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)

The identification of predictive or surrogate markers of response to HER1/epidermal growth factor receptor (EGFR) inhibitor treatment would permit selection of patients most likely to respond to such treatment. Markers could consist of tumor characteristics (e.g., characteristics of the receptor or downstream signaling molecules and determinants of resistance) or host characteristics (e.g., pharmacokinetic parameters and toxicities). The occurrence of rash may constitute a surrogate marker of response to erlotinib (Tarceva) treatment in patients with non-small-cell lung cancer and other cancers. The erlotinib marker identification program has been designed to identify and investigate other candidate markers by analysis of a large number of clinical samples from patients enrolled in erlotinib trials in non-small-cell lung cancer, including the phase III TALENT and TRIBUTE trials of erlotinib combined with chemotherapy and the phase III BR.21 trial of erlotinib monotherapy in advanced non-small-cell lung cancer. This program should both contribute to understanding of the molecular biology of HER1/EGFR inhibition and result in identification of potential markers that can be evaluated in the clinical setting.
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PMID:Identifying predictive and surrogate markers of erlotinib antitumor activity other than rash. 1468 21

Both intrinsic and acquired resistance to chemotherapeutic drugs are major obstacles in the treatment of non-small-cell lung cancer. Apart from classical drug resistance mechanisms, the failure of tumor cells to undergo apoptosis also plays an important role in drug resistance. Mutations and defects in the apoptotic pathway are, therefore, additional factors that determine drug resistance. The tumor suppressor gene p53, the retinoblastoma gene, and the bcl-2 family members are important factors in this pathway. Recently much attention has been drawn to different apoptotic pathways induced by naturally occurring death receptor ligands (such as tumor necrosis factor, Fas ligand, and tumor necrosis factor-related apoptosis-inducing ligand) or induced by drugs that affect the downstream pathway from the epidermal growth factor receptor. Insight regarding the proteins that determine sensitivity for chemotherapeutic drugs could provide new targets for cancer treatment, which may help to at least partly overcome drug resistance in non-small-cell lung cancer
Clin Lung Cancer 2002 Nov
PMID:The role of apoptosis-related genes in non-small-cell lung cancer. 1470 67

Drug costs and reimbursement issues for targeted therapies for lung cancer and how they affect pharmacy practice are discussed. Lung cancer is the most frequent cause of cancer death in the western world. Despite improvements in treatment results, less than 15% of patients survive five years after their primary diagnosis. Major advances in the understanding of cancer biology have led to the identification of several potential targets for cancer treatment. In non-small cell lung cancer (NSCLC) one of the most promising new targets has been the epidermal growth factor receptor (EGFR), which is overexpressed in most squamous cell subtypes and > or = 65% of adenocarcinomas and large cell subtypes. Gefitinib is an orally available small-molecule tyrosine kinase inhibitor that targets the intracellular domain of the EGFR. It has demonstrated activity and tolerable toxicity in patients with NSCLC. Because of its daily oral route of administration, patient compliance and education are of paramount importance, and the pharmacist plays an increasingly important role in patient management.
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PMID:Pharmacy practice issues with targeted therapy for lung cancer. 1471 23

Docetaxel is one of the most active single agents in the treatment of advanced non-small-cell lung cancer (NSCLC). Weekly administration of docetaxel markedly reduces myelosuppression and also reduces nonhematologic toxicity. Phase II trials with single-agent weekly docetaxel have been completed in first- and second-line treatment of advanced NSCLC; preliminary results of treatment with weekly docetaxel-based combination regimens are also available. In patients who were elderly or had poor performance status, weekly docetaxel produced a 19% response rate, 28% 1-year survival, and was well tolerated. As second-line therapy, response rates to weekly docetaxel were similar to results with administration every 3 weeks, although no direct comparisons exist. Combination regimens, particularly weekly docetaxel/gemcitabine, also appear active and well tolerated and should be further evaluated. Addition of various targeted agents (eg, epidermal growth factor receptor inhibitors, antiangiogenesis agents) also merits evaluation.
Clin Lung Cancer 2002 May
PMID:The role of weekly docetaxel in the treatment of advanced non-small-cell lung cancer. 1472 Mar 43

Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and high mortality. The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau. The main categories of targeted therapeutics applicable for NSCLC include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, gene therapy, and vaccines. Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC. The anti-epidermal growth factor receptor (EGFR) group contains trastuzumab and IMC-C225, monoclonal antibodies against EGFRs that are overexpressed in many cancers. OSI-774 and ZD1839 are inhibitors of EGFR tyrosine kinase, a key enzyme of the signaling pathway. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumor activity. Antiangiogenesis agents that have shown promise include TNP-470, recombinant endostatin, and angiostatin. Antibodies to vascular endothelial growth factor (VEGF) also seem to control tumor progression and may prolong survival. LY317615, an inhibitor of protein kinase Cb, augmented the tumor growth delay produced by cytotoxic drugs. All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs. These new agents are more target specific, less toxic, easier to administer, and may lead to enhanced safety and survival for patients with advanced NSCLC.
Clin Lung Cancer 2002 Mar
PMID:Targeted therapy using novel agents in the treatment of non-small-cell lung cancer. 1472 Mar 53

The epidermal growth factor receptor (EGFR) is a promising target for cancer therapy and a number of EGFR-targeted agents have been developed. Those most advanced in development are the EGFR tyrosine kinase inhibitors gefitinib ('Iressa', ZD1839) and erlotinib ('Tarceva', OSI-774), and the monoclonal antibody cetuximab ('Erbitux', IMC-C225). This review provides a clinical overview of these agents, highlighting their antitumour activities in different tumour types. Epidermal growth factor receptor-targeted agents are generally well tolerated and are not typically associated with the severe adverse events often seen with cytotoxic chemotherapy. Gefitinib is the agent with the most extensive clinical experience, particularly in non-small-cell lung cancer (NSCLC). Recently, gefitinib became the first-approved EGFR-targeted agent, for use in patients with previously treated advanced NSCLC in Japan, the USA and other countries. Further studies are required to explore the full potential of these novel agents either as monotherapy or combination therapy.
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PMID:Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors. 1476 Mar 65

ZD-6474, one of a series of inhibitors of vascular endothelial growth factor receptor tyrosine kinase, which also has activity against the epidermal growth factor receptor tyrosine kinase, is under development by AstraZeneca for the potential treatment of solid tumors. Phase II trials in non-small-cell lung cancer, small-cell lung cancer and myeloma were ongoing in January 2003.
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PMID:ZD-6474. AstraZeneca. 1476 34

Gefitinib blocks epidermal growth factor receptor autophosphorylation and subsequently the signal transduction pathways implicated in proliferation, metastasis, invasion, and angiogenesis. Reported adverse reactions to gefitinib include liver injury that is not fully understood. Liver injury was observed in 5 (12.2%) of 41 patients with non-small cell lung cancer who received gefinitib monotherapy. Onset of liver injury was seen between 28 and 56 days after initiation of administration. Two patients had Grade 2 liver injury and 3 patients, Grade 3. In 4 patients, liver injury was temporary, lasting during a period of continuous gefitinib administration. In another patient, gefitinib was discontinued because of the onset of liver injury, which improved when gefitinib administration was restarted. Gefitinib is necessary in most patients whose lung cancer is refractory to cytotoxic chemotherapy, because no other treatment regimens are available at present. The rate of liver injury in cases treated with gefitinib is high, and so it is necessary to observe liver function carefully, but the liver injury due to this drug is often transient. However, the use of gefitinib in many cases appears to be a necessity.
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PMID:[Transient liver injury caused by gefitinib]. 1476 65

Potent and specific, or relatively specific, inhibitors of epidermal growth factor receptor (EGFR) signaling, including monoclonal antibodies and small molecular weight compounds, have been successfully developed. Both types of agent have been found to have significant antitumor activity, especially when used in combination with radio- hormone- and chemotherapy in preclinical studies. Because of the potentiation of the conventional drug activity in these combination settings, inhibitors of EGFR signaling have often been referred to as sensitizers for chemotherapy or radiation, as well as drug resistance reversal agents. Phase II clinical trials in head-and-neck as well as lung cancer suggested this concept of chemosensitization might translate into the clinic, but this remains to be definitively proven in randomized, double-blind Phase III trials. Given the extensive preclinical literature on EGFR blocking drugs and the advanced clinical development of such agents, it is surprising that the possibility of development of acquired resistance to the EGFR inhibitors themselves, a common clinical problem with virtually all other currently used anticancer drugs, remains a largely unexplored subject of investigation. Here we summarize some of the possible mechanisms that can result in acquired resistance to EGFR-targeting drugs. Alternative combination therapies to circumvent and delay this problem are suggested.
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PMID:Acquired resistance to EGFR inhibitors: mechanisms and prevention strategies. 1496 51

Combination chemotherapy regimens have emerged as the standard approach in advanced non-small-cell lung cancer. Meta-analyses have demonstrated a 2-month increase in median survival after platinum-based therapy vs. best supportive care, and an absolute 10% improvement in the 1-year survival rate. Just as importantly, cytotoxic therapy has produced benefits in symptom control and quality of life. Newer agents, including the taxanes, vinorelbine, gemcitabine, and irinotecan, have expanded our therapeutic options in the treatment of advanced non-small-cell lung cancer. Despite their contributions, we have reached a therapeutic plateau, with response rates seldom exceeding 30-40% in cooperative group studies and 1-year survival rates stable between 30% and 40%. It is doubtful that substituting one agent for another in various combinations will lead to any further improvement in these rates. The thrust of current research has focused on targeted therapy, and epidermal growth factor receptor inhibition is one of the most promising clinical strategies. Epidermal growth factor receptor inhibitors currently under investigation include the small molecules gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774), as well as monoclonal antibodies such as cetuximab (IMC-225, Erbitux). Agents that have only begun to undergo clinical evaluation include CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, and PKI166 and GW572016, both examples of dual kinase inhibitors (inhibiting epidermal growth factor receptor and Her2). Preclinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy. However, serious clinical challenges persist. These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which to test these compounds. Both gefitinib and erlotinib have shown clinical activity in pretreated, advanced non-small-cell lung cancer, but placebo-controlled randomized Phase III studies evaluating gefitinib in combination with standard cytotoxic therapy, to our chagrin, have failed to demonstrate a survival advantage compared with chemotherapy alone.
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PMID:Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. 1496 61


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