Posted by rob on March 28, 2006 under Uncategorized | 
SAN DIEGO, March 27 /PRNewswire-FirstCall/ -- SGX Pharmaceuticals, Inc.(Nasdaq: SGXP) announced today that it has entered into a license andcollaboration agreement with Novartis focused on the development andcommercialization of BCR-ABL inhibitors for the treatment of drug resistantChronic Myelogenous Leukemia (CML). Under the terms of the agreement, SGX will receive from Novartis $25million in upfront payments and the purchase of SGX common stock. Along withsuccess-based milestones, but excluding royalties, total payments to SGX couldexceed $515 million, including a minimum of two years of research funding. The success of Gleevec(TM) (imatinib), the first targeted therapy inPhiladelphia Positive (Ph+CML) proven to inhibit BCR-ABL, has fundamentallychanged the treatment of Ph+CML. However, a subset of patients developsresistance to Gleevec or cannot tolerate therapy. For these patients thereare currently no other approved treatment options. Drug candidates from SGX'slead series, developed from its FAST(TM) proprietary drug discovery platform,have exhibited activity against wild-type and drug resistant BCR-ABL mutants,including the most challenging T315I mutant. "Novartis is the leader in developing novel targeted therapies to treatCML," said Mike Grey, president and chief executive officer of SGXPharmaceuticals. "With their extensive experience developing andcommercializing Gleevec as well as development of the novel investigationalcompound, nilotinib/AMN107, we believe they are the ideal partner with whom todevelop our series of next-generation BCR-ABL inhibitors. This is atremendous validation of our FAST technology for generation of novel leadmolecules for key therapeutic targets."
Background on the Agreement SGX will be responsible for completing preclinical development of the leadcandidate and submitting an Investigational New Drug application with the Foodand Drug Administration. SGX will also be responsible for the completion ofan initial phase I clinical study, after which time Novartis will beresponsible for conducting further clinical development and commercializationof the compound. In addition to the upfront and milestone payments, SGX will receiveroyalty payments upon successful commercialization of products developed underthe collaboration. SGX retains an option to co-commercialize, in the U.S.,oncology products developed under the agreement. If exercised, the optionwould enable SGX to reinforce the commercial presence in the North Americanhematology markets which the company plans to establish with the potentiallaunch of Troxatyl(TM) in the second half of 2007, assuming the successfulcompletion of the ongoing Phase II/III clinical trial for the treatment ofthird-line acute myelogenous leukemia and regulatory approval of Troxatyl forthis initial indication in 2007.
Background on CML: Prognosis and Treatments Chronic myelogenous leukemia is a malignant cancer of the bone marrowcausing rapid and abnormal growth of white blood cells. According to theNational Institutes of Health, approximately 4,600 new cases of CML arediagnosed annually, accounting for 7 to 20 percent of leukemia cases. CML isassociated with a chromosome abnormality called the Philadelphia chromosome.Since its approval in 2001, Gleevec has become the standard of care for Ph+CML. Results from the IRIS study (International Randomized Interferon versusSTI571), the largest clinical trial to date for newly diagnosed adult patientswith Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) inchronic phase, show that 90.3 percent of patients who were initiallyrandomized to take Gleevec were still alive after 54 months. The prevalence of CML has increased substantially because Gleevec therapymakes it possible for patients with CML to live with the disease much longerthan possible with previously used treatments. Gleevec works directly onleukemic cells by inhibiting the action of BCR-ABL tyrosine kinase, the enzymeresponsible for uncontrolled growth of leukemic cells. Despite this clinicalsuccess, resistance to Gleevec has emerged in a subset of patients. Oncepatients lose response to optimized doses of Gleevec, the only currentlyapproved treatment is bone marrow transplantation preceded by high-dosechemotherapy and radiation, for which many CML patients are not eligible. "We believe that a BCR-ABL inhibitor developed through this collaborationcould have the potential to be used both as a monotherapy in second-linetreatment of refractory or relapsed CML, and in combination with Gleevec oranother agent in first-line treatment of CML," added Dr. Stephen Burley, chiefscientific officer of SGX Pharmaceuticals.
About FAST(TM) Drug Discovery FAST, short for Fragments of Active Structures, is SGX's proprietaryfragment-based drug discovery platform for rapid identification of novel,potent and selective small molecule inhibitors of drug targets. FASTaddresses many of the limitations of traditional approaches utilized by largepharmaceutical companies to find lead compounds, making it an attractivetechnology for targets that have not yielded promising leads fromhigh-throughput screening. FAST is based on a proprietary fragment library of approximately 1,000structurally diverse, low molecular weight compounds. FAST integrates aseries of technologies, including:
* A high-throughput capability to generate many different crystal structures of a target protein in parallel; * The evaluation of the library of fragments and direct visualization of bound fragments utilizing X-ray crystallography; and * The use of novel computational and structure-based design methods and iterative synthetic chemistry to optimize these fragments into drug candidates.
SGX believes these combined technologies generate an efficient platformfor drug discovery that delivers lead compounds active against a wide range oftargets, while accessing high chemical diversity and the potential for gooddrug-like properties.
About SGX Pharmaceuticals SGX Pharmaceuticals is a biotechnology company focused on the discovery,development and commercialization of innovative cancer therapeutics. TheCompany's lead product candidate, Troxatyl(TM), is currently being evaluatedin a pivotal phase II/III trial for the treatment of third-line acutemyelogenous leukemia, an indication for which there is currently no approvedtherapy or standard of care. SGX has developed a pipeline of oncology drugcandidates based on its enabling, proprietary FAST(TM) drug discoveryplatform, including a portfolio of next generation BCR-ABL inhibitors. FASTallows for the rapid identification of novel, potent and selective smallmolecule compounds for well validated but challenging targets. Moreinformation on SGX's pipeline and drug discovery platform can be found athttp://www.sgxpharma.com .
SGX Pharmaceuticals Forward-Looking Statements Statements in this press release that are not strictly historical innature are forward-looking statements. These statements include but are notlimited to statements related to SGX's research and drug discovery anddevelopment programs and statements regarding the potential value and scope ofthe collaboration with Novartis, SGX's receipt of potential research andmilestone payments, royalty payments or profits from sales of productsdeveloped under the collaboration, SGX's co-commercialization options andcommercialization strategies, expectations regarding the timing of initiationand completion of development, including clinical trials, and product launchmilestones with respect to drug candidates under the collaboration,expectations with respect to the further development and potential regulatoryapproval of Troxatyl, the activity of BCR-ABL inhibitors, the potential ofBCR-ABL-based therapies as treatments for CML alone or in combination withother treatments, the expansion of treatment options available to patientswith CML, future plans and activities regarding the collaboration and SGX'sBCR-ABL program, the effectiveness and efficiency of SGX's FAST technology togenerate novel lead molecules for key therapeutic targets and SGX's ability todiscover, develop and commercialize cancer therapeutics. These statements areonly predictions based on current information and expectations and involve anumber of risks and uncertainties. Actual events or results may differmaterially from those projected in any of such statements due to variousfactors, including the risks and uncertainties inherent in drug discovery,development and commercialization, collaborations with others, and litigation.In particular, the results of early clinical trials may not be predictive offuture results, and SGX cannot provide any assurances that any of its productcandidates will have favorable results in future clinical trials or receiveregulatory approval. In addition, SGX's results may be affected by risks thatthe required regulatory approvals will be received in a timely manner, or atall, risks related to the implementation of its collaboration with Novartis,competition from other biotechnology and pharmaceutical companies, itseffectiveness at managing its financial resources, its ability to successfullydevelop and market products, the level of efforts that its collaborativepartners devote to development and commercialization of its productcandidates, difficulties or delays in its clinical trials, difficulties ordelays in manufacturing its clinical trials materials, the scope and validityof patent protection for its products, regulatory developments involvingfuture products and its ability to obtain additional funding to support itsoperations. For a discussion of these and other factors, please refer to therisk factors section of the final prospectus from SGX's initial publicoffering filed with the United States Securities and Exchange Commission onFebruary 1, 2006 as well as other subsequent filings with the Securities andExchange Commission. You are cautioned not to place undue reliance on theseforward-looking statements, which speak only as of the date hereof. Thiscaution is made under the safe harbor provisions of the Private SecuritiesLitigation Reform Act of 1995. All forward-looking statements are qualifiedin their entirety by this cautionary statement and SGX undertakes noobligation to revise or update this press release to reflect events orcircumstances after the date hereof.
SGX Pharmaceuticals Announces Strategic Collaboration to Develop and Commercialize BCR-ABL Inhibitors for the Treatment of Chronic Myelogenous Leukemia (CML)
Posted by rob on March 23, 2006 under Uncategorized |
K562 is the chronic myelogenous leukemia (CML)-derived cell line that expresses high levels of chimeric oncoprotein Bcr-Abl. The deregulated (permanent) kinase activity of Bcr-Abl leads to continuous proliferation of K562 cells and their resistance to the apoptosis promotion by conventional drugs. The photodynamic treatment (PDT) based on the application of 5-aminolevulinic acid (ALA) and irradiation with blue light (ALA-PDT) resulted in the suppression of K562 cells proliferation. It was followed by a necrosis-like cell death [K. Kuzelová, D. Grebenová, M. Pluskalová, I. Marinov, Z. Hrkal, J. Photochem. Photobiol. B 73 (2004) 67-78]. ALA-PDT led to the perturbation of the Hsp90/p23 multichaperone complex of which the Bcr-Abl is the client protein. Bcr-Abl protein was suppressed whereas the bcr-abl mRNA level was not affected. Further on, we observed several changes in the cytoskeleton organization. We detected ALA-PDT-mediated disruption of filamental actin structure using FITC-Phalloidin staining. In connection with this we uncovered certain cytoskeleton organizing proteins involved in the cell response to the treatment. Among these proteins, Septin2, which plays a role in maintaining actin bundles, was suppressed. Another one, PDZ-LIM domain protein 1 (CLP36) was altered. This protein acts as an adaptor molecule for LIM-kinase which phosphorylates and thus inactivates cofilin. Cofilin was indeed dephosphorylated and could thus be activated and operate as an actin-depolymerizing factor. We propose the scheme of molecular response of K562 cells to ALA-PDT.
Photodynamic treatment (ALA-PDT) suppresses the expression of the oncogenic Bcr-Abl kinase and affects the cytoskeleton organization in K562 cells.
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An article presented in this issue of Molecular Pharmacology (p. …) provides an intriguing example of how tyrosine kinase inhibitors can be put to many uses. In this article, the action of dasatinib (BMS-354825) is contrasted to that of imatinib, a kinase inhibitor that is currently being used to treat chronic myelogenous leukemia and other disorders. Both inhibitors target several tyrosine kinases, including Bcr-Abl and the platelet-derived growth factor receptor (PDGFR). Up to this point, the PDGFR has not been a primary therapeutic target for these agents. The work of Chen and colleagues shows that BMS-354825 is a particularly potent inhibitor of PDGFR, and that the compound also targets Src kinase. The authors suggest that this combination of activities could be useful in the treatment of vascular obstructive diseases. While a lack of absolute specificity has classically been regarded as a pharmacologic drawback, this study exemplifies that drugs with multiple molecular targets can potentially provide a very beneficial spectrum of therapeutic activities in multiple disease states.
New Assignments for Multi-tasking Signal Transduction Inhibitors (Relates to Article by Chen, et al. FastForward 25 January 2006).
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Methotrexate (MTX) is used as an immunosuppressive agent for acute graft-versus-host disease (GVHD) prophylaxis following hematopoietic cell transplantation (HCT). Concerns that folate intake may impair MTX effectiveness or selectively rescue leukemic cells have led to variations in clinical practice regarding supplemental folic acid during MTX administration. A retrospective, observational study was undertaken to determine the association between folic acid intake (days 0-18 post transplant) and MTX toxicity and efficacy following HCT. The study population consisted of 311 adult patients who received a myeloablative HCT for chronic myelogenous leukemia, all four scheduled doses of MTX, and did not require leucovorin rescue. Multiple linear regression models were used to assess the relationships between folic acid intake (days 0-18 post-HCT) and oral mucositis index (OMI) scores, time to engraftment and risk of detectable acute GVHD. No statistically significant differences in mean OMI scores, time to engraftment, risk of acute GVHD, days to acute GVHD, risk of relapse or survival were observed when comparing patients taking, on average, 400 mug (28%) folic acid per day. Our results suggest that concurrent folic acid supplementation does not change MTX effectiveness or toxicity in this patient population.Bone Marrow Transplantation (2006) 37, 687-692. doi:10.1038/sj.bmt.1705303; published online 27 February 2006.
Folic acid supplementation during methotrexate immunosuppression is not associated with early toxicity, risk of acute graft-versus-host disease or relapse following hematopoietic transplantation.
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Ruth MC,
Old WM,
Emrick MA,
Meyer-Arendt K,
Aveline-Wolf LD,
Pierce KG,
Mendoza AM,
Sevinsky JR,
Hamady M,
Knight RD,
Resing KA,
Ahn NG
An important strategy for “shotgun proteomics” profiling involves solution proteolysis of proteins, followed by peptide separation using multidimensional liquid chromatography and automated sequencing by mass spectrometry (LC-MS/MS). Several protocols for extracting and handling membrane proteins for shotgun proteomics experiments have been reported, but few direct comparisons of different protocols have been reported. We compare four methods for preparing membrane proteins from human cells, using acid labile surfactants (ALS), urea, and mixed organic-aqueous solvents. These methods were compared with respect to their efficiency of protein solubilization and proteolysis, peptide and protein recovery, membrane protein enrichment, and peptide coverage of transmembrane proteins. Overall, approximately 50-60% of proteins recovered were membrane-associated, identified from Gene Ontology annotations and transmembrane prediction software. Samples extracted with ALS, extracted with urea followed by dilution, or extracted with urea followed by desalting yielded comparable peptide recoveries and sequence coverage of transmembrane proteins. In contrast, suboptimal proteolysis was observed with organic solvent. Urea extraction followed by desalting may be a particularly useful approach, as it is less costly than ALS and yields satisfactory protein denaturation and proteolysis under conditions that minimize reactivity with urea-derived cyanate. Spectral counting was used to compare datasets of proteins from membrane samples with those of soluble proteins from K562 cells, and to estimate fold differences in protein abundances. Proteins most highly abundant in the membrane samples showed enrichment of integral membrane protein identifications, consistent with their isolation by differential centrifugation.
Analysis of membrane proteins from human chronic myelogenous leukemia cells: comparison of extraction methods for multidimensional LC-MS/MS.
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Imamura M,
Asano S,
Harada M,
Ikeda Y,
Kato K,
Kato S,
Kawa K,
Kojima S,
Morishima Y,
Morishita Y,
Nakahata T,
Okamura J,
Okamoto S,
Shiobara S,
Tanimoto M,
Tsuchida M,
Atsuta Y,
Yamamoto K,
Tanaka J,
Hamajima N,
Kodera Y
A nationwide survey of hematopoietic cell transplantation (HCT) was started in Japan in 1991, and the analyzed survey data have been presented as the annual report of the Japan Society for Hematopoietic Cell Transplantation. The 10-year overall survival (OS) rates after HCT for each disease are as follows: acute myelogenous leukemia, 44.2%; acute lymphocytic leukemia, 33.7%; adult T-cell leukemia, 24.6%; chronic myelogenous leukemia, 53.3%; myelodysplastic syndrome, 37.3%; non-Hodgkin’s lymphoma, 41.5%; Hodgkin’s lymphoma, 50.8%; aplastic anemia, 72.5%; breast cancer, 37.1%; germ cell tumor, 52.6%; and ovarian cancer, 44.2%. The 5-year OS rates for multiple myeloma and lung cancer were 40.6% and 23.6%, respectively. Except in cord blood transplantation, engraftment was accomplished in more than 90% of patients. The respective frequencies of acute graft-versus-host disease (GVHD) and chronic GVHD were 41.1% and 34.9% for related bone marrow transplantation (BMT), 66.8% and 34.5% for unrelated BMT, 52.9% and 36.0% for allogeneic peripheral blood stem cell transplantation, and 53.3% and 32.1% for allogeneic cord blood transplantation. OS for each disease was analyzed by patient age, stem cell source, donor type, disease status, and disease type. These data provide objective and valuable information for hematologists as well as for patients who need HCT.
Current status of hematopoietic cell transplantation for adult patients with hematologic diseases and solid tumors in Japan.
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The role of signal transducers and activators of transcription (STAT)5 in chronic myelogenous leukemia (CML) is controversial. To clarify the role of STAT5 signaling in P210(BCR/ABL) leukemogenesis, P210 was introduced into primary murine STAT5A-deficient (-/-) bone marrow (BM) cells, which unlike STAT5A/5B double knockout BM cells, have no major intrinsic hematopoietic defects. Interestingly, only 21% of mice reconstituted with P210-transduced STAT5A (-/-) BM cells developed classic CML, compared to 80-100% of P210/STAT5A (+/+) and P210/STAT5A (+/-)-reconstituted animals. The remainder of P210/STAT5A (-/-) animals died from an acute B-cell lymphoblastic leukemia (ALL)-like disease (32%) or a CML/ALL mix (47%), reflecting impairment in the induction and maintenance of CML, which normally predominates in this mouse model. Of mice that ultimately developed CML, P210/STAT5A (-/-) animals had prolonged survival and increased myeloid immaturity. Importantly, reconstitution of wild-type mice with BM cells co-expressing P210 and dominant negative STAT5 also profoundly reduced the incidence of CML, without impairing the induction of ALL. Altogether, these findings indicate that STAT5 and STAT5A play an important role in the pathogenesis of the CML-like disease in mice. A greater understanding of the STAT5 target genes involved in CML induction may lead to new therapeutic targets that influence CML progenitor cell biology.
STAT5 signaling is required for the efficient induction and maintenance of CML in mice.
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Dysregulation of receptor tyrosine kinase (RTK) activity has been implicated in the progression of a variety of human leukemias. Most notably, mutations and chromosomal translocations affecting regulation of tyrosine kinase activity in the Kit receptor, the Flt3 receptor, and the PDGFbeta/FGF1 receptors have been demonstrated in mast cell leukemia, acute myeloid leukemia (AML), and chronic myelogenous leukemias (CML), respectively. In addition, critical but non-overlapping roles for the Ron and Kit receptor tyrosine kinases in the progression of animal models of erythroleukemia have been demonstrated [Persons, D., Paulson, R., Loyd, M., Herley, M., Bodner, S., Bernstein, A., Correll, P. and Ney, P., 1999. Fv2 encodes a truncated form of the Stk receptor tyrosine kinase. Nat. Gen. 23, 159-165.; .]. The various classes of RTKs implicated in the progression of leukemia have been recently reviewed ]. Here, we will discuss the mechanism by which alterations in these receptors result in transformation of hematopoietic cells, in the context of what is known about the molecular regulation of RTK activity, with a focus on our recent studies of the Ron receptor tyrosine kinase.
Molecular regulation of receptor tyrosine kinases in hematopoietic malignancies.
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Leukemic bcr-abl positive dendritic cells (DCs) are likely to be present in vivo in chronic myelogenous leukemia (CML) patients, but no data are available on their functional qualities. We analyzed the circulating BDCA-1+ myeloid DC compartment in 15 chronic phase CML patients. Phenotypic features of CML DCs were comparable with that of normal DCs, except for the CD80 and CD40 antigens, significantly under-represented in CML patients. Nonetheless, no differences were found between normal samples and leukemic DCs in the allostimulatory ability, as well as in the production of cytokines and polarization of T cell responses. CML DCs were analyzed by fluorescence in situ hybridization (FISH) and found positive for the bcr-abl translocation. However, when bcr-abl+ DCs were tested for their ability to stimulate an autologous T-cell response in vitro, we could not detect a specific recognition. We conclude that an apparently normal circulating DC compartment carrying the Ph+ chromosome can be identified in CML patients; however, these cells appear unable to trigger a protective anti-leukemic immune response in autologous T cells.
Circulating myeloid dendritic cell directly isolated from patients with chronic myelogenous leukemia are functional and carry the bcr-abl translocation.
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Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder that is characterized by the presence of a reciprocal translocation between chromosomes 9 and 22 and results in the formation of the Philadelphia (Ph1) chromosome and is present in most of CML patients. The Ph1 chromosome forms a chimeric gene that encodes an abnormal P210 mRNA transcript in most CML patients. Surveillance for minimal residual disease by detection of BCR/ABL transcripts is currently done mostly by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Quantitation of BCR/ABL transcripts can monitor tumor load and the outcome of therapy. Absolute quantification determines the input copy number of the transcript of interest, usually by plotting the amount of PCR product onto a standard curve based on serial dilutions of the same product cloned in plasmids. Relative quantification describes the change in expression of the target gene in the patient sample relative to that of a control transcript by using the 2-DeltaDeltaCt calculation. The results of real-time RT-PCR for BCR/ABL transcripts are often analyzed by using plasmid DNA standard curves. In the present study, 79 BCR/ABL transcript-positive samples from CML patients who were being monitored for minimal residual disease by real-time quantitative RT-PCR were studied to determine whether the 2-DeltaDeltaCt approach was equivalent to the plasmid standard curve method. BCR/ABL P210 transcripts were quantitated using both the plasmid standard curve method and the 2-DeltaDeltaCt calculation. The comparison of both methods revealed a highly significant and linear correlation between the plasmid standard curve method and the 2-DeltaDeltaCt calculation (R2=0.98, PValidation of the 2-DeltaDeltaCt calculation as an alternate method of data analysis for quantitative PCR of BCR-ABL P210 transcripts.
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BACKGROUND: The t(3;21)(q26;q22) translocation is associated with myeloid leukemias and results in a chimeric oncoprotein containing AML1/RUNX1 variably fused to EAP, MDS1, and/or EVI1. METHODS: The current study describes what to the authors’ knowledge is the first large case series reported to date of 26 t(3;21)(q26;q22)-associated leukemias, in which 24 cases arose after chemotherapy. Conventional G-band karyotyping and flow cytometry immunophenotyping were performed. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect fusion transcripts between AML1 and EAP, MDS1, or EVI1, followed by DNA sequencing. RESULTS: In all 16 patients with chronic myeloproliferative disorders, including 14 with chronic myelogenous leukemia (CML), the occurrence of t(3;21) heralded myeloid blast transformation. Fifteen (93%) patients had been previously treated with hydroxyurea. Eight patients with chronic myeloproliferative disorders (CMPD) were found to have t(3;21) with t(9;22) as the sole cytogenetic abnormality; in 5 other patients this was accompanied by trisomy 8. Among 10 cases of t(3;21)-associated acute myeloid leukemia, 8 were secondary tumors after chemotherapy for other neoplasms that had been treated with regimens including fludarabine and 5-fluorouracil in 3 patients each and etoposide in 2 patients. The immunophenotype of the blasts in all 22 tested cases was similar, with uniform expression of myeloid markers and CD34 and variable expression of CD7 and CD9, but minimal morphological myeloid maturation. Dysplastic micromegakaryocytes and bone marrow fibrosis were observed predominantly in CMPD cases. RT-PCR followed by DNA sequencing showed that the AML1-/MDS1-/EVI1 (AME) fusion transcript was detected in all 5 cases assessed. Among the patients with CMPD, 8 died of disease (at a median of 6.5 mos) and 5 achieved disease remission with bone marrow transplantation. Among patients with acute myeloid leukemia/myelodysplastic syndrome, 7 died of disease (at a median of 2 mos) and 2 had persistent leukemia with short follow-up. CONCLUSIONS: Activation of AME through t(3;21) defines a highly aggressive, therapy-related leukemic blast syndrome. Prior treatment with hydroxyurea or other antimetabolites is implicated as a contributory cause. Cancer 2006. (c) 2006 American Cancer Society.
t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy.
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Identification of cytotoxic T lymphocyte (CTL) epitopes from additional tumor antigens is essential for the development of specific immunotherapy of malignant tumors. CML28, a recently discovered cancer-testis (CT) antigen from chronic myelogenous leukemia, is considered to be a promising target of tumor-specific immunotherapy. Because HLA-A*0201 is one of the most common histocompatibility molecule in Chinese, we aim at identifying CML28 peptides presented by HLA-A*0201. A panel of CML28-derived antigenic peptides was predicted using a computer-based program. Four peptides with highest predicted score were synthesized and tested for their binding affinities to HLA-A*0201 molecule. Then these peptides were assessed for their immunogenicity to elicit specific immune responses mediated by CTLs both in vitro, from PBMCs sourced from four healthy HLA-A*0201(+) donors, and in vivo, in HLA-A*0201 transgenic mice. One of the tested peptides, CML28((173-181)), induced peptide-specific CTLs in vitro as well as in vivo, which could specifically secrete IFN-gamma and lyse major histocompatibility complex (MHC)-matched tumor cell lines endogenously expressing CML28 antigen and CML28((173-181) )pulsed Jurkat-A2/Kb cells, respectively. These results demonstrate that CML28((173-181) )is a naturally processed and presented CTL epitope with HLA-A*0201 motif and has a promising immunogenicity both in vitro and in vivo. As CML28 is expressed in a large variety of histological tumors besides chronic myelogenous leukemia, we propose that the newly identified epitope, CML28((173-181)), would be of potential use in peptide-based, cancer-specific immunotherapy against a broad spectrum of tumors.
Identification of a new HLA-A*0201-restricted cytotoxic T lymphocyte epitope from CML28.
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Dasatinib [BMS 354825] is an orally active, small molecule, dual inhibitor of both SRC and ABL kinases that is under development with Bristol-Myers Squibb for the treatment of patients with chronic myelogenous leukaemia (CML) and imatinib-acquired resistance/intolerance. While imatinib remains a frontline therapy for CML, patients with advanced disease frequently develop resistance to imatinib therapy through multiple mechanisms. These mechanisms include insufficient potency at therapeutic doses, activation of alternate oncogenic pathways, and overexpression of the multidrug-resistant gene. One of the possible causes of imatinib-acquired resistance is associated with increased expression of the SRC-related kinase Lyn and loss of BCR-ABL dependence arising from sequence mutations. In December 2005, Bristol-Myers Squibb announced that it has completed the rolling NDA submission to the US FDA for dasatinib in the treatment of CML in chronic, accelerated or blast phases, as well as Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) in patients with resistance or intolerance to prior treatment. At the Bristol-Myers Squibb R&D Day in May 2005, the company stated that it plans to evaluate dasatinib in solid tumours. In in vitro assays, dasatinib induced apoptosis and had potent activity in the imatinib-resistant tumour cells lines and CML patient specimens. It effectively inhibited the proliferation of cells expressing nearly all imatinib-resistant isoforms. In vivo, dasatinib has shown efficacy, with no apparent toxicity, when administered orally in SCID mice with xenografts of imatinib-sensitive and resistant human CML cells lines. Dasatinib is also undergoing preclinical evaluation for its potential as a therapy against multiple myeloma. Bristol-Myers Squibb has a composition-of-matter patent covering this research approach that will expire in 2020.
Dasatinib: BMS 354825.
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Multidrug resistance (MDR) due to over-expression of the MDR1 (ABCB1) gene and its P-glycoprotein (Pgp) product is an obstacle in the treatment of hematological malignancies. In this study, we have evaluated the potency of KT-5720 to reverse Pgp-dependent MDR in vitro and in vivo. KT-5720 (but not its close derivatives, K252a and K252b) reversed multidrug resistance of LM1/MDR cell line at non-toxic concentrations and increased accumulation of rhodamine 123 (Rh123). KT-5720 significantly reversed MDR1-dependent resistance of primary malignant cells from patients with chronic myelogenous leukemia in blast crisis (CML-BC) and advanced multiple myeloma (MM). Moreover, KT-5720 (at 5mg/kg) sensitized the bone marrow of MDR1 transgenic mice model towards daunorubicin (at 8mg/kg) without general toxic effects. Therefore, KT-5720 can be considered as candidate for combination therapy in various hematological malignancies where Pgp activity is a major impediment for cure.
In vitro and in vivo reversal of MDR1-mediated multidrug resistance by KT-5720: Implications on hematological malignancies.
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Semisynthetic homoharringtonine (ssHHT) is now being evaluated in phase II clinical trials for the treatment of chronic myelogenous leukemia and acute myelogenous leukemia patients. Here, we examined the mechanism of the apoptosis induced by ssHHT in myeloid leukemia cells. First, we have shown that ssHHT induces apoptosis in HL60 and HL60/MRP cell lines in a time- and dose-dependent manner, and independently of the expression of Bax. The decrease of mitochondrial membrane potential and the release of cytochrome c were observed in the apoptotic cells induced by ssHHT. To unveil the relationship between ssHHT and the mitochondrial disruption, we have shown that ssHHT decreased myeloid cell leukemia-1 (Mcl-1) expression and induced Bcl-2 cleavage in HL60 and HL60/MRP cell lines. The Bcl-2 cleavage could be inhibited by the Z-VAD.fmk caspase inhibitor. However, Mcl-1 turnover was very rapid and occurred before caspase activation. The Mcl-1 turnover was only induced by ssHHT and cycloheximide, but not by daunorubicin and cytosine arabinoside, and could be restored by proteasome inhibitors. Second, we confirmed that ssHHT rapidly induced massive apoptosis in acute myelogenous leukemia patient cells. We have also confirmed the release of cytochrome c and a rapid turnover of Mcl-1 in these patient cells, taking place only in apoptotic cells induced by ssHHT but not in cells undergoing spontaneous apoptosis. Finally, we have shown that ssHHT inhibits protein synthesis in both cell line and patient cells. We suggest that the inhibition of protein synthesis and resulting Mcl-1 turnover play a key role in the apoptosis induced by ssHHT. Our results encourage further clinical trials for the use of ssHHT in acute myelogenous leukemia. [Mol Cancer Ther 2006;5(3):723-31].
Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells.
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Thirty-four men and 36 women (median age 43 and 45 years, respectively) underwent stem cell transplantation (SCT) for acute leukaemia in first complete remission or chronic myelogenous leukaemia in first chronic phase between 1981 and 2001 from HLA-identical siblings. The conditioning regimen included TBI and all grafts were partially depleted of T cells. Changes in quality of life (QOL), reproduction and sexuality were studied using a questionnaire, and the previously given information related to these problems was assessed. In addition, endocrine status was assessed and semen analysis was performed. After SCT, patients reported less energy (n=50) and a deterioration in the job situation (n=31). Patients experienced a negative change in sexual relations (n=41). Important problems of sexual dysfunction were vaginal dryness in women (n=19) and erectile dysfunction in men (n=16). None of the patients was fertile based on their gonadotrophin levels, sperm concentrations and reproductive outcomes. Women experienced climacteric symptoms (n=24). Quality of life was negatively influenced by these changes. One-fifth of the patients were not satisfied with the information given with regard to reproduction, premature menopause and sexual problems.Bone Marrow Transplantation advance online publication, 20 March 2006; doi:10.1038/sj.bmt.1705350.
Quality of life, reproduction and sexuality after stem cell transplantation with partially T-cell-depleted grafts and after conditioning with a regimen including total body irradiation.
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Imatinib mesylate is a small molecule tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukaemia (CML). However, it is likely that patients with CML will require prolonged and perhaps life-long therapy. In general, the side-effects of imatinib therapy have been mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side-effects. Here, we describe a novel form of fluid retention presenting as multiple joint effusions in a patient with advanced phase CML on high-dose imatinib, as well as successful measures that were undertaken to control this adverse event. Although fluid retention, including periorbital oedema, pleural and pericardial effusions, as well as life-threatening cerebral oedema have been previously described and attributed to imatinib, this is the first case of imatinib-associated polyarticular effusions that we are aware of. Further work will be required to confirm a casual relationship between imatinib therapy and this novel side-effect, as well as to determine the underlying pathophysiologic mechanisms.
Multiple joint effusions associated with high-dose imatinib therapy in a patient with chronic myelogenous leukaemia.
Posted by rob on March 22, 2006 under Uncategorized |
By JUDITH W. WINNE
Courier-Post Staff
It’s not hard to imagine the crippling stress in Teresa Kao’s life.
Diagnosed with breast cancer in December 2004, the Voorhees patient underwent chemotherapy, surgery and radiation. The deaths of her mother and brother, within six months of her diagnosis, deepened her sorrow, as well as the worry line in her brow.
Now, Kao’s spirits have lifted, helped in great part by a free, local program that emphasizes nontraditional therapies and practices — meditation, restorative yoga, massage, acupuncture and nutrition.
“I think I feel much more serene and much more positive now,” said the 56-year-old Kao. “It made a big difference in my life.”
Next month, the Dr. Diane Barton Complementary Medicine Program at the Cancer Institute of New Jersey at Cooper kicks off a series of nutrition workshops in Voorhees called Fighting Cancer With Food.
The first topic, called Nutrition and Cancer, is April 4. Other sessions for cancer patients will spotlight fatigue-fighting, organic and fiber-rich foods, as well as other nutrition-related subjects.
Alicia Michaux, the cancer institute’s oncology dietitian, noted that for patients who have had treatment for their cancer, there are special problems.
“Fatigue is a common side effect,” said Michaux. “Some of the foods that are more energizing are the foods that are nutrient-dense. For example, foods that have an adequate amount of protein in them, chicken, fish, eggs, low-fat cheese.
“Things that are nutrient-dense aren’t filled with empty calories. I try not to encourage a lot of sugar and processed foods just because they contain a lot of empty calories, and they fill patients up. Protein in the body helps rebuild and replenish muscle mass, so it can actually help patients in their strengthening process, and continue with the treatment and help them fight fatigue.”
Michaux, 30, said a diet of well-balanced, whole foods is the goal. Such meals are obviously a smart choice for everyone, whether they have cancer or not.
The emphasis is on sensible, rather than fad or oddball, diets. Advocates in the program stress the word complementary, rather than alternative, medicine.
Their point is that the medicine is meant as an adjunct to surgery, radiation and chemotherapy, not an alternative to them.
Indeed, the program is named for Dr. Diane Barton of Moorestown, a beloved physician who died of ovarian cancer last summer.
“This was her dream,” said Bonnie Mehr, who heads the complementary medicine program and was Barton’s friend for a decade. “Diane believed in the mind/body connection.”
Dr. Generosa Grana, Barton’s friend and oncologist, said Barton had pushed her to get a program going. Grana, the director of Cooper’s cancer institute, noted that patients find practices like restorative yoga useful and healing.
“It helps them deal, not just with the physical, but the emotional, aspects of the disease,” said Grana.
Food is woven into the fabric of the complementary medicine program. At Live, Lunch and Learn sessions, participants munch on healthy, free lunches as Cindy Faust leads members in discussions that range from anger to sexuality. (The next session is 11:30 a.m. March 30 .)
“Food has to become a lifestyle,” said Faust, a Cherry Hill clinical social worker who battled breast cancer more than a quarter century ago.
“Eating healthy is fun,” said Faust. “It’s creative. It doesn’t have to be difficult at all. And it helps you take responsibility for your own health. It’s something you can do.”
Faust, now 56, turned to vegetarianism.
“I believe it helped keep me alive,” she said.
Good nutrition is often a priority, or should be, for those battling a serious illness and those who want to prevent cancer. The American Institute for Cancer Research, an organization that fosters research on diet and cancer prevention, notes that the majority of research on diet and cancer suggests eating fruit, vegetables, whole grains and beans will lower the risk of developing cancer.
Antioxidants in blueberries and tomatoes have been tagged as cancer-fighting foods. Of course, patients have no guarantees that a diet rich in fruits, vegetables and whole grains will prevent cancer or its reoccurrence. But like any insurance policy consumers buy, a good diet is surely a sound investment.
“I’m very conscious of food and nutrition,” said Mary McCall of Deptford. McCall received a grim diagnosis of Stage Four bladder cancer seven years ago. Remarkably, she recovered. Three years ago, she was diagnosed with chronic myelogenous leukemia. There is no cure, but her treatment is an oral form of chemotherapy, said the 64-year-old McCall.
McCall, 64, has found yoga helpful in coping with pain and swelling in her legs, a result of cancer surgery.
A huge fan of the complementary medicine program, she nevertheless noted the toll cancer has taken.
“You’re a wounded warrior,” she said.
Barton, the complementary medicine program’s namesake, a woman who died too young at 46, would have likely understood.
“She was one gutsy lady who tried everything and fought for what she believed in,” said Faust. “It (the program) is a fitting tribute to her.”
Reach Judith W. Winne at (856) 486-2441 or jwinne@courierpostonline.com
Published: March 22. 2006 3:00AM
CourierPostOnline – South Jersey’s Web Site
Posted by rob on March 20, 2006 under Uncategorized |
MELBOURNE, Australia and MENLO PARK, Calif., March 19 /PRNewswire-FirstCall/ -- ChemGenex Pharmaceuticals Limited (Nasdaq: CXSP; ASX: CXS)announced today that the United States Food and Drug Administration (FDA) hasgranted Orphan Drug status for the company's most advanced drug, Ceflatonin,for the treatment of chronic myeloid leukemia (CML). Ceflatonin is the firstof a new class of novel drugs that induces apoptosis (programmed cell death)and inhibits angiogenesis (new blood vessel formation). Ongoing or soon to beinitiated clinical trials are and will be evaluating Ceflatonin in a broadrange of conditions, including: chronic myeloid leukemia (CML),myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Orphan drug status is granted by the FDA to promote the development ofdrugs for diseases affecting less than 200,000 people in the United States.Orphan drug status entitles ChemGenex to seven years of market exclusivity forthe use of Ceflatonin in the treatment of CML; protocol assistance by the FDAto optimize drug development in the preparation of a dossier that will meetregulatory requirements; and reduced fees associated with applying for marketapproval. A similar designation for Ceflatonin in the European market, with similaradvantages, was granted by the European Union on September 9, 2004, based on apositive recommendation by the Committee for Orphan Medicinal Products (COMP)of the European Medicines Agency (EMEA). The European Union granted Ceflatoninorphan status on October 20, 2004 for the treatment of acute myeloid leukemia(AML). "The decision by the U.S. FDA to grant Ceflatonin orphan drug status forCML is further incentive to move Ceflatonin as quickly as possible through theclinical development and regulatory approval process worldwide," said GregCollier, ChemGenex chief executive officer and managing director. "We are veryencouraged by the growing body of clinical data on Ceflatonin in resistantCML, MDS and AML, and by the ongoing support of key opinion leaders in thefield. Now with the granting of Orphan Drug status by the FDA, we are fullycommitted to accelerate our development efforts to help address the unmetmedical needs of CML patients worldwide."
About Ceflatonin(R) Ceflatonin (HHT) is a potent inducer of apoptosis (programmed cell death)in myeloid cells and inhibits angiogenesis (blood vessel formation).Ceflatonin has confirmed Phase 2 clinical activity in resistant CML, both as asingle agent and in combination with other approved drugs. ChemGenex isdeveloping Ceflatonin for the treatment of CML, myelodysplastic syndrome (MDS)and acute myeloid leukemia (AML).
Recent studies have demonstrated that Ceflatonin has potential in CMLpatients who are developing resistance to tyrosine kinase inhibitor (TKI)therapy, including Gleevec(R), and in-combination with TKI's in early stageCML to increase the cytogenetic and molecular response rate. A summary of recent clinical data on Ceflatonin includes the followingstudies:
* In a nine patient single-agent Phase 1/2 study in accelerated-phase CML who had become resistant to Gleevec, seven (80%) patients returned to chronic-phase and 6 (67%) achieved a complete hematologic response.
* In a separate five patient single-agent Phase 2 study in late chronic-phase CML, five (100%) achieved a complete hematologic response and two (40%) achieved a cytogenetic response. Two patients with detectable resistance mutations achieved a complete hematologic response and their mutations (p-loop) were not longer detectable after Ceflatonin treatment.
* In another recent 10 patient Phase 1/2 study, Ceflatonin was added to Gleevec in patients who had a partial or complete cytogenetic response, in order to reduce bcr-abl transcript counts further. Seven (70%) patients had a significant decrease in bcr-abl counts. Two patients with partial cytogenetic responses achieved complete cytogenetic responses. Two patients achieved a complete molecular response, or not detectable evidence of residual disease.
* Pre-clinical studies on Ceflatonin have shown both additive and synergistic activity when combined with Gleevec, as measured by a reduction in the marker (bcr-abl protein expression) that is a hallmark of resistance in CML.
A multinational Phase 2/3 study in CML patients harboring the T315I pointmutation, known to confer complete resistance to tyrosine kinase (TKI)inhibitors like Gleevec, is scheduled to begin in Q2, 2006. A secondmultinational Phase 2/3 study in CML patients resistant to TKI inhibitors isscheduled to begin soon thereafter. Each study will include centers in theUnited States, Germany, France and Italy. Ceflatonin is not approved by the FDA as a treatment in any indication andis currently being evaluated in clinical trials for efficacy and safety forfuture regulatory applications. Gleevec(R) is a registered trademark of the Novartis PharmaceuticalsCorporation.
About Chronic Myeloid Leukemia Chronic Myeloid Leukemia (CML) is a cancer of the blood cells caused by anacquired genetic defect called the bcr-abl mutation. This defect occurs whengenetic material from two chromosomes (9 and 22) swaps places, creating theso-called Philadelphia chromosome. The bcr-abl mutation interferes with normalcell replication processes, leading to an abnormal proliferation of whiteblood cells. CML usually occurs in adults and typically progresses through threephases. Patients generally are diagnosed in 'chronic phase', progress throughan 'accelerated phase' and then may die if the disease progresses to 'blastphase'. CML incidence is relatively consistent occurring at about 1 to 2 per100,000 people and the global CML market for therapeutics is estimated at inexcess of US$2 billion. Patients with chronic phase CML have been effectively treated in recentyears by the drug Gleevec. However, over time many patients become resistantto the therapeutic effects of the drug and the disease progresses.
About ChemGenex Pharmaceuticals Limited (http://www.chemgenex.com) ChemGenex Pharmaceuticals is a pharmaceutical development companydedicated to improving the lives of patients by developing therapeutics in theareas of oncology, diabetes, obesity, and depression. ChemGenex harnesses thepower of genomics for target discovery and validation, and in clinical trialsto develop more individualized therapeutic outcomes. ChemGenex's leadcompound, Ceflatonin(R), is currently in phase 2/3 clinical trials forleukemia and Quinamed(R) is in phase 2 clinical trials for prostate, breastand ovarian cancers. The company has a significant portfolio of anti-cancer,diabetes, obesity and depression programs, several of which have beenpartnered with international pharmaceutical companies. ChemGenex currentlytrades on the Australian Stock Exchange under the symbol "CXS" and on NASDAQunder the symbol "CXSP".
Safe Harbor Statement Certain statements made herein that use the words "estimate," "project,""intend," "expect," "believe," and similar expressions are intended toidentify forward-looking statements within the meaning of the US PrivateSecurities Litigation Reform Act of 1995. These forward-looking statementsinvolve known and unknown risks and uncertainties which could cause the actualresults, performance or achievements of the company to be materially differentfrom those which may be expressed or implied by such statements, including,among others, risks or uncertainties associated with the development of thecompany's technology, the ability to successfully market products in theclinical pipeline, the ability to advance promising therapeutics throughclinical trials, the ability to establish our fully integrated technologies,the ability to enter into additional collaborations and strategic alliancesand expand current collaborations and obtain milestone payments, thesuitability of internally discovered genes for drug development , the abilityof the company to meet its financial requirements, the ability of the companyto protect its proprietary technology, potential limitations on the company'stechnology, the market for the company's products, government regulation inAustralia and the United States, changes in tax and other laws, changes incompetition and the loss of key personnel. These statements are based on ourmanagement's current expectations and are subject to a number of uncertaintiesthat could change the results described in the forward-looking statements.Investors should be aware that there are no assurances that results will notdiffer from those projected.
SOURCE ChemGenex Pharmaceuticals Limited
Web Site: http://www.chemgenex.com
Orphan Drug Designation Granted by the U.S. FDA for Ceflatonin(R)
Posted by rob on March 19, 2006 under Uncategorized |
Contact: Juliette Savin
press@biomedcentral.com
44-207-631-9931
BioMed Central
Cancer cells lose drug resistance following electrical stimulation in vitro
Drug-resistant tumour cells lose their drug resistance when exposed to low intensity, low frequency electric pulses for three days. A study published today in the open access journal BMC Cancer reveals that treating drug-resistant tumour cells with electric pulses in vitro restores the cells’ ability to take up the anti-cancer drug doxorubicin.
The research group led by Luca Cucullo and Damir Janigro from the Cleveland Clinic Lerner College of Medicine, Ohio, USA exposed rat and human tumour cells to very low intensity (7.5 microamps) 50 Hertz alternating current pulses, with a ten-second interval, for three days in vitro. Such electrical stimulation is known not to damage cells but to decrease the proliferation of tumour cells. The tumour cell lines used overexpress the MDR1 protein, which makes them resistant to anti-cancer drugs such as doxorubicin. Following the three days of electrical stimulation, the cells were exposed to increasing concentrations of doxorubicin for three hours.
Janigro et al.’s results show that electrical stimulation led to an increased uptake of doxorubicin, which caused the cells to die, even at low doxorubicin concentrations. Exposing the cells to an electric current was more effective than treating the cells with an MDR1 inhibitor. These findings suggest the potential application of electrical stimulation to improve the efficacy of existing chemotherapeutic treatments.
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Article:
Alternating current electrical stimulation enhanced chemotherapy: a novel strategy to bypass multidrug resistance in tumor cells
Damir DJ Janigro, Catalin CP Perju, Vincent VF Fazio, Kerri KLH Hallene, Gabriele GD Dini, Mukesh MKA Agarwal and Luca LC Cucullo
BMC Cancer 2006, (in press)
Cancer cells lose drug resistance following electrical stimulation in vitro
