Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Improved understanding of tumor biology has led to the identification of numerous growth factors that are involved in malignant transformation and tumor progression. Many of these factors induce cellular responses through receptors with intrinsic tyrosine kinase (TK) activity. Therefore, inhibiting receptor TK activity is a way to effectively block the tumorigenic effects that arise from these pathways. The HER family of TK receptors is overexpressed or dysregulated in many types of human cancer. As a result these receptors were identified as targets for cancer therapy. Several agents have been developed that reversibly, or irreversibly, inhibit one, two or all of the HER receptors. Tarceva and Iressa are HER1-TK inhibitors that are advanced in development. Clinical data show that these agents as monotherapy have antitumor activity in patients with various types of solid tumor and are well tolerated; encouraging data are also produced when Tarceva or Iressa are combined with chemotherapeutic agents. Other dual or pan-HER, reversible or irreversible, TK inhibitors are being investigated in phase I trials. Early data show that they are generally well tolerated and have provided evidence of antitumor activity. HER-TK inhibitors are exciting agents that are likely to have a substantial impact on the way we treat patients with cancer.
 ...
PMID:HER-targeted tyrosine-kinase inhibitors. 1242 50

Overexpression of epidermal growth factor receptor (EGFR) in epithelial tumors, including head and neck, lung, breast, colon and other solid tumors, has frequently been correlated with poor prognosis, thus stimulating efforts to develop new cancer therapies that target EGFR. Monoclonal antibodies and tyrosine kinase inhibitors specifically targeting EGFR are the most well-studied and hold substantial promise of success. Several compounds of monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have been studied and clinical trials are now underway to test the safety and efficacy of these targeting strategies in several human tumors. This review will address each of these agents alone or in combination with radiation or chemotherapy and highlight some of these promising developments. Cetuximab (Erbitux) is being evaluated in combination with radiation or chemotherapy in Phase III trials. Other compounds such as h-R3, ABX-EGF, EMD-55900 and ICR-62 have proved to be effective in targeting malignant cells alone or in combination with traditional therapies. Tyrosine kinase inhibitors targeting the intracellular domain of EGFR, including ZD-1839 (gefitinib, Iressa), OSI-774 (Erlotinib/Tarceva), PD-153053, PD-168393 and CI-1033, have been studied in clinical setting alone or in combination with radiation or chemotherapy. ZD-1839 is being studied in a Phase III trial in patients with advanced non-small cell lung cancer. EGFR targeted treatment by monoclonal antibodies and tyrosine kinase inhibitors have been proven to sensitize tumor cells to the effects of chemotherapy and radiation therapy. The synergistic activities and nonoverlapping toxicities of these compounds allow concomitant administration with cytotoxic therapy. Challenges of evaluating EGFR targeted agents exist in selecting the optimal dosages and determining long-term toxicity.
 ...
PMID:Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer. 1282 Jul 79

Erlotinib HCl (Tarceva; Genentech, Inc, South San Francisco, CA) is an orally available, highly selective, reversible inhibitor of epidermal growth factor receptor (HER1/EGFR) tyrosine kinase. Inhibition of tyrosine kinase activity prevents HER1/EGFR phosphorylation, the associated downstream signaling events, and may block tumorigenesis mediated by inappropriate HER1/EGFR signaling. In vitro and in vivo studies show that erlotinib has activity against human colorectal, head and neck, non-small cell lung, and pancreatic tumor cells. Recent preclinical studies suggest that erlotinib may also have activity against tumors that are dependent on HER2 activation for growth and/or survival. Preclinical studies have addressed the feasibility of using erlotinib in combination with various chemotherapeutic agents, radiotherapy, and targeted agents. Combining agents that have different mechanisms of action has the potential to improve efficacy and inhibit the development of resistance. For example, in preclinical studies, combining erlotinib with cisplatin, doxorubicin, gemcitabine, or low-dose paclitaxel has an additive effect on antitumor activity with no increase in toxicity. Preclinical data provide a strong rationale for investigating erlotinib in the clinical setting. However, additional studies are required to gain further insights into the processes that regulate or influence the antitumor activity of erlotinib.
 ...
PMID:Preclinical studies with Erlotinib (Tarceva). 1284 Jul 97

Erlotinib HCI (Tarceva; Genentech, Inc, South San Francisco, CA) is an orally available, quinazoline-based agent that competes with adenosine triphosphate for binding with the intracellular catalytic domain of epidermal growth factor receptor (HER1/EGFR) tyrosine kinase, inhibiting phosphorylation. This action blocks downstream signal transduction and inhibits the tumorigenic effects associated with ligand-dependent and ligand-independent HER1/EGFR activation. In preclinical studies, erlotinib has substantial antitumor activity against various human tumor xenografts alone and in combination with chemotherapeutic drugs. Phase I data showed that erlotinib was well tolerated, with encouraging antitumor activity in patients with various types of solid tumors. Furthermore, phase II monotherapy trials in patients with advanced non-small cell lung cancer, ovarian cancer, and head and neck squamous cell cancer, respectively, show favorable activity compared with single-agent chemotherapy in similar patient populations. Phase III trials with erlotinib in non-small cell lung cancer and pancreatic cancer are in progress, as are a range of studies in various indications designed to optimize the use of erlotinib alone and in combination with chemotherapy, radiotherapy, and other targeted agents.
 ...
PMID:Erlotinib (Tarceva): an update on the clinical trial program. 1284 Jul 99

The improved understanding of the molecular biology of urothelial malignancies is helping to define the role of new targets and prognostic indices that can direct the most appropriate choice of treatment for advanced disease. Many human tumors express high levels of growth factors and their receptors that can be used as potential therapeutical targets. Tyrosine-kinase receptors, including many growth factor receptors such the receptors for epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and Her2/neu, have been found overexpressed in urothelial tumors. For many of these growth factor receptors, the degree of expression has been associated with the progression of cancer and a poor prognosis. Among the best studied growth factor receptors are the two members of EGF receptor familiy EGFr (ErbB-1), and Her2/neu (ErbB-2). Several preclinical studies in bladder cancer models, have confirmed that systemic administration of growth factor inhibitors inhibits the growth and metastasis of human transitional cell carcinoma established in the bladder wall of athymic nude mice. Additional studies indicate that therapy with EGFR inhibitors enhances the activity of conventional cytoreductive chemotherapeutic agents, in part by inhibiting tumor cell proliferation, angiogenesis, and inducing apoptosis. Novel targeted therapy hold promise to improve the current results of bladder cancer treatment. Based on the success seen with anti-HER2 monoclonal antibodies (Herceptin) and the promising results with EGFR targeted agents (IMC-C225 Cetuximab, ZD1389 Iressa, OSI-774 Tarceva, GW 57016) in other tumor types, and based on the results obtained in preclinical models, there is a great interest in assessing these agents in patients with bladder cancer. Several trials are now ongoing testing these new agents alone or in combination with chemotherapy in bladder cancer patients. The integration of these newer biologic agents, probably to supplement rather than to supplant chemotherapeutic drugs, should be a primary direction of research with the objective to interfere with multiple aspects of bladder cancer progression. However, the value of integration of biologically targeted agents into combined modality treatment for patients with bladder cancer has still to be proven.
 ...
PMID:Novel approaches with targeted therapies in bladder cancer. Therapy of bladder cancer by blockade of the epidermal growth factor receptor family. 1285 May 30

The epidermal growth factor receptor (EGFR) is a transmembrane receptor involved in the regulation of a complex array of essential biological processes such as cell proliferation and survival. Dysregulation of EGFR signaling network has been frequently reported in multiple human cancers and has been associated with the processes of tumor development, growth, proliferation, metastasis and angiogenesis. Inhibition of the EGFR was associated with antitumor effects in preclinical models. On the bases of these data, therapeutics targeting the EGFR were explore in clinical trials. Tarceva (OSI-774, OSI Pharmaceuticals, Uniondale, NY) is a small molecule selective inhibitor of the EGFR tyrosine kinase (TK). In preclinical studies, Tarceva inhibited the phosphorylation of the EGFR in a dose and concentration dependent manner resulting in cell cycle arrest and induction of apoptosis. In in vivo studies, the agent caused tumor growth inhibition and shoved synergistic effects when combined with conventional chemotherapy. Subsequent single agent phase I studies and phase I studies in combination with chemotherapy demonstrated that the agent has a good safety profile and induced tumor growth inhibition in a substantial number of patients with a variety of different solid tumor. Preliminary report from phase II studies confirmed the excellent tolerability of Tarceva as well as showed encouraging preliminary activity. Phase III studies have either been completed or are ongoing in several tumor types such as lung cancer and pancreatic cancer. In summary, Tarceva is a novel inhibitor of the EGFR TK which has shown promising activity in initial studies and is currently undergoing full development as an anticancer drug.
 ...
PMID:Development of the epidermal growth factor receptor inhibitor Tarceva (OSI-774). 1290 62

Improved understanding of tumor biology has led to the identification of numerous growth factors that are involved in malignant transformation and tumor progression. Many of these factors induce cellular responses through receptors with intrinsic tyrosine kinase (TK) activity. Therefore, inhibiting the activity of TK receptors is one of the ways to effectively block the disordered proliferation of cancer that arises from these pathways. The human epidermal growth factor receptor (HER) family is overexpressed or dysfunctional in many human malignancies. Therefore, these receptors have been identified as targets for cancer therapy. Several agents have been developed that reversibly or irreversibly inhibit one, two, or all of the HER receptors. Iressa and Tarceva are HER1-specific TK inhibitors that are in advanced development. The large phase II study of Iressa (IDEAL1) in patients with non-small-cell lung cancer (NSCLC) in whom previous platinum-based therapy has failed, found that the median survival time (MST) was 7.6 months, which was no less than that with Docetaxel treatment. Other dual or pan-HER, reversible or irreversible, TK inhibitors are being investigated in phase I trials. Early data show that they are generally well tolerated and have provided evidence of against activity tumors. HER-TK inhibitors are likely to have a substantial impact on the treatment of cancer patients.
 ...
PMID:Molecular target-based cancer therapy: tyrosine kinase inhibitors. 1295 75

The epidermal growth factor receptor (EGFR) has emerged in recent years as a key target of molecular therapy for solid tumors. The postembryonic role of EGFR is normally limited. In cancer, however, abnormal EGFR-tyrosine kinase (TK) activity plays a central role in many of the processes involved in tumor progression, such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Several different approaches have been taken to inhibit EGFR-mediated activity in tumor cells, including monoclonal antibodies directed at the ligand-binding portion of the EGFR and small-molecule agents that directly inhibit the intracellular TK domain of EGFR. Two of these TK inhibitors, gefitinib and erlotinib (OSI-774, Tarceva ), have shown antitumor activity and good tolerability across several tumor types in early dose-finding clinical trials, particularly for non-small-cell lung cancer (NSCLC). In heavily pretreated patients with advanced NSCLC, gefitinib showed clinically significant tumor responses and symptom relief with good tolerability. Based on these results, gefitinib has now been approved for the third-line treatment of advanced NSCLC. The use of gefitinib in standard treatment programs or combined with other molecular targeted agents may substantially improve the outlook for patients with NSCLC or other types of solid tumors
 ...
PMID:Biologically targeted treatment of non-small-cell lung cancer: focus on epidermal growth factor receptor. 1464 89

Erlotinib (Tarceva) is an orally available selective small-molecule inhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentration of 2 nM for purified tyrosine kinase. This agent has been shown to produce stasis or regression of tumor growth in human cancer xenograft models, including non-small-cell lung cancer models. Ongoing preclinical investigations indicate that inhibition of the MAPK and Atk signaling pathways downstream of HER1/EGFR may be required for optimal antitumor effects. Erlotinib exhibits inhibition of MAPK and Atk kinases at concentrations higher than those required for HER1/EGFR tyrosine kinase inhibition; such findings suggest that maximal inhibition of HER1/EGFR, requiring high erlotinib doses, is necessary for optimum antitumor activity. These considerations are supported by tumor models, including non-small-cell lung cancer models, showing dose-related antitumor effects up to high doses of erlotinib. Erlotinib exhibits additive antitumor effects when combined with chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel, gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy, and other targeted agents (e.g., bevacizumab [Avastin]). Recent studies indicate that erlotinib inhibits the EGFRvIII mutant at concentrations higher than those required for inhibition of wild-type receptor. Ongoing investigation will help to determine optimal dosing and dose frequency of erlotinib in various cancers in the clinical setting.
 ...
PMID:Erlotinib: preclinical investigations. 1468 18

Rash is a class effect of HER1/epidermal growth factor receptor (EGFR)-targeted agents, and has occurred with high frequency and in a dose-dependent manner in clinical trials of these agents in cancer patients. Analysis of phase II trials of erlotinib (Tarceva) in non-small-cell lung cancer, head and neck cancer, and ovarian cancer shows a significant association between rash severity and objective tumor response. Rash severity was highly significantly associated with survival in patients with non-small-cell lung cancer receiving erlotinib; median survival in patients with no rash was 46.5 days, compared with 257 days in those with grade 1 rash (P < .0001) and 597 days in those with grade 2/3 rash (P < .0001). Similarly, for the combined non-small-cell lung cancer, head and neck cancer, and ovarian cancer studies, median survival in patients with no rash was 103 days, compared with 191 days in those with grade 1 rash (P = .0001) and 266 days in those with grade 2/3/4 rash (P = .0001). Similar findings have been made with cetuximab (Erbitux) and in some settings with gefitinib (Iressa). The strong association of rash severity with response/survival suggests that rash may serve as a marker of response to erlotinib treatment and may be used to guide treatment to obtain optimal response. Dosing erlotinib at the maximum tolerated dose, which is associated with more frequent and more severe rash, may improve response rates and survival durations. Further study of the potentially important association between rash and outcome of treatment with EGFR-targeted agents is needed.
 ...
PMID:Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? 1468 20


1 2 3 4 5 6 7 8 9 10 Next >>