Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article reviews the current state of efforts targeting the ErbB family of tyrosine kinase receptors in cancer therapy. In particular, preliminary results will be discussed of studies of the first generation of therapeutics to enter clinical evaluation in malignant diseases. Results of recently conducted clinical studies with ZD1839 (Iressa), OSI-774 (Tarceva), Cetuximab (IMC-C225) and trastuzumab (Herceptin) and several other compounds are presented. Potential advantages and disadvantages of these different therapeutic modalities, as well as future challenges of evaluating ErbB-targeted agents in the clinic, are presented.
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PMID:The ErbB receptor family: a therapeutic target for cancer. 1192 83

The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression. Epidermal growth factor receptor-activated signalling pathways control cell proliferation, apoptosis, angiogenesis and metastatic spread in the majority of human epithelial cancers. Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy. Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals. Several anti-epidermal growth factor receptor agents are in clinical development for cancer therapy. Among these, IMC-225 (cetuximab), a chimeric human-mouse monoclonal IgG1 antibody, OSI-774 (Tarceva) and ZD1839 (Iressa), two small molecule epidermal growth factor receptor-selective tyrosine kinase inhibitors, are currently in Phase II and III development as single agents or in combination with conventional therapies, such as radiotherapy or chemotherapy. Results from Phase I - II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types.
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PMID:Anti-epidermal growth factor receptor drugs in cancer therapy. 1203 20

The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been determined to 2.6-A resolution, both with and without an EGFRK-specific inhibitor currently in Phase III clinical trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva(TM)). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor. Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermolecular contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.
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PMID:Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. 1219 40

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.
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PMID:HER-targeted tyrosine-kinase inhibitors. 1242 50

Numerous small molecule synthetic tyrosine kinase inhibitors are in clinical development for the treatment of human cancers. These fall into three broad categories: inhibitors of the epidermal growth factor receptor tyrosine kinase family (e.g., Iressa trade mark and Tarceva trade mark ), inhibitors of the split kinase domain receptor tyrosine kinase subgroup (e.g., PTK787/ZK 222584 and SU11248) and inhibitors of tyrosine kinases from multiple subgroups (e.g., Gleevec trade mark ). In addition, agents targeting other tyrosine kinases implicated in cancer, such as Met, Tie-2 and Src, are in preclinical development. As experience is gained in the clinic, it has become clear that unleashing the full therapeutic potential of tyrosine kinase inhibitors will require patient preselection, better assays to guide dose selection, knowledge of mechanism-based side effects and ways to predict and overcome drug resistance.
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PMID:Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. 1251 54

Overexpression of the epidermal growth factor receptor (EGFR) is correlated with a poor prognosis in several human malignancies. In addition, cancers overexpressing EGFR respond poorly to both chemotherapy and radiation therapy. Therefore, EGFR is a viable target for cancer therapy. This review will address how EGFR blockade modulates signal transduction, leading to alterations in the cell cycle progression with secondary inhibition of proliferation and differentiation of cancer cells. As a prototypical example, erlotinib (Tarceva), a reversible EGFR tyrosine kinase inhibitor will be discussed. This drug has demonstrated promising antitumor activity in Phase II trials in several solid tumors and definitive Phase III studies to demonstrate clinical benefit have completed accrual.
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PMID:Erlotinib (Tarceva): a promising drug targeting epidermal growth factor receptor tyrosine kinase. 1282 Jul 72

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.
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PMID:Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer. 1282 Jul 79

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.
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PMID:Erlotinib (Tarceva): an update on the clinical trial program. 1284 Jul 99

Erlotinib [Tarceva, R 1415, CP 358774, OSI 774, NSC 718781] is a small molecular, once-a-day, orally active inhibitor of the epidermal growth factor receptor tyrosine kinase. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is one of a class of anticancer drugs that target the underlying molecular mechanism involving oncogenes and tumour suppressor genes, which play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is undergoing clinical development as an oral tablet by an alliance between OSI Pharmaceuticals, Genentech and Roche. OSI Pharmaceuticals, Genentech and Roche have entered an agreement for the global development and commercialisation of erlotinib. Under the terms of the agreement, Genentech and OSI will share costs and profit-taking for commercialising the product in the US. The overall costs of the development programme will be shared equally between the three companies. OSI will keep certain co-promotion rights in the US and Genentech will be responsible for commercialising the drug in the US should the FDA approve it. Roche will take the responsibility for obtaining regulatory approval and commercialisation in territories outside the US and pay royalties to OSI on net sales of the product in these markets. Initially, the alliance partners intend to pursue development of erlotinib in all the major tumour markets, particularly for non-small cell lung cancer (NSCLC) in which the group will focus on front-line combination approaches. Pfizer and OSI Pharmaceuticals in the US were developing erlotinib as a treatment for solid tumours. However, in June 2000, Pfizer merged with Warner-Lambert. The resulting company retained the Pfizer name, but in order to meet Federal Trade Commission requirements for the merger Pfizer granted all developmental and marketing rights for erlotinib to OSI Pharmaceuticals. This divestiture of the erlotinib portfolio, in effect, gave OSI a royalty-free, cashless license to the drug. In November 2001, OSI announced a partnership deal with HopeLink Corporation, a healthcare information technology company with an Internet-based Clinical Trial Service. The partnership will enable OSI to heighten awareness of its clinical trials and shorten patient accrual times. It will initially involve the presentation of the OSI phase III pancreatic and refractory NSCLC trials via Hopelink's Syndicated Network. In addition to this the two companies have also agreed to develop additional products and service together that will increase the efficiency of the clinical trial process, increase awareness of clinical trials, and enhance patient accrual techniques. OSI has also entered into an agreement with Therradex, a contract research organisation (CRO) to monitor phase II trials for erlotinib in NSCLC, ovarian and head and neck cancer. In addition, OSI entered into an agreement in 2001 with the US NCI. The NCI is conducting trials in a variety of different cancers. A phase III front-line NSCLC trial (TRIBUTE) of erlotinib in combination with carboplatin and paclitaxel was initiated in July 2001. The multicentre study is being conducted by Genentech in 1000 patients in the US, and will determine whether the addition of erlotinib to carboplatin chemotherapy is able to improve the duration of patient survival. Enrolment for this trial was completed in July 2002. An independent Data Monitoring Committee (DMC) has since reviewed the data from the trial and concluded that there are no safety or efficacy concerns that would warrant stopping the trial. However, the DMC did recommend stopping erlotinib at the time of disease progression or at the start of second-line therapy. A front-line phase III study of erlotinib in NSCLC (TALENT) in combination with gemcitabine and cisplatin chemotherapy was initiated by Roche in Europe in November 2001. Enrolment into this study was completed in September 2002, with approximately 1200 patients. Roche has confirmed that the study woulde has confirmed that the study would be included in the alliance's potential regulatory submission for front-line therapy in chemotherapy-naive patients in the US. Data from the trial is expected in the second half of 2003. OSI has opened two additional phase Ib studies to examine the potential of erlotinib in combination with carboplatin and paclitaxel in one study and gemcitabine and cisplatin in the other. A phase I study of erlotinib is also being conducted in patients with lung cancer in Japan. OSI received fast-track status from the US FDA in September 2002 for erlotinib as a second- or third-line treatment for patients with incurable stage IIIB/IV NSCLC who have failed to respond to standard therapy for advanced metastatic disease. Fast-track status was also granted to erlotinib in May 2002 for the treatment of chemotherapy-naive stage III/IV NSCLC. There are important differences between phase III studies of erlotinib and AstraZeneca's direct competitor drug gefitinib, which recently returned disappointing results in a frontline NSCLC trial with combination chemotherapy. In assessing the survival benefit of erlotinib with chemotherapy, the dose employed of 150 mg/day is the maximum tolerated dose (MTD), whereas the gefitinib trials were conducted at relatively lower doses than the MTD determined in earlier phase I studies. OSI is also investigating the survival benefit of erlotinib in a phase III study in refractory NSCLC patients, a key registration study. Patient size of the NSCLC trial was increased from 330 to 700 as OSI shifted emphasis from its pancreatic cancer trials. Phase II development for this indication was initiated based on data from a phase I trial, which had completed patient enrolment by April 2003. OSI and the US NCI signed a collaborative research agreement in 2001. The NCI is developing erlotinib through its CTEP programme for multiple tumour types including epithelial malignancies, gastrointestinal and genitourinary tracts, gynaecological malignancies and brain tumours. OSI supplies erlotinib for the trial, but the NCI provides the funding and manages the trials. A series of approximately ten phase Ib trials are already underway or were set to start in the US in 2001 to determine safety, tolerance and pharmacokinetic parameters of erlotinib in combination with a number of commonly used chemotherapeutic agents. The Wall Street Journal reported on 25 February 2002, that analysts at Robert Stephens, New York, USA, have forecast Tarceva to reach annual sales of >$US1 billion. Other analysts, at Merrill Lynch & Co., have predicted that products belonging to the same class as Tarceva could reach combined worldwide sales of $US6 billion to $US10 billion annually. In an earlier report by the Financial Times on 10 May 2001, it was stated that approximately 12 new anticancer agents are expected to be approved by the FDA through to the end of 2002. These agents, of which Tarceva is one, were said to have the potential to generate total sales of $US2.6 billion. Goldman Sachs have forecast Tarceva to reach peak sales of $US250 million for the indication of head and neck cancer alone. Previously in January 2001, the Financial Times claimed that OSI Pharmaceuticals, one of the development partners for Tarceva, stood to gain $US187 million pending regulatory approval. Genentech and Roche were each said to be buying $US35 million worth of OSI's stock and paying upfront fees. Tarceva is facing competition by two similar compounds, developed by AstraZeneca and ImClone, respectively.
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PMID:Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415. 1284 90

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.
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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


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