Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ASCO 2001 was a banner year for innovative systemic therapy for sarcomas. Imatinib mesylate (STI571, Gleevec) shows clear activity not only in chronic myelogenous leukemia, for which the drug received Food and Drug Administration approval, but also in gastrointestinal stromal tumors as well, by virtue of imatinib mesylate binding to the abl, kit, and platelet-derived growth factor receptor tyrosine kinases. Ecteinascidin-743 (ET-743) demonstrates activity against a fraction of other soft-tissue sarcomas. Gemcitabine-based regimens show at least some activity against a subset of soft-tissue sarcomas. Given the lack of new agents for sarcoma therapy since the development of ifosfamide, these studies give hope that the term "effective systemic therapy for sarcoma" might become a reality.
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PMID:Sarcoma. 1152 51

Developing drugs to specifically inhibit oncogenes has been a major goal of cancer research for many years. Identifying the appropriate intracellular targets and understanding the signal transduction pathways in which these molecules participate are critical to this process. A large number of the activated oncogenes implicated in the pathogenesis and progression of malignancy are tyrosine kinases. Bcr-Abl, the causative molecular abnormality in chronic myeloid leukemia (CML), is a prototypic oncogenic kinase and an attractive drug target. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) was recently approved for the treatment of CML and provides proof of principle for the strategy of targeted signal transduction inhibition. This drug is effective in the chronic phase of CML, a single gene disorder driven by Bcr-Abl, and in the advanced phases of CML, showing that inhibition of a single oncogene in a multigene disorder also may be of benefit. The success of imatinib mesylate in CML led rapidly to clinical trials in other cancers associated with activation of two other tyrosine kinases known to be sensitive to imatinib mesylate, c-Kit and the platelet-derived growth factor receptor. Gastrointestinal stromal tumors, which have activating mutations in c-Kit, are now also being found to respond to kinase inhibition with the drug. The general approach of specifically targeting activated kinases with small-molecule drugs is likely to be effective in other tumors in the future.
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PMID:The biology of signal transduction inhibition: basic science to novel therapies. 1174 Aug 1

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors span a wide clinical spectrum from benign to malignant and have long been recognized for their nearly absolute resistance to chemotherapy and radiation treatment. Surgery is the primary treatment modality for GISTs, but GISTs represent an incurable malignancy for patients with metastatic or unresectable disease. Thus, novel approaches to the treatment of GISTs were desperately needed. Gastrointestinal stromal tumors are characterized by expression of the transmembrane receptor tyrosine kinase KIT, which is defined by the CD117 antigen and is the product of the c-kit proto-oncogene. Activating or gain-of-function mutations in the c-kit gene have been identified in the majority of GIST cases. The resulting constitutive KIT tyrosine kinase activity was hypothesized to provide growth and survival signals to GIST cells and to be crucial to the pathogenesis of the disease. This hypothesis became testable with the identification of the signal transduction inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ), which blocks the tyrosine kinase activity of KIT as well as the kinase activity of the normal c-abl gene product, the oncogenic Bcr-Abl chimeric fusion protein of chronic myeloid leukemia, and the platelet-derived growth factor receptor. Preclinical experiments showed rapid inhibition of ligand-independent KIT phosphorylation, decreased cellular proliferation, and induction of apoptosis after exposure of GIST cells to imatinib mesylate in vitro. These results provided the rationale to move forward with clinical testing of imatinib mesylate as an anticancer therapy for GIST. In early 2000, a dramatic clinical and radiographic response to imatinib mesylate was shown in a single patient with advanced, chemotherapy-resistant GIST. The powerful scientific rationale for this proof-of-concept study, together with the durable and significant response observed in this first GIST patient treated with imatinib mesylate, have provided the driving force for rapid clinical development of this targeted therapy in this solid tumor indication.
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PMID:Targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options. 1174 Aug 3

The development of the targeted signal transduction inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) has prompted new ways of thinking about the treatment of chronic myeloid leukemia, other sensitive solid tumors such as gastrointestinal stromal tumors, and malignancies in general. The stresses associated with the extraordinary pace of testing and approval of imatinib mesylate provide lessons to government regulatory agencies, pharmaceutical companies, university researchers, professional societies, and the media in terms of their approach to cancer care, drug development, and dissemination of information. Such medical breakthroughs can generate an enormous, and occasionally overwhelming, volume of new information to be assimilated; misinformation and exaggeration should be avoided. Furthermore, in today's Internet age of information, a large fraction of a patient's medical knowledge and/or opinions may have been obtained and forged online, with input from other patients, and patients are clearly more informed about their illnesses and their options than in the past. The availability of imatinib mesylate has already profoundly changed the nature and sequence of treatment recommendations for patients with chronic myeloid leukemia, but a great deal still remains to be learned and new clinical trials must be designed to address numerous questions about the optimal use of this powerful new medication.
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PMID:Signal transduction inhibition: changing paradigms in cancer care. 1174 Aug 5

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the digestive tract, are believed to arise from the interstitial cells of Cajal. GISTs are characterized by mutations in the proto-oncogene KIT that lead to constitutive activation of its tyrosine kinase activity. The tyrosine kinase inhibitor STI571, active against the BCR-ABL fusion protein in chronic myeloid leukemia, was recently shown to be highly effective in GISTs. We used 13,826-element cDNA microarrays to define the expression patterns of 13 KIT mutation-positive GISTs and compared them with the expression profiles of a group of spindle cell tumors from locations outside the gastrointestinal tract. Our results showed a remarkably distinct and uniform expression profile for all of the GISTs. In particular, hierarchical clustering of a subset of 113 cDNAs placed all of the GIST samples into one branch, with a Pearson correlation >0.91. This homogeneity suggests that the molecular pathogenesis of a GIST results from expansion of a clone that has acquired an activating mutation in KIT without the extreme genetic instability found in the common epithelial cancers. The results provide insight into the histogenesis of GIST and the clinical behavior of this therapeutically responsive tumor.
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PMID:Gastrointestinal stromal tumors with KIT mutations exhibit a remarkably homogeneous gene expression profile. 1175 74

Landmark clinical studies of new drugs developed to target specific forms of cancer were reported in 2001. Herceptin, a monoclonal antibody against the Her2/neu receptor tyrosine kinase, prolonged the survival of women with Her-2/neu positive metastatic breast cancer, when combined with chemotherapy. STI-571, a small molecule inhibitor of the Bcr-Abl, c-kit and platelet derived growth factor receptor tyrosine kinases, produced dramatic clinical responses in patients with Bcr-Abl positive chronic myeloid leukemia and c-kit positive gastrointestinal stromal tumors. These examples have galvanized the cancer research community to extend kinase-inhibitor therapy to other cancers.
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PMID:Rational therapeutic intervention in cancer: kinases as drug targets. 1179 May 64

The field of oncology is experiencing a paradigm shift from broad-spectrum cytotoxic therapies to more specific molecularly based targeted therapies. The activity of imatinib mesylate in chronic myelogenous leukemia and gastrointestinal stromal tumors (GIST) has reinforced our faith in translational research and its potential impact on the cure of cancer and improvement in quality of life for patients. This breakthrough has been particularly exciting for the field of sarcoma and for patients with advanced GIST, for whom no other effective therapy was available. Unfortunately, as is becoming increasingly clear, cancer is a very complex problem with multiple mechanisms and pathways that function either independently or interdependently enabling cell survival. We are therefore far away from having solved the problem. Attempts at refining the currently available therapeutic armamentarium to maximize the therapeutic index (dose intensification with growth factor support) must continue in parallel with laboratory-based research identifying critical targets to be inhibited or blocked. Identification of new agents with some activity, such as gemcitabine and ecteinascidin (ET-743), is also of paramount importance.
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PMID:Systemic therapy for advanced soft-tissue sarcomas. 1204 39

Novartis has launched imatinib, an inhibitor of tyrosine kinases, including Bcr-Abl, for the treatment of chronic myeloid leukemia (CML). Imatinib selectively inhibits activation of target proteins involved in cellular proliferation. It also inhibits c-KIT tyrosine kinase activity and is equally effective against both wild-type and constitutively active enzyme. Close correlation between in vitro responses to IFNalpha and imatinib suggested that it may be an alternative to IFNalpha therapy for chronic-phase CML, and the compound has the advantage that it can be administered orally. Futhermore, Bcr-Abl-expressing cells treated with imatinib undergo apoptosis. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. In February 2002, the FDA approved imatinib for the treatment of inoperable and/or metastatic malignant gastrointestinal stromal tumors (GIST); in September 2001, launch for the indication was expected in 2002. In November 2000, imatinib was granted Orphan Drug status in Japan for the target indication of Philadelphia chromosome-positive leukemia. By May 2001, imatinib had entered phase II trials for small cell lung cancer, prostate cancer and glioma. Imatinib has been launched in more than 35 countries, including the US, Brazil, Switzerland, Australia and the UK. By December 2001, the drug had also been launched in Japan. The drug is marketed as Gleevec (imatinib mesilate) in the US, and Glivec (imatinib) outside the US. In August 2001, Deutsche Bank estimated sales of SFr 233 million in 2001, rising to SFr 850 million in 2005; while Bear Stearns & Co predicted sales of SFr 250 million in 2001, rising to SFr 800 million in 2005.
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PMID:Imatinib. Novartis. 1205 2

Cancer therapy directed at specific, frequently occurring molecular alterations in signaling pathways of cancer cells has been validated through the clinical development and regulatory approval of agents such as Herceptin for the treatment of advanced breast cancer and Gleevec for chronic myelogenous leukemia and gastrointestinal stromal tumors. While most novel, target-directed cancer drugs have pregenomic origins, one can anticipate a postgenomic wave of sophisticated "smart drugs" to fundamentally change the treatment of all cancers. With these prospects, interest in this new class of therapeutics extends from basic research scientists to practicing oncologists and their patients. An extension of the initial successes in molecular oncology will occur more quickly and successfully through an appreciation of lessons learned with the first group of agents in their progress through clinical development.
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PMID:Smart drugs: tyrosine kinase inhibitors in cancer therapy. 1208 69

Imatinib is an example of a new group of drugs being developed using the principle of molecular targeting. Imatinib is able to kill the cancer cells and not the body's healthy cells. Imatinib mesylate is indicated for the treatment of patients with Kit (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors and patients with Philadelphia chromosome-positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alfa.
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PMID:Imatinib mesylate. 1212 63


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