Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among the most promising agents in clinical development to treat non-small-cell lung cancer (NSCLC) are the epidermal growth factor receptor (EGFR) targeting agents. A series of recent studies have demonstrated the activity of anti-EGFR targeted therapies for NSCLC. In advanced NSCLC that is refractory to chemotherapy, antitumor responses have been reported with EGFR tyrosine kinase inhibitors (ZD1839 and OSI-774). The role of ZD1839 and OSI-774 as possible additions to standard chemotherapy in the first-line setting has also been evaluated, and the studies conducted to date should respond to the question of whether these compounds could provide a survival benefit. Other areas of research involve looking at the role of EGFR tyrosine kinase inhibitors in the neoadjuvant treatment of stage III NSCLC and the planning of chemoprevention studies. These exciting results and plans are further complemented by an emerging number of compounds in clinical development, including both monoclonal antibodies (ie, IMC-C225) and other tyrosine kinase inhibitors, directed at the EGFR.
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PMID:Targeting epidermal growth factor receptor in lung cancer. 1204 41

The overexpression of HER2, a transmembrane glycoprotein tyrosine kinase, has been implicated in mitogenesis, cell survival, invasion and angiogenesis. Preclinical evidence suggests that HER2 overexpression contributes to tumor progression in non-small cell lung cancer (NSCLC) and retrospective clinical correlative studies show that it is probably associated with poor clinical outcome. Trastuzumab (Herceptin, Genentech Inc., South San Francisco, CA) is a recombinant humanized monoclonal antibody that targets HER2 and is currently approved for use in the treatment of patients with HER2-overexpressing metastatic breast cancer. Two primary mechanisms proposed for the activity of trastuzumab are downregulation of HER2 and induction of antibody-dependent cell-mediated cytotoxicity. Evidence from preclinical studies of trastuzumab in NSCLC and other cell lines, the presence of HER2 overexpression in NSCLC clinical specimens and the clinical benefit derived from trastuzumab in phase II and III metastatic breast cancer trials have led to the development of clinical trials of trastuzumab in NSCLC. Phase II studies of trastuzumab in patients with stage IIIB or IV NSCLC are being conducted to test the efficacy of trastuzumab as a single agent or in combination with chemotherapy. Preliminary results show combinations of chemotherapy plus trastuzumab are well tolerated, with encouraging response rates of 21-40%. A randomized phase II trial of chemotherapy with or without trastuzumab showed promise in a small subgroup of patients with 3+ HER2 overexpression by immunohistochemistry or HER2 DNA amplification by fluorescence in situ hybridization. Taken together, these data indicate that trastuzumab warrants further investigation in a clinical study in selected patients with NSCLC.
Lung Cancer 2002 Jul
PMID:Non-small cell lung cancer clinical trials with trastuzumab: their foundation and preliminary results. 1205 63

Docetaxel (Taxotere) has shown activity both as a single-agent and in combination with multiple other cytotoxic agents in the front-line therapy of advanced, metastatic non-small-cell lung cancer (NSCLC). A randomized, phase III trial demonstrated a survival advantage for docetaxel over best supportive care in the front-line setting, with docetaxel achieving a 2-year survival of 12% vs 0% for best supportive care. Combinations of docetaxel with the platinum agents have been the most extensively studied in the front-line setting and have produced notably high response rates and encouraging median survivals. When compared to the paclitaxel/cisplatinum combination in a large, phase III randomized trial, the combination of docetaxel and cisplatin resulted in similar response, median survival, and 1-year survival rates. Another randomized phase III trial compared docetaxel/platinum combinations to the US Food and Drug Administration (FDA)-approved vinorelbine (Navelbine)/cisplatin regimen. The docetaxel/cisplatin combination produced a superior overall survival, 2-year survival, and overall response rates compared to vinorelbine/cisplatin. The combination of docetaxel and carboplatin (Paraplatin) demonstrated similar survival and response, and was associated with quality-of-life benefits over the vinorelbine/cisplatin arm. Docetaxel has been successfully combined with gemcitabine in multiple trials with impressive response and survival rates, and an acceptable toxicity profile. A large phase IIb trial demonstrated therapeutic equivalence and lesser toxicities for the docetaxel/gemcitabine combination compared to the combination of docetaxel and cisplatin. The docetaxel/gemcitabine combination therefore represents a viable nonplatinum regimen for first-line treatment of NSCLC. Other combinations that have been tested include docetaxel with vinorelbine, and docetaxel with irinotecan (CPT-11, Camptosar). Docetaxel is active in NSCLC and should be investigated further in combination with novel molecularly targeted drugs such as tyrosine kinase inhibitors, andfarnesyl transferase inhibitors.
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PMID:Docetaxel for locally advanced or metastatic non-small-cell lung cancer. Current data and future directions as front-line therapy. 1210 98

Following two decades of research on the biology of cancer and in particular of lung cancer, we have now a large number of molecular targets that can be utilized to create specific medicines against these cancers. Non-small cell lung cancer represents numerically the most important solid tumor in Western world, and is poorly affected by current therapies, where surgery represents almost the only curative therapy for about 25% of patients who are resectable at diagnosis. An abundant number of targeted therapies are being investigated in NSCLC. Among them are the metalloproteinase inhibitors, several tyrosine kinase inhibitors and several attempts of gene replacement have also been made. Promising results have so far been obtained with some of these approaches, and the outcome of large randomized studies is awaited. Small cell lung cancer (SCLC) represents about 20% of lung carcinomas, and several of the novel approaches that are being attempted for NSCLC, are also being investigated for SCLC. All these novel therapies open a new era of anticancer treatment that will likely complement the currently available therapies in the near future.
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PMID:Clinical impact of novel treatment strategies. 1236 78

Although treatment of advanced non-small-cell lung cancer has been improved with the availability of such new agents as the taxanes, topoisomerase inhibitors, vinorelbine (Navelbine), and gemcitabine (Gemzar), platinum-based combination therapy has appeared to reach a threshold of therapeutic effectiveness. A paradigm shift in approach to non-small-cell lung cancer and other tumors may be heralded by the development of agents targeting specific biologic pathways in tumor development. Such new agents include antibody epithelial growth factor receptor (EGFR) inhibitors (eg, the monoclonal antibodies trastuzumab [Herceptin] and cetuximab [IMC-C225, Erbitux]) and EGFR tyrosine kinase inhibitors (eg, ZD1839 [Iressa] and OSI-774), angiogenesis inhibitors (eg, matrix metalloproteinase inhibitors), vascular endothelial growth factor (VEGF) inhibitors (eg, monoclonal antibody to VEGF ligand and small-molecule tyrosine kinase), and signal transduction inhibitors (eg, ISIS-3521, an antisense oligonucleotide to protein kinase C-alpha). A number of these agents have entered advanced-phase clinical investigation. It is likely that targeted therapy will have applications in combination with cytotoxic chemotherapy or radiation therapy at all stages of treatment, including maintenance therapy. It is even possible that these new biologic therapies will be used together as rational combinations (based on pathologic diagnosis) for advanced non-small-cell lung cancer.
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PMID:Targeted therapy in non-small-cell lung cancer. 1237 97

When compared with best supportive care alone, the second-line treatment of non-small cell lung cancer (NSCLC) with 75 mg/m(2) docetaxel significantly improved the 1-year survival rate (37 vs. 12%) and lengthened time to disease progression (median 12.3 vs. 7.0 weeks) in study TAX 317. Quality of life was superior with docetaxel and the need for tumor-related therapy was reduced. Docetaxel 75 mg/m(2) in this setting is safe, and offers clinically meaningful benefit to patients. These findings are supported by data from study TAX 320 in which a heavily pre-treated population of advanced NSCLC patients was randomized to receive docetaxel 100 mg/m(2), docetaxel 75 mg/m(2) or a comparator arm of either vinorelbine or ifosfamide. Treatment with either dose of docetaxel significantly increased the proportion of patients without disease progression at 26 weeks. By intent to treat analysis, 1-year survival was 32% in patients randomized to docetaxel 75 mg/m(2). This was significantly greater than the 19% 1-year survival rate in the comparator arm. Prior exposure to paclitaxel did not lessen the response rate or survival advantage of docetaxel in this second-line setting. Future development is likely to lie in the combination of docetaxel with novel molecular-targeted agents such as EGFR tyrosine kinase inhibitors.
Lung Cancer 2002 Dec
PMID:Second line chemotherapy for NSCLC: establishing a gold standard. 1248 Jan 89

The continuous growth of tumors depends on the altered regulation of the cell cycle, which is in turn modulated by signals from growth factors and their receptors. Blockade of insulin-like growth factor (IGF)-I and IGF-IR by antisense or dominant negative plasmid transfection can suppress tumorigenicity and induce regression of established tumors. We have constructed two recombinant adenoviruses: an adenovirus expressing truncated IGF-IR (ad-IGF-IR/950) with an engineered stop codon at amino acid residue 950, and an adenovirus expressing the soluble extracellular domain of IGF-IR (ad-IGF-IR/482) with an engineered stop codon at amino acid residue 482. Ad-IGF-IR/950 produces a defective receptor with an intact alpha subunit and a defective beta subunit lacking the tyrosine kinase domain. Dominant negative inhibition results from competition of the defective receptor with normal IGF-IR subunits, or the competition with normal IGF-IR for ligand by the soluble receptor. We were able to show here that ad-IGF-IR/950 induced the increased expression of IGF-IR on the cell surface and ad-IGF-IR/482 induced the secretion of the soluble fragment of IGF-IR. The transduction of both ad-IGF-IR/950 and ad-IGF-IR/482 could blunt the growth-stimulatory effect of IGF-I on human lung cancer cell lines. Both ad-IGF-IR/950 and ad-IGF-IR/482 effectively blocked IGF-I-induced Akt kinase activation. Intratumoral injection of ad-IGF-IR/482 virus showed significant growth suppression in established lung cancer xenografts. These findings suggest that these ad-IGF-IR/dn (950, 482) have the potential to be effective and practical cancer gene therapy strategies.
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PMID:Recombinant adenoviruses expressing dominant negative insulin-like growth factor-I receptor demonstrate antitumor effects on lung cancer. 1248 29

Erlotinib (CP-358774, OSI-774, Tarceva), a quinazoline derivative, is an orally active epidermal growth factor receptor tyrosine kinase inhibitor under development jointly by Genentech, OSI (formerly Oncogene Science) and Roche, both as monotherapy and combination therapy for the potential treatment of solid tumors, including non-small-cell lung cancer (NSCLC) and pancreatic, breast, head and neck cancers [203487]. Development of the compound is most advanced for NSCLC and pancreatic cancer; in July 2001, phase III combination trials were initiated for NSCLC [416835]. In October 2001, phase III monotherapy trials in NSCLC and phase III combination trials in pancreatic cancer were also initiated [426704]. In Japan, the compound was in phase I studies in January 2002 [439189].
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PMID:Erlotinib OSI/Roche/Genentech. 1249 17

Recently, therapies targeting signaling pathways involved in the pathogenesis of different tumors have been developed. Studies have shown that the tyrosine kinase inhibitor STI-571 (Gleevec) is used successfully against tumors expressing the c-kit oncogene, such as gastrointestinal stromal tumors (GISTs). A recent in vitro study also demonstrated an antiproliferative effect of STI-571 on small-cell lung cancer (SCLC) cell lines. To determine the expression of c-kit in SCLC, we retrospectively analyzed presence of c-kit by immunohistochemistry in biopsy samples from patients with SCLCs. Formalin-fixed, paraffin-embedded archival tissue samples from 30 SCLCs were stained with an antibody directed against c-kit (CD117) by immunohistochemistry. Thirty cases of SCLCs, including 17 males (age 44 to 89) and 13 females (age 21 to 85), were examined. Sixteen of 30 (53.3%) SCLCs showed c-kit expression. Kaplan-Meier survival analysis with a log-rank test revealed that patients with c-kit expression had a tendency toward lower survival than c-kit-negative patients (median survival, 6 months versus 31 months, P =.062). Based on previously established anti-c-kit effects of STI-571 on SCLC cell lines and our findings, clinical trials may be considered for selected SCLC patients with c-kit expression. Furthermore, determination of c-kit in SCLC may have a prognostic value in SCLC patients.
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PMID:Analysis of c-kit protein expression in small-cell lung carcinoma and its implication for prognosis. 1450 52

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancer. The molecular pathogenesis of chronic myelogenous leukemia (CML) in particular, depends on formation of the bcr-abl oncogene, leading to constitutive expression of the tyrosine kinase fusion protein, Bcr-Abl. Based on these observations, imatinib was developed as a specific inhibitor for the Bcr-Abl protein tyrosine kinase. The expanding understanding of the basis of imatinib-mediated tyrosine kinase inhibition has revealed a spectrum of potential new antitumor applications beyond the powerful activity already reported in the treatment of CML. Imatinib has shown activity in vivo against PDGF-driven tumor models including glioblastoma, dermatofibrosarcoma protuberans and chronic myelomonocytic leukemia. Antiangiogenic effects have been demonstrated by inhibition of PDGF-, VEGF (vascular endothelial growth factor)- and bFGF- (basic fibroblast growth factor) induced angiogenesis in vivo, and by inhibition of angiogenesis and tumor growth in an experimental bone metastasis model. Imatinib has been shown to reduce interstitial fluid pressure in an experimental colonic carcinoma model by blocking PDGF-mediated effects on tumor-associated blood vessels and stromal tissue. It is also a potent inhibitor of the Kit receptor tyrosine kinase, and has demonstrated activity clinically against the Kit-driven gastrointestinal stromal tumor (GIST) and experimentally in small-cell lung cancer cell lines. The pharmacology of imatinib and its activity in various tumor models is discussed.
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PMID:Pharmacology of imatinib (STI571). 1252 70


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