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)

The term "targeted cancer therapies" refers to treatment strategies designed to inhibit the product of an oncogene involved in the process of neoplastic transformation. Different categories of targeted therapies can be identified: 1) Therapies directed at oncogenes that are directly involved in the initiation of neoplastic transformation: the use of imatinib for the treatment of CML or GIST is the classical model in this subgroup. Single agent targeted therapies generally produce high response rates in this situation. 2) Therapies directed at oncogenes involved at a later stage of neoplastic transformation. These oncogenes contribute to tumor progression but not necessarily to the onset of malignant transformation. The use of trastuzumab for HER2-amplified breast adenocarcinoma is the classical model in this subgroup. These treatments are associated with low response rates when used as single agent therapy, whereas generally displaying a synergistic or additive effect with classical chemotherapy in models currently available. In contrast, when these targeted therapies are applied to tumor models where the targeted gene is present but not directly involved in the process of malignant transformation, no antitumor efficacy is generally observed. Recently, the identification of HER1 mutations in subsets of lung carcinoma as a predictive factor for response to gefitinib and erlotinib provided an example of how the empiric use of a targeted treatment may enable to identify new nosological entities. The present paper reviews examples of targeted cancer therapies and their results.
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PMID:Targeted cancer therapies. 1574 38

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.
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PMID:The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. 1589 16

Pancreatic cancer (PanC) is an extremely lifethreatening neoplasm due to its late discovery, rapid progression and resistance to chemo- and radiotherapy. In the past years a significant research attention turned to this cancer. Extensive genomic analysis of PanC revealed numerous alterations, however, none of them emerged yet as a key regulator of tumor progression. Our increasing knowledge on the molecular targets in various cancer types started to change their management. Examples of success of the molecular therapies (in CML, GIST, NSCLC) may initiate more activity in pancreatic cancer as well.
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PMID:Genomics of pancreatic cancer: does it make any improvement in diagnosis, prognosis and therapy? 1599 49

The phenylaminopyrimidine-derivate Imatinib mesylate has been developed for targeted inhibition of the Abelson kinase (c-ABL), which is constitutively activated when translocated to the genetic locus of the breakpoint cluster region (leading to the BCR/ABL fusion gene), thereby forming the causative pathogenetic event for the development of chronic myeloid leukemia (CML). Of note, due to its physico-chemical properties, kinase specificity of Imatinib is limited. Despite of its well documented clinical efficacy mediated by inhibition of constitutively activated tyrosine kinases such as BCR/ABL in CML, PDGF-RA in HES and mutated c-kit in GIST patients, other tyrosine kinases such as Flt-3, Lck and mitogen-activated kinases (MAPK) are affected as well. Accordingly, it has recently been shown that therapeutic doses of Imatinib also target a variety of immune cells, e.g. by modulating the differentiation of dendritic cells (DC) as well as by impeding proper T-cell and macrophage function. In contrast, combining Imatinib with Interleukin 2 (IL-2) potently activates NK-cells and led to the description of a new subclass of DC, so-called IK-DC. The latter mediate Imatinib/IL-2-induced regression of tumors in pre-clinical animal models via production of high amounts of IFN-gamma and the death receptor ligand TRAIL. Thus, Imatinib exerts potent immuno-modulatory effects in vitro and in vivo, which will be discussed together with their clinical relevance in detail throughout this review.
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PMID:The kinase inhibitor imatinib--an immunosuppressive drug? 1750 22

Imatinib mesilate, which efficiently inhibits BCR-ABL,and KIT as well as platelet-derived growth factor receptor (PDGF-R) kinases, is highly effective for clinical treatment of CML, Ph+ALL, and advanced GIST with good tolerability, respectively. Acquired resistance to the drug,however, becomes an clinically emerging problem with long-standing use. Meanwhile, sunitinib malate,which inhibits three VEGF-Rs and FLT 3 in addition to KIT as well as PDGF-R, was clinically evaluated in the phase II clinical trials for imatinib-resistant or intolerant GIST, and advanced renal cell carcinoma in Japan. Sunitinib is therapeutically effective for both on imatinib-resistant GIST and advanced renal cell carcinoma with modest tolerability, and is now under review for approval in Japan.
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PMID:[Imatinib . Sunitinib]. 1768 1

Imatinib mesylate (imatinib) inhibits the c-Kit-dependent tyrosine kinase activities and highly effective in the treatment of CML and GIST patients. Although pancreatic cancer is reported to express c-Kit, imatinib does not effectively inhibit pancreatic cancer cell growth at physiological concentrations. Therefore, we investigated the mechanism of resistance of pancreatic cancer to imatinib treatment. Imatinib inhibited growth of pancreatic cancer cell lines in concentration and time-dependent fashion regardless of c-Kit expression. However, 5 microM imatinib, which is almost a mean maximal plasma concentration in clinical setting, failed to suppress pancreatic cancer cell growth. Western blot analysis demonstrated that 5 microM imatinib treatment for 1h activated the MEK-MAPK pathway and the activation was independent of Ras activation. Administration of 5 microM imatinib and 1 microM U0126 (MEK inhibitor) significantly suppressed pancreatic cell growth. Our results indicate that a combination therapy of imatinib and MEK inhibitor can be a new therapeutic strategy to suppress the progression of pancreatic cancer.
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PMID:MEK inhibitor enhances the inhibitory effect of imatinib on pancreatic cancer cell growth. 1834 44

Numerous options are currently available for tumour typing. This has raised intense interest in the elucidation of prognostic and predictive markers. A prognostic biomarker provides information about the patients overall cancer outcome, regardless of therapy, whilst a predictive biomarker gives information about the effect of a therapeutic intervention. A predictive biomarker can be a target for therapy. Amongst the genes that have proven to be of relevance are well-known markers such as ER, PR and HER2/neu in breast cancer, BCR-ABL fusion protein in chronic myeloid leukaemia, c-KIT mutations in GIST tumours and EGFR1 mutations in NSCLC. Several reasons for the difficult elucidation of new markers will be addressed including the involvement of cellular pathways in tumour biology instead of single genes and interference in disease outcome as a result of anticancer therapies. Future perspectives for the development of prognostic and predictive markers will be given.
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PMID:Prognostic versus predictive value of biomarkers in oncology. 1839 36

As of today, advanced non-small cell lung cancer is still an incurable disease. However, recent researches on the biology of adenocarcinoma have led to considerable progress in the treatment of this subgroup of patients. The administration of bevacizumab and pemetrexed as first-line therapy, erlotinib in the maintenance phase and erlotinib again combined with vandetanib as second-line therapy, gives patients with lung adenocarcinoma new hope. In particular, in metastatic adenocarcinoma with an EML4-ALK fusion oncogene, crizotinib (a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases), led to a response rate of 64%, which is similar to the results achieved in chronic myeloid leukemia and GIST with imatinib. Overall, the application of all available active therapies during the natural history of adenocarcinoma may lead to a survival benefit that was unimaginable only a few years ago. This article reviews the main studies on molecular targeted therapies in various lines of treatment of advanced lung adenocarcinoma.
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PMID:Targeted therapies and other agents as first-line maintenance and beyond: particular benefit in pulmonary adenocarcinoma patients. 2142 83

Glivec is a drug used in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISI). It is an expensive drug which would be out of reach for most patients in Kenya. Norvatis Pharmaceutical together with Axios International a healthcare management company and Max Foundation have made it possible for patients in developing countries to get access to the drug at no cost. Patients meet the cost of the confirmatory test and are recruited into the programme to receive the drug at no cost. A total of 201 patients are in the programme in Nairobi, mainly drawn from Kenyatta National Hospital the major referral hospital in Kenya. The age range is nine years to 75 years with a mean age of 39.5 years. Males make up 56.5% while females are 43.5%. CML are 173 (86%) while GIST patients are 28 (13.9%). Most of the CML cases are referred in the chronic stable phase (87.8%) and 85.7% have been on hydroxyurea as the initial treatment. Compliance rates are approximately 80%.
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PMID:The GLIVEC international patient assistance programme: the Nairobi experience. 2159 20

A biomarker is defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic/pharmacodynamic responses to a therapeutic intervention". Various assays, including immunohistochemistry, gene constitution such as amplification, mutation, and rearrangement, gene and protein expression analysis such as single gene or protein expression, exhaustive analysis and gene or protein signature and single nucleotide polymorphism have been used to identify biomarkers in recent years. No therapeutic effects have yet been predicted based on the results of such exhaustive gene analysis because of low reproducibility although some correlate with the prognosis of patients. Biomarkers such as HER2 for breast cancer or EGFR mutation for lung cancer and KRAS mutation in colon cancer have contributed to identify a patient population that might show a good and bad treatment response, respectively. On the other hand, other biomarkers such as bcr-abl, c-kit gene mutation and CD20 expression, which are positive for CML, GIST and B cell lymphoma, respectively, have crucial biological significance but have not necessarily been used for practical clinical screening since pathological diagnosis coincide with finding of biomarkers. Hence, much work remains to be done in many areas of biomarker research.
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PMID:Critical comments for roles of biomarkers in the diagnosis and treatment of cancer. 2165 49


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