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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In oncology, the term 'targeted therapy' is used to describe drugs that target only the cancer cells and spare normal cells thereby reducing host toxicity while simultaneously increasing the eradication of cancer. Trastuzumab and imatinib are well known examples of successful targeted therapy. Newer agents like gefitinib and cetuximab offer hope that targeted therapy also may yield therapeutic benefit for such refractory malignancies as lung and colon cancers. One of many remaining challenges is to identify markers, molecular or clinical, that predict for responsiveness to a specific targeted therapy (e.g. HER2/neu positivity and trastuzumab responsiveness). However, using emerging technologies such as gene or protein profiling, it may be possible to predict a tumor's responsiveness to a particular targeted therapy based on its molecular signature. If true, clinicians might then possess the ability to predict a tumor's clinical behavior and shape its density through specific, targeted interventions.
Lung Cancer 2003 Aug
PMID:Targeted therapy in non-small cell lung cancer: myth or reality. 1286 56

The Erb-B family of receptors plays an important role in lung carcinogenesis and tumor development, and EGFR and HER2 are highly expressed in bronchial preneoplasia. In invasive tumors, EGFR are expressed in 50-90%, and mostly in squamous cell carcinomas, but also in adenocarcinomas and large cell carcinomas, while HER2 is less frequently expressed (20-30%) and mostly expressed in adenocarcinomas. Bronchioloalveolar cell carcinomas may present a distinct EGFR profile compared to the other NSCLCs and evidence and consequences are discussed. The genetic mechanisms responsible for overexpression of EGFR and HER2 proteins might be numerous, including gene dosage (overrepresentation or amplification) as well as translational and post-translational mechanisms. However, for EGFR and HER2 there is a positive correlation between gene copy numbers and level of protein expression demonstrated by fluorescence in situ hybridization analysis and immunochemistry. Gene amplification for EGFR and HER2 is demonstrated in only 5-10% of the tumors. The treatment status and therapeutic limitation with trastuzumab (Herceptin) in lung cancer compared to breast cancer is discussed.
Lung Cancer 2003 Aug
PMID:Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. 1286 60

HER2 is reported to be overexpressed in 20% of cases of non-small-cell lung cancer (NSCLC), principally adenocarcinoma. Trastuzumab is a monoclonal antibody against HER2 that, when combined with a taxane, improves survival compared with chemotherapy alone in advanced breast cancer. In view of these observations, we conducted a phase II HER2 screening and efficacy trial of trastuzumab plus weekly docetaxel in cases of advanced NSCLC in which primary platinum-based therapy had failed. Patients with advanced or metastatic NSCLC were screened for HER2 overexpression by immunohistochemistry. Patients with HER2-positive tumors (2+ or 3+) were initially randomized to either single-agent trastuzumab or docetaxel. After completing 2 treatment cycles, all patients went on to receive the trastuzumab/docetaxel combination regardless of response to the single agents. Treatment consisted of docetaxel 30 mg/m2 weekly for 6 weeks followed by a 2-week break and trastuzumab 4 mg/kg intravenously on week 1 followed by 2 mg/kg per week thereafter. Cycle length was 8 weeks. Sixty-nine patients with NSCLC (33 men, 36 women) were screened between August 1999 and March 2001. Only 13 patients (19%) had HER2-positive disease; all 13 enrolled in the efficacy trial. Of 9 patients receiving docetaxel alone, 1 partial response (PR) was seen. None responded to trastuzumab alone. The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8% of cases, stable disease in 23%, progression in 46%, and nonassessable disease in 23%. Estimated event-free and overall survival times were 4.3 and 5.7 months, respectively. Treatment was well tolerated. The screening component of this trial demonstrated that the target population for trastuzumab therapy in NSCLC is relatively small. Because of the limited clinical activity of trastuzumab-based therapy in this cohort and the similar disappointing reports from other studies of trastuzumab in NSCLC, this trial was closed to further accrual. In view of the limited target population for HER2 inhibition, future efforts and resources should be directed toward molecular targets other than HER2 in NSCLC.
Clin Lung Cancer 2004 Jan
PMID:Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial. 1496 75

Research over the past decade has led to an increased understanding of the pathophysiology of lung cancer. The HER2/neu receptor is a member of the ErbB family of signaling-transduction receptors and appears to play a major role in the development of lung cancer as well as many other solid tumors. HER2/neu is overexpressed in 16% to 57% of patients with non-small cell lung cancer (NSCLC) and studies have shown that HER2/neu overexpression imparts a poor prognosis in both resected and advanced NSCLC, as it does in breast cancer. Trastuzumab, a humanized monoclonal antibody that recognizes the HER2/neu protein receptor, has been approved by the US Food and Drug Administration for patients with HER2/neu-positive metastatic breast cancer. In NSCLC preclinical studies, marked synergistic growth inhibition occurred when standard cytotoxic chemotherapy was combined with trastuzumab in HER2/neu-expressing cell lines. In the clinical setting, trastuzumab has proven safe and feasible in combination with cytotoxic chemotherapy in both single-institution and multi-institutional cooperative group studies. Unlike the experience in advanced breast cancer, cardiac toxicity is a marginal concern in this population. However, to date, clinical studies with trastuzumab in patients with NSCLC have not shown a demonstrable advantage for the majority of patients.
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PMID:The role of HER2/neu expression and trastuzumab in non-small cell lung cancer. 1498 84

Lung cancer is the leading cause of death worldwide. Current treatment modalities, including chemotherapy, radiotherapy and surgery, provide only limited improvement in the natural course of this disease. Therefore, the development of new therapeutic strategies is highly awaited. This review focuses on recent achievements on a novel class of anticancer drugs targeting the EGFR (Epidermal Growth Factor Receptor). The EGFR family is a group of four structurally similar growth factor receptors with tyrosine-kinase activity (EGFR, HER2/neu, ErbB-3, ErbB-4), which dimerize upon binding with a number of ligands, including EGF (Epidermal Growth Factor) and TGF (Transforming Growth Factor), allowing downstream transduction of mitogenic signals. Overexpression of EGFR and HER2 is frequently found in non-small-cell lung cancer (NSCLC), which accounts for over 80% of all malignant lung tumors, and has been associated with a worse clinical outcome. New agents developed to inhibit EGFR function include monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized. In particular, final results of phase II (IDEAL 1 and 2) and III (INTACT 1 and 2) studies of ZD1839 are reported. In IDEAL trials (ZD1839 single agent in patients pre-treated with chemotherapy) there was clear evidence of tumor regression, symptoms improvement and overall clinical benefit, whereas in the two INTACT trials (ZD1839 in combination with standard platinum-based chemotherapy in chemo-naive patients) ZD1839 did not improve either survival or other clinical endpoints. Possible explanations for these contradictory results and future perspectives are discussed.
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PMID:Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer. 1503 19

HER gene family (HER1-HER4) encodes structurally similar transmembrane proteins (EGFR, HER2, ErB-3, and ErB-4) with tyrosine kinase activity. Dimerised on binding with a number of ligands, including epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha), these proteins stimulate epithelial cell proliferation. HER2 and EGFR overexpression is detected in the cells of many tumours, mainly in breast, lung and oral cancer and may be connected with HER2 gene amplification or point mutations as well as with the presence of overactive polymorphic forms of HER1 gene. The first medication of a proved efficacy in breast cancer treatment was trastuzumab (Herceptin)--monoclonal antibody against HER2 protein. Trastuzumab was effective only in the case of patients with high HER2 expression evaluated by immunohistochemical methods and with gene amplification ascertained by fluorescence in situ hybridisation assays. In non-small-cell lung cancer (NSCLC), HER2 overexpression was detected only in a few cases. Therefore, trastuzumab treatment seems to be problematic in NSCLC patients. A small molecule quinazoline (erlotinib, Tarceva) is a promising therapeutic agent selectively blocking EGFR. Phase III Tarceva clinical trail in NSCLC patients showed that their survival is prolonged and that the medication acts together with other chemotherapeutic agents like cisplatin and gemcitabine.
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PMID:Anti-HER therapeutic agents in the treatment of non-small-cell lung cancer. 1531 69

Cancer chemotherapy remains the only treatment modality with curative activity against multiple forms of metastatic malignancy. Over the past decade, cytotoxic and anti-endocrine drugs have been supplemented by targeted therapies that seek to exploit the molecular lesions that underlie the carcinogenic process or maintain the cancer phenotype. Success with, for example, Imatinib and Trastuzumab has suggested that identification and validation of the drug target is the starting point for the optimal route to the development of active drugs. However, in reality, our understanding of the biology of cancer is still too rudimentary to allow drug developers to rely on the simplistic linear pathway of target identification and validation, lead identification and optimisation, followed by Phase I, II and III trials. As pre-clinical and clinical drug developers investigate the second wave of targeted agents, it is worthwhile reflecting on experience gained during the initial development of cytotoxic drugs. For example, the clinical activity of alkylating agents and antimetabolites was demonstrated before the targets for these drugs were defined in any detail. Recent experience with signal transduction modifiers has again shown that agents initially developed to exploit one target may actually hit other targets, and that interaction with these other targets may be responsible for the clinical activity of the compound. Using lung cancer, the world's single biggest cancer problem, as an example the development of recently evaluated drugs, both cytotoxic and targeted, is reviewed. On the basis of this Review, it is concluded that drug developers should design pre-clinical studies and early clinical trials in a manner that allows both the pharmacology of the drug as well as the biology of the target to inform the development process.
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PMID:How to develop a successful cancer drug--molecules to medicines or targets to treatments? 1576 42

An important recent advance in anticancer therapy was the development of molecular-targeting drugs, such as the epidermal growth-factor receptor (EGFR)-targeting drug ZD1839 (Iressa) and the HER2-trageting anti-HER2 monoclonal antibody trastuzumab (Herceptin). ZD1839 and trastuzumab are reported to improve the therapeutic efficacy of treatment for non-small-cell lung cancer (NSCLC) and breast cancer, respectively, although the effectiveness of either drug alone is not satisfactory. NSCLC cells often express both EGFR and HER2. We therefore investigated whether a combination of ZD1839 and trastuzumab had an additive or synergistic antitumor effect. In culture ZD1839 inhibited the growth of four NSCLC cell lines (A549, NCI-H23, NCI-H727, and NCI-H661) that expressed various levels of EGFR, HER2, HER3, and HER4. A significant cytotoxic effect was observed when ZD1839 was combined with trastuzumab in A549 cells. However, this combination had no apparent effect in NCI-H23 cells. Significant G(1)-phase arrest, increased p27 expression and decreased cyclin E or D1 levels were detected in A549 cells treated with ZD1839 and trastuzumab. No significant effects were detected in NCI-H23 cells examined. The combination treatment significantly inhibited the phosphorylation of EGFR, HER2, retinoblastoma, extracellular signal-regulated kinase-1/2, and protein kinase B/Akt in A549 cells, but not in NCI-H23 cells. Our results indicated that increased levels of constitutive EGFR/HER2 heterodimers were formed in A549 cells in the presence of ZD1839, whereas no heterodimer formation was detected in NCI-H23 cells. We therefore suggest that combination treatment with ZD1839 and trastuzumab might have improved therapeutic efficacy against NSCLC cells expressing both EGFR and HER2.
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PMID:Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer. 1625 59

Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, ZD1839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab/Herceptin, Pertuzumab/Omnitarg/rhuMab-2C4, Cetuximab/Erbitux/IMC-C225, Panitumumab/Abenix/ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.
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PMID:Targeting the EGFR pathway for cancer therapy. 1716 18

Human monoclonal anti-Her2/neu antibody (herceptin, also named trastuzumab) failed in the treatment of lung cancer when in combination with two chemotherapy agents gemcitabine and cisplatin, despite of its clinical benefit in women with Her2 positive breast cancer. The capacity of herceptin to activate human complement and complement-dependent cytotoxicity against tumor cells was investigated in a study of tumor immunotherapy. We found that the expression of membrane complement regulatory proteins (mCRPs), CD55 and CD59 on non-small cell lung cancer (NSCLC) cells was closely correlated with histological types, prognosis and preoperational adjutant chemotherapy of the disease. Herceptin-mediated complement cytotoxicity to two human lung carcinoma cell lines exerted stronger killing effect on tumor cells after the neutralization of mCPRs via their antibodies. Furthermore, treatment of herceptin combined with chemo-agents had advantages over chemotherapy alone, while CD55 and CD59 expression levels both declined remarkably in A549 and H157 cell lines after incubation with IC50 cisplatin for 72 h. Our data indicated that overexpression of mCRPs on tumor cells contributes to herceptin's acquisition of resistance to NSCLC, and its anticancer efficacy was enhanced when mCRPs were neutralized or cisplatin could be used to down-regulate their expression.
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PMID:Neutralization of complement regulatory proteins CD55 and CD59 augments therapeutic effect of herceptin against lung carcinoma cells. 1942 17


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