Her only option was a clinical trial in Florida. Baker lives in Ohio, so every 28 days, she hops a plane. “I made up my mind when I was going to do this I would call this my leukemic adventure,” she says.
In his clinical trial, Dr. Bhalla is studying two drugs that are more potent than Gleevec, AMN107 and dasatinib. He says they are making a big difference in the progression of the disease in patients who have developed resistance to Gleevec.
With this type of leukemia, parts of chromosomes 9 and 22 switch places, creating abnormality called the Philadelphia Chromosome. Knowing this, Dr. Bhalla tells Ivanhoe, “We have a target in this disease.”
When it comes to AMN107, Baker has rave reviews. “You don’t lose your hair,” she says. “You don’t get really, really sick.” And it’s working. Before the treatment, her Philadelphia Chromosome level was at 90 percent, and now it’s down to 2.5 percent — a big improvement. Today, she’s happily enjoying life and looking forward to fulfilling many other adventures.
Some patients with CML who can get to remission are then able to get a bone marrow transplant, which can be a cure for this disease. Dr. Bhalla says these new drugs have made this option available to more and more patients with CML who have a bone marrow match.
If you would like more information, please contact:
Linda Loudon
Moffitt Cancer Center
Cancer Answers, FOW/LCS
12902 Magnolia Dr.
Tampa, FL 33612
(800) 456-7121
Link
Posted by rob on June 17, 2006 under Uncategorized |
By Ron Winslow, The Wall Street Journal
Kevin Williams had taken the breakthrough cancer drug Gleevec for more than two years, but the medicine made little headway against the leukemia ravaging his blood and its side effects sapped his stamina.
A year ago, the 41-year-old computer programmer enrolled in a clinical trial for an experimental drug called dasatinib and was free of cancer within nine months. Today, he has both his energy and his optimism back. “I may not be totally cured,” Mr. Williams says, but with the new drug, “I think I have a much better chance for long-term survival.”
The question is, does dasatinib offer a similar chance for the company developing it: Bristol-Myers Squibb Co.?
For decades, Bristol-Myers was the king of oncology. Then it lost patent protection on its blockbuster medications and its lead in research to nimbler biotech companies. Now the company is hoping that a long-planned comeback in cancer research can drive a turnaround from one of the darkest periods in its corporate history.
Dasatinib (whose tentative trade name is Sprycel) isn’t a silver bullet for the company’s woes, but it represents a promising first result from years of expensive research. Developed in Bristol-Myers’s own labs, dasatinib has already won approval from a Food and Drug Administration advisory panel and is expected to win full FDA approval by June 28, just 31/2 years after it was first tested in patients. That would make it one of the fastest trips ever through the U.S. regulatory process.
The company has three other compounds in human studies for a variety of cancers, with hopes that they might be approved before the end of the decade. And the company is seeking to expand uses for the colorectal cancer drug Erbitux that it co-markets with ImClone Systems Inc. in a bid to bolster its sales.
“They’re making progress,” says Tim Anderson, an analyst at Prudential Equity Group. But he cautions, “I don’t think they’re there with a fully built-out franchise yet.”
Converting this emerging portfolio of drugs into a robust revenue stream will take years. In the meantime, a healthy pipeline may be a lure for suitors. Lately, the company has been at the top of the list of potential drug industry takeover targets. Many analysts believe only uncertainty over whether the Federal Trade Commission will challenge an agreement that protects the patent of cholesterol pill Plavix, the company’s biggest seller, is keeping potential acquirers at bay.
A Bristol-Myers spokesman, citing company policy, declined to comment on takeover speculation.
Bristol-Myers paved the way for some of the earliest cancer drugs. Beginning in the 1970s, it introduced a steady stream of chemotherapy agents, including platinum-based drugs such as carboplatin and the blockbuster Taxol for breast cancer. In 2000, its annual sales of oncology drugs peaked at $2.7 billion.
But after the U.S. patent for Taxol expired that year, the company’s overall cancer drug sales tumbled to $1.5 billion by 2005. At the same time, momentum in oncology shifted to new so-called targeted drugs, designed to attack tumors directly with less-toxic effects than are associated with chemotherapy. Thanks in part to the high prices the new agents could command, drugs such as Genentech Inc.’s Herceptin and Novartis AG’s Gleevec became blockbusters, vaulting those companies to the lead in cancer sales.
In late 2001, Bristol-Myers paid $2 billion for rights to ImClone’s targeted colon cancer remedy Erbitux, only to have the FDA reject the drug a few weeks later. (The company ultimately renegotiated its deal with ImClone and the drug was eventually approved.) Then the company was rocked by a scandal involving inflated product sales to wholesalers — a practice known as channel stuffing.
As they plotted their way out of the turmoil, company officials determined to regain prominence in cancer drugs. “This is one of the pillars upon which our company has been built,” says Frank Pasqualone, head of Bristol-Myers’s oncology business.
A major effort was directed at dasatinib, which was discovered by immunologists at Bristol-Myers and then found to have a molecular structure that led company scientists to believe it could inhibit two cancer causing genes. One is known as src, which is active in the breast and other solid tumors; the other is abl, which is what Gleevec blocks in patients with chronic myelogenous leukemia, or CML. Applied to human cancer cells in a test tube, the drug produced stunning results: It was as much as 300 times more potent than Gleevec. A big question was whether such potency, and its ability to home in on several mutations of the abl gene, would make it too toxic for patients.
In late 2003, doctors at M.D. Anderson Cancer Center, Houston, and the University of California at Los Angeles, began testing it in the first patients. Six months later, they saw the first major response: the drug had sharply reduced levels of the mutant gene from patients’ bone marrow. “We knew we had a direct impact on the disease,” says Robert LaCaze, the company’s vice president for global oncology marketing. “It was a lot sooner than we had anticipated.”
Since then, dasatinib has been tested on several hundred patients, yielding more convincing evidence of its benefit. Side effects include fluid retention and nausea. An FDA advisory panel voted overwhelmingly two weeks ago to recommend approval of dasatinib for chronic myelogenous leukemia patients who are resistant to Gleevec. Barring last-minute surprises, the company expects the FDA, which typically follows the advice of its panels, to make a decision by June 28.
Doctors say the new drug, and potentially a similar new compound from Novartis that is considered about a year behind dasatinib, offers hope for patients who don’t respond to or can’t tolerate Gleevec.
The next step is to establish dasatinib as a front-line treatment, and thus make it a direct rival to Gleevec and its $2.2 billion in annual sales. Trials are already under way to test the drug against Gleevec. The move will be tough even if those trials succeed, because Gleevec is well established in the market with impressive long-term results, doctors and analysts say. About 10,000 new cases of CML are diagnosed in the U.S. each year and a recent five-year follow-up of patients on Gleevec indicates that fewer than 5 percent of them per year become resistant to the drug.
Still, some analysts’ estimates for dasatinib sales in 2010 range from $500 million to nearly $1 billion based on usage with patients who failed with Gleevec and on expectations that a combination of the drugs will be used.
Dasatinib may prove to be effective against other types of cancers. Once a new drug reaches the market, it is available for doctors to try with other patients. In any event, Bristol-Myers is testing the drug against other cancers with hopes of broadening its market well beyond CML.
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Posted by rob on June 15, 2006 under Uncategorized |
New Leukemia Drugs Help Those Who Fail Gleevec
By Amanda Gardner
HealthDay Reporter
WEDNESDAY, June 14 (HealthDay News) — The prognosis picture for people with chronic myelogenous leukemia (CML) has just gotten even rosier.
Two new studies find that two novel molecular therapies show promise in patients who can’t tolerate, or are resistant to, Gleevec.
“Five years ago, the standard of therapy for these patients was transplant. The response was good, but with great cost, and the patients spent the rest of their lives hovering around the hospital,” said Dr. Mark H. Kirschbaum, director of new drug development in the division of hematology and hematopoietic cell transplantation at City of Hope, in Duarte, Calif.
“Now you can treat them with a pill,” he said.
And because the two new drugs — Sprycel (dasatinib) and Tasigna (nilotinib) — work in different ways, they may help an even wider range of patients.
“It’s just a very complementary strategy that would, in my mind, argue for using dasatinib in combination with Gleevec or nilotinib as a way to prevent resistance in the future,” said Dr. Charles L. Sawyers, senior author of the dasatinib trial and an investigator with the Howard Hughes Medical Institute at UCLA’s Jonsson Cancer Center.
Both studies appear in the June 15 issue of the New England Journal of Medicine.
Sprycel could receive U.S. Food and Drug Administration approval in as little as two weeks, Sawyers said. An FDA advisory panel recommended approval earlier this month.
Gleevec’s success means that it is now the drug against which all other CML therapies are ranked. Data presented at the recent annual meeting of the American Society of Clinical Oncologists (ASCO) showed that overall five-year survival for people with CML was 89 percent (95 percent if only deaths related to CML were considered). At the same time, 93 percent of patients taking the drug had still not progressed from the chronic to the acute phase of the illness.
But not all the findings were so positive. While the relapse rate for Gleevec in newly diagnosed patients taking it as front-line therapy is low — about 4 percent per year — patients who started on a different drug before getting Gleevec tend to relapse earlier, the researchers found.
“Gleevec is great, there’s no question,” Sawyers said, but not everyone will benefit indefinitely. “There is a reason to have a second drug, and the second drug [Sprycel] looks good.”
Another expert agreed.
“Gleevec is doing a fantastic job of taking, but there are still some folks who don’t respond or who can’t tolerate the drug,” said Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society. “These drugs begin to fill in these gaps.”
Participants in the phase 1 trial of Sprycel had been diagnosed with CML for an average of about eight years, and had already relapsed while on Gleevec. Some were now in the more advanced acute phase of the disease.
All participants were given 15 milligrams to 240 milligrams of Sprycel a day in four-week treatment cycles once or twice daily. The drug comes in the form of a pill.
Sprycel produced a good response in 37 of 40 patients with chronic-phase disease, and in 31 of 44 patients in the acute phase.
“We’re seeing basically Gleevec-like results,” Sawyers said. The study was funded by grants from the Leukemia and Lymphoma Society and the U.S. National Institutes of Health.
There were some side effects with dasatinib therapy, including panniculitis, an inflammation of the fat under the skin. A research letter in the same issue of the journal detailed panniculitis in two patients taking dasatinib.
For the second study, also a phase 1 trial, 119 patients with Gleevec-resistant CML received nilotinib orally at different doses once or twice daily.
The drug appeared to be active against CML and the safety profile was “relatively favorable,” the researchers found. The study was funded by drug maker Novartis Pharmaceuticals.
According to experts, nilotinib is like a “super-Gleevec,” a variation on the same molecular theme. Sprycel, on the other hand, works in a completely different way.
Between the two of them, many patients who can’t take Gleevec are still being helped.
“The net is getting wider,” Kirschbaum said. “Now we need a Gleevec for everything.”
“This is emblematic of the sort of situation that we’re going to be seeing more and more of as we go forward,” Lichtenfeld added.
More information
For more on CML, head to the Leukemia and Lymphoma Society (www.leukemia-lymphoma.org ).
SOURCES: Charles L. Sawyers, M.D., investigator, Howard Hughes Medical Institute, UCLA’s Jonsson Cancer Center, Los Angeles; Mark H. Kirschbaum, M.D., director, new drug development, hematology malignancies, division of hematology and hematopoietic cell transplantation, City of Hope, Duarte, Calif.; Len Lichtenfeld, M.D., deputy chief medical officer, American Cancer Society, Atlanta; June 15, 2006, New England Journal of Medicine
Copyright © 2006 ScoutNews, LLC. All rights reserved.
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Dasatinib treats resistant cases of CML
By University of California – Los Angeles
Jun 15, 2006, 11:29
An experimental therapy that battles drug resistance in Chronic Myeloid Leukemia (CML) has proved “extremely effective” in fighting cancer, giving patients for whom all conventional therapies have failed another option, researchers at UCLA’s Jonsson Cancer Center reported.
The Bristol-Myers Squibb therapy, Sprycel (dasatinib), treats CML that has mutated and becomes resistant to the leukemia pill Gleevec, said Dr. Charles Sawyers, a professor of hematology/oncology, a Jonsson Cancer Center researcher and lead author of the study, published in the June 15, 2006 issue of the peer-reviewed New England Journal of Medicine.
The results are from a Phase I study of Sprycel. The early results were so favorable that several Phase II studies were launched last year and are almost completed. Because these trials have moved so quickly and because more positive results are anticipated, an advisory panel for the U.S. Food & Drug Administration on June 2 recommended that the agency approve the drug, which could happen before the end of the month, Sawyers said. Like Gleevec, Sprycel also is taken in pill form.
Sawyers characterized the Phase I study results as remarkable, saying the first human trial confirmed the pre-clinical laboratory work and scientific discovery done at UCLA’s Jonsson Cancer Center, where the mechanisms and mutations behind Gleevec resistance were uncovered. The Phase I study was done jointly with MD Anderson Cancer Center.
“This shows that if you have a precise molecular understanding of a drug target you can very quickly decipher the reasons for response and failure to therapy and quickly come up with backup treatment strategies,” said Sawyers, a Howard Hughes Medical Institute investigator. “Gleevec remains a spectacular step forward in the field of targeted therapy. However, some patients develop resistance to the drug after several years of therapy. These patients now have another effective option in this drug.”
Drug development often can take decades. However, it has been just five years since Gleevec was approved. In that time, UCLA scientists were able to discover how the CML in some patients mutated and became resistant to Gleevec and test an existing compound on laboratory models and then in patients with great success.
Resistance in CML patients is associated with mutations in the Bcr-Abl gene that interfere with the drug’s mechanism of action. Sprycel blocks 14 of 15 documented CML mutations known to lead to resistance, Sawyers said. It’s about 300 times more potent than Gleevec as well.
Over five years, about 20 percent of patients become resistant to Gleevec, Sawyers said. One of the reasons Sprycel works so well to combat that resistance is that it binds to the mutant proteins in a different way than Gleevec, and it also inhibits several other tyrosine kinases believed to play roles in cancer growth, Sawyers said.
“The main message is that this drug is extremely effective in CML patients who have failed all standard therapy including Gleevec,” Sawyers said. “The basic science findings all panned out. What we predicted based on laboratory studies proved true in human trials. While there was some concern that this drug might be more toxic because it is more potent, we are delighted to find that it is very well tolerated.”
The UCLA Phase I study enrolled 84 patients – 40 with chronic phase CML, 11 with accelerated phase CML, a more serious form of the disease, and 23 whose CML was in blast crisis, the last and most serious phase of CML. Additionally, 10 patients with acute lymphoblastic leukemia (ALL) were enrolled because they tested positive for the Philadelphia chromosome, the genetic abnormality that characterizes most cases of CML and the primary mutation targeted by the drug.
A major cytogenetic response – a substantial reduction in cells containing the Philadelphia chromosome in the bone marrow – was found in 45 percent of chronic phase patients, Sawyers said. In the patients with accelerated and blast phase CML and in patients with ALL, a major cytogenetic response was reported in 43 percent of patients. The responses have lasted for up to two years in some cases and although the study is complete, a number of patients continue to take the drug and are still being monitored.
Sawyers said it’s possible that Gleevec and Sprycel might be used together in patients with CML as a very effective one-two punch to fight cancer and battle drug resistance.
Lakewood resident Kevin Williams, 41, married and a father of two, was diagnosed with CML in June of 2000. He was put on interferon, the standard treatment for CML at that time. The side effects were brutal . Williams felt as if he had a bad flu all the time. He lost weight and was constantly tired. When it became clear that the interferon was not working, Williams’ UCLA oncologist prescribed Gleevec, which had just been approved by the FDA.
After about 10 months on Gleevec, Williams and his oncologists noticed that he was becoming resistant to the drug. His white blood cell count was more difficult to maintain and Williams had to take more and more Gleevec to achieve a stable response. And he was showing no cytogenetic response at all. The mutated cells in his bone marrow that were causing his CML were not decreasing in number. In June 2005, Williams enrolled in a Jonsson Cancer Center study of Sprycel. A bone marrow test in February surprised Williams and his oncologists – there was absolutely no evidence in his marrow of the mutated cells. Williams was 100 percent negative for cancer just nine months after he started taking Sprycel.
“I feel like this drug has given me my life back again,” said Williams, a computer programmer. “I can now do all the things I used to do before. I feel great.”
Williams has returned to his active life, going snow skiing and road racing his motorcycle. He also spends quality time with his wife, Teresa, and his daughter, Kerri, 13, and son, Brian, 7.
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EAST HANOVER, N.J., June 14 /PRNewswire-FirstCall/ — The first-ever published clinical trial data about the investigational drug Tasigna(R) (nilotinib) showed the compound helped more than 90% of patients diagnosed with an unresponsive form of leukemia, a life-threatening disease.
The data were published today in the New England Journal of Medicine.
In less than five months of treatment, 92% of patients with chronic phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) achieved a complete hematologic response with normal white blood cell counts after having shown resistance or intolerance to optimized Gleevec(R) (imatinib mesylate)* tablets therapy.
In more than a third of these patients, the Ph chromosome, the genetic abnormality that characterizes most cases of CML, was undetectable after treatment with Tasigna, as measured by standard laboratory methods. A total of 106 patients with Ph+ CML participated in this study: 33 patients in blast crisis, 56 patients in accelerated phase, and 17 patients in chronic phase. In addition, 13 patients with Ph+ acute lymphoblastic leukemia were included in the study.
Both Tasigna and Gleevec inhibit Bcr-Abl, the definitive cause of Ph+ CML – in effect, shutting down production of the Ph chromosome. Tasigna was specifically designed to be a highly selective inhibitor of Bcr-Abl and its mutations, which can cause resistance to treatment.
“By selectively inhibiting Bcr-Abl and its common mutations, Tasigna produced dramatic positive responses in patients who had limited treatment options,” said Hagop Kantarjian, MD, Professor of Medicine and Internist, Chair, Department of Leukemia, M.D. Anderson Cancer Center. “These extremely encouraging results reinforce the validity of treating this cancer by specifically targeting the one protein known to cause the disease.”
Patients in the most advanced phases of CML also responded to Tasigna therapy. The overall rate of hematologic response (normalization of white blood cell counts) for patients in accelerated phase was 72% and the rate of cytogenetic response (reduction or elimination of the Ph+ chromosome) was 48%. Among patients in blast crisis, the response rates were 39% and 27%, respectively.
The study investigators concluded that Tasigna was generally well tolerated. Common adverse events included myelosuppression, transient indirect hyperbilirubinemia and skin rashes. Additionally, the investigators noted that Tasigna was usually not associated with certain toxicities seen with Gleevec (e.g. fluid retention, superficial edema, weight gain), or with rare cases of pleural and pericardial effusions.
About Tasigna
Discovered in the biomedical research facilities of Novartis, Tasigna (investigational name AMN107) entered Phase I clinical studies just 21 months after it was first synthesized. It is a next generation tyrosine kinase inhibitor in Ph+ CML with a high affinity and specificity to attach itself to Bcr-Abl and to 32 of 33 mutant forms commonly associated with Ph+ CML. The U.S. Food and Drug Administration (FDA) has granted both fast track designation and orphan drug status to Tasigna. Tasigna also received orphan drug status from the European Medicines Agency (EMEA). Novartis is now planning to submit Tasigna for U.S. and EU regulatory approval in late 2006 compared to earlier estimates for submissions in 2007.
As an investigational compound, the safety and efficacy profile of Tasigna has not yet been established. Access to Tasigna is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the compound’s potential benefits and risks and data will be filed with regulatory authorities such as the U.S. FDA and the European Medicines Agency for regulatory approval.
About Gleevec
Gleevec (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. Follow-up is limited. Gleevec tablets are also indicated for the treatment of patients with Ph+ CML in blast crisis, in accelerated phase, or in chronic phase after failure of interferon- alpha (IFN-a) therapy.
Important Safety Information(1)
Severe (NCI Grades 3/4) lab abnormalities-including neutropenia (3%-48%), anemia (<1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (3%-6%)-and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (eg, pleural effusion, pulmonary edema, and ascites) and superficial edema (1.8%-11%), hemorrhage (1%-19%) and musculoskeletal pain (2%-9%), were reported among Gleevec patients. Severe fluid retention appears to be dose related, was more common in the advanced phase studies (where the dosage was 600mg/day), and is more common in the elderly. Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life-threatening. There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure, and papilledema and gastrointestinal perforation.
Bullous dermatologic reactions (eg, erythema multiforme and Stevens- Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing cases note a resolution or improvement of bullous reaction following dose reduction with or without supportive care.
Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse events, or hematologic adverse events. Therapy with Gleevec was discontinued for adverse events in 3% to 5% of patients.
Patients with severe hepatic impairment should be treated at a starting dose of 300 mg/day and should be closely monitored.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec tablets should increase by at least 50% and clinical response should be carefully monitored in patients receiving Gleevec tablets with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full prescribing information for other potential drug interactions).
For daily dosing of 800mg and above, dosing should be accomplished using the 400mg tablets to reduce exposure to iron.
Use of Gleevec tablets is contraindicated in patients with hypersensitivity to imatinib or to any other component of Gleevec tablets.
Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec tablets.
Because of the potential for serious adverse reactions in nursing infants, women should be advised to avoid breast-feeding while taking Gleevec tablets.
Common Side Effects(1)
The majority adult patients who received Gleevec in clinical studies experienced adverse events at some time. Most adverse events were mild to moderate in severity. The most frequently reported adverse events (all Grades) were superficial edema (58%-74%), nausea (47%-73%), muscle cramps (28%-62%), vomiting (21%-58%), diarrhea (39%-57%), musculoskeletal pain (38%-49%), and rash with related terms (26%-47%).**
Supportive care may help the management of most mild to moderate adverse events so that the prescribed dose can be maintained whenever possible.
Gleevec tablets should be taken with food and a large glass of water to minimize gastrointestinal (GI) irritation. Gleevec tablets should not be taken with grapefruit juice.
The foregoing release contains forward-looking statements that can be identified by terminology such as “promising,” “extremely encouraging results,” “planning,” “will be filed,” or similar expressions, or by express or implied discussions regarding potential future sales of Gleevec, or regarding the long-term impact of a patient’s use of Tasigna or Gleevec. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Tasigna and Gleevec to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Tasigna will be approved for sale in any market. Nor can there be any guarantee regarding potential future sales of Tasigna or Gleevec. Neither can there be any guarantee regarding the long-term impact of a patient’s use of Tasigna or Gleevec. In particular, management’s expectations regarding Tasigna and Gleevec could be affected by, among other things, unexpected clinical trial results, including new clinical data and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry, and general public pricing pressures; and other risks and factors referred to in the Company’s current Form 20-F on file with the U.S. Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
About Novartis
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including central nervous system disorders, organ transplantation, cardiovascular diseases, dermatological diseases, respiratory disorders, cancer and arthritis. The company’s mission is to improve people’s lives by pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG (NYSE: NVS) – a world leader in pharmaceuticals and consumer health. In 2005, the Group’s businesses achieved sales of USD 32.2 billion and pro forma net income of USD 6.1 billion. The Group invested approximately USD 4.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 96,000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com/.
(*) Known as Glivec(R) (imatinib) outside the U.S.
(**) Numbers indicate the range of percentages in 4 studies among adult
patients with Ph+ CML in blast crisis, accelerated phase, and chronic
phase.
(1) Gleevec(R) (imatinib mesylate) tablets prescribing information. East
Hanover, NJ: Novartis Pharmaceuticals Corporation; 2005.
Media only: Investors only:
Geoff Cook Jill Pozarek
Novartis Oncology Novartis Corporation
P: 1 862-778-7692 P: 1 212-830-2445
F: 1 773-781-2074
Dana Kahn Cooper
P: 1 732-817-1800
F: 1 732-817-1834
Website: http://www.novartis.com/ |
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Posted by rob on June 11, 2006 under Uncategorized |
From shacky
