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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although Erbitux (cetuximab) has proven therapeutic benefit in the clinical setting, the molecular determinants predicting responsiveness to this agent are still not very well understood. Here, we assessed the relationship between basal total and activated (pY1068) epidermal growth factor receptor (EGFR) levels in a tumor and the responsiveness to cetuximab monotherapy or combination-based treatment using human xenograft models. Cetuximab treatment alone (0.25-1 mg/mouse/injection, q3d, i.p.) effectively delayed the growth of GEO and L2987 tumors by a minimum of 10 days corresponding to log cell kill values of >or=1.0. Borderline activity was seen in the A549 and WiDr xenografts. However, cetuximab failed to show any significant antitumor activity in the HT29, HCT116, LOVO, Colo205, LX-1, HCC70, and N87 models. All of the studied tumors had detectable yet variable levels of EGFR. For combination regimens, cetuximab (1 mg/mouse/injection, q3dx5, i.p.) and cisplatin (4.5 mg/kg/injection, q3dx5, i.v.) proved to be significantly more efficacious than individual monotherapies in the cisplatin-refractory yet cetuximab-responsive GEO tumor model (P < 0.001). However, no therapeutic enhancement was observed in the cisplatin and cetuximab weakly responsive A549 xenograft. Similarly, combinations of CPT-11 (48 mg/kg/injection, q3dx5, i.v.) with cetuximab (1 mg/mouse/injection, q3dx5, i.p.) failed to show any improvements over individual monotherapies in the cetuximab resistant/weakly responsive HT29, A549, and WiDr models. We conclude that preclinical activity associated with cetuximab monotherapy does not correlate directly with relative basal levels of total or activated (pY1068) EGFR in a tumor. Moreover, robust single-agent activity by cetuximab may be the best predictor for this agent to potentiate chemotherapy-mediated antitumor activities.
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PMID:Cetuximab preclinical antitumor activity (monotherapy and combination based) is not predicted by relative total or activated epidermal growth factor receptor tumor expression levels. 1643 68

Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the "humanization of antibodie" or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies "armed" with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.
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PMID:Monoclonal and bispecific antibodies as novel therapeutics. 1664 69

Anti-EGFR (epidermal growth factor receptor) therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, demonstrate activity in a variety of tumor types. While both inhibit the EGFR pathway, they act via different mechanisms. Monoclonal antibodies bind to the extracellular domain of EGFR, preventing ligand binding and interrupting the signaling cascade. Tyrosine kinase inhibitors bind to the intracellular domain of EGFR and inhibit the downstream effects of EGFR ligand binding. Both categories of agents have been evaluated in a variety of clinical settings and tumor types, including colorectal cancer, non-small-cell lung cancer (NSCLC), and squamous cell carcinoma of the head and neck (SCCHN). Phase II/III trials in patients with previously treated or untreated metastatic colorectal cancer, including those with documented refractory disease, demonstrate activity of the monoclonal antibody cetuximab (Erbitux) as a single agent or in combination with both irinotecan (Camptosar)- and oxaliplatin (Eloxatin)-based chemotherapy. Activity of cetuximab added to chemotherapy in patients who previously progressed on the same regimen suggests an ability to overcome chemotherapy resistance in some patients. In NSCLC, phase II trials of the TKI gefitinib (Iressa) plus combination chemotherapy showed impressive activity with considerable toxicity. Large, randomized, phase II trials (IDEAL 1 and 2) reported modest activity of gefitinib in NSCLC; however, phase III trials (INTACT 1 and 2)failed to demonstrate a benefit to adding gefitinib to chemotherapy. A similar trend was noted in trials of erlotinib (Tarceva) (TALENT and TRIBUTE). Phase II/III trials have shown promising activity of cetuximab in SCCHN, generating significantly improved survival in combination with radiotherapy over radiotherapy alone in locally advanced disease and significantly improved response rates in combination with chemotherapy over chemotherapy alone in recurrent/metastatic disease, with little enhancement of toxicity profiles. Limited clinical experience with TKIs in SCCHN suggests similar degrees of single-agent activity and dermatologic toxicities. Levels of EGFR expression and the presence of EGFR mutations correlate with responsiveness to TKI therapy, while it remains unclear whether a relationship exists between level of EGFR expression and cetuximab efficacy in colorectal cancer. Anti-EGFR therapies are good candidates for combination with other treatment modalities, including chemotherapy and radiotherapy, due to their tolerable safety profile and nonoverlapping toxicities. In addition, these agents represent important treatment options in patients ineligible for chemotherapy due to refractory or resistant disease. Ongoing trials continue to investigate both the monoclonal antibodies and TKIs in various treatment settings.
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PMID:Anti-EGFR therapies: clinical experience in colorectal, lung, and head and neck cancers. 1673 79

We hypothesized that immunoliposomes (ILs) constructed using Fab' from the humanized anti-EGFR monoclonal antibody, EMD72000, can provide efficient intracellular drug delivery in EGFR-overexpressing colorectal tumor cells.ILs were constructed modularly with various MAb fragments, including Fab' from EMD72000 (matuzumab) or C225 (cetuximab, Erbitux) covalently linked to stabilized liposomes containing chemotherapeutic drugs or probes. Immunoliposome preparation was optimized, including Fab' reduction and linkage, and evaluated for specific binding and cytotoxicity in epidermal growth factor receptor (EGFR)--overexpressing colorectal cancer cell lines in vitro. Flow cytometry showed that EGFR-targeted ILs, but not non-targeted liposomes or irrelevant ILs, were efficiently bound and internalized by a variety of EGFR-overexpressing colorectal cancer cells. Linkage of the Fab' to a longer PEG chain (Mal-PEG3400-DSPE) resulted in an increased uptake of immunoliposomal constructs when compared to previously used materials (Mal-PEG2000-DSPE). ILs derived from EMD72000-Fab' were used to deliver doxorubicin to EGFR-overexpressing target cells in vitro. Immunoliposomal doxorubicin was significantly more cytotoxic than the corresponding non-targeted liposomal drug in target cells, such as HCT116, while equivalent in cells lacking EGFR-overexpression, such as Colo205. We conclude that EGFR-targeted ILs derived from the humanized MAb EMD72000 provide efficient and targeted delivery of anticancer drugs in colorectal cancer cells overexpressing EGFR.
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PMID:EGFR-targeted immunoliposomes derived from the monoclonal antibody EMD72000 mediate specific and efficient drug delivery to a variety of colorectal cancer cells. 1677 80

Glioblastoma multiforme (GBM) is responsible for most of the deaths associated with primary brain tumors. Standard treatment includes maximal surgical resection followed by chemotherapy and concomitant radiotherapy. Most patients, however, recur shortly after treatment. Second line treatment has little efficacy and the majority of patients die soon from the disease. Recent advances in molecular biology have implicated the epidermal growth factor receptor (EGFR) signaling pathways in the progression and resistance to standard therapies for GBM. This has prompted the evaluation of EGFR tyrosine- kinase inhibitors with encouraging results. Cetuximab is a monoclonal antibody targeted against the extra cellular domain of the EGFR with activity against different tumor types, either alone or in combination with chemotherapy and/or radiation therapy. Here we describe three patients with recurrent, heavily pretreated, EGFR expressing GBM who responded to treatment with single agent cetuximab.
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PMID:Long term responses with cetuximab therapy in glioblastoma multiforme. 1703 33

Anti-EGFR monoclonal antibodies LA22 and Erbitux bind to different epitopes of EGFR. The chemimmunoconjugates of MMC with LA22 or Erbitux were prepared, and in vitro cytotoxicity assays with A549 cells showed that LA22-MMC was much more potent than Erbitux or Erbitux-MMC. Viabilities of A549 cells treated with LA22-MMC, Erbitux or Erbitux-MMC were 35%, 94%, and 81%, respectively. Immunoscintigraphy of xenografts of human A431 and A549 cells in nude mice both showed that (125)I-labeled-LA22-MMC enriched in tumor sites prominently. Most importantly, in vivo assays showed LA22-MMC was significantly more effective than free drug MMC in the treatment of subcutaneous xenografts of human A431 cells in nude mice (83% inhibition for LA22-MMC and 30% for MMC). We concluded that LA22-MMC could be a very potent drug for treatment of solid tumors.
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PMID:Inhibition of human tumor xenograft growth in nude mice by a conjugate of monoclonal antibody LA22 to epidermal growth factor receptor with anti-tumor antibiotics mitomycin C. 1695 Feb 1

RON is a member of the c-MET receptor tyrosine kinase family. Like c-MET, RON is expressed by a variety of epithelial-derived tumors and cancer cell lines and it is thought to play a functional role in tumorigenesis. To date, antagonists of RON activity have not been tested in vivo to validate RON as a potential cancer target. In this report, we used an antibody phage display library to generate IMC-41A10, a human immunoglobulin G1 (IgG1) antibody that binds with high affinity (ED50 = 0.15 nmol/L) to RON and effectively blocks interaction with its ligand, macrophage-stimulating protein (MSP; IC50 = 2 nmol/L). We found IMC-41A10 to be a potent inhibitor of receptor and downstream signaling, cell migration, and tumorigenesis. It antagonized MSP-induced phosphorylation of RON, mitogen-activated protein kinase (MAPK), and AKT in several cancer cell lines. In HT-29 colon, NCI-H292 lung, and BXPC-3 pancreatic cancer xenograft tumor models, IMC-41A10 inhibited tumor growth by 50% to 60% as a single agent, and in BXPC-3 xenografts, it led to tumor regressions when combined with Erbitux. Western blot analyses of HT-29 and NCI-H292 xenograft tumors treated with IMC-41A10 revealed a decrease in MAPK phosphorylation compared with control IgG-treated tumors, suggesting that inhibition of MAPK activity may be required for the antitumor activity of IMC-41A10. To our knowledge, this is the first demonstration that a RON antagonist and specifically an inhibitory antibody of RON negatively affects tumorigenesis. Another major contribution of this report is an extensive analysis of RON expression in approximately 100 cancer cell lines and approximately 300 patient tumor samples representing 10 major cancer types. Taken together, our results highlight the potential therapeutic usefulness of RON activity inhibition in human cancers.
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PMID:Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member. 1698 59

Epidermal growth factor receptor (EGFR) inhibitors are associated with unique and dramatic dermatologic side effects. Cetuximab, erlotinib, and gefitinib have been approved for patients with colorectal and non-small cell lung cancer refractory or intolerant to chemotherapy. Our aim was to describe key clinical features of common dermatologic adverse reactions among EGFR inhibitors, focusing mainly on skin toxicity, as well as to discuss the pathology, possible causes, and suggested treatments for these reactions. The most commonly encountered adverse effect was a mild skin toxicity characterized by a sterile follicular and pustular rash that may be treated empirically and usually does not require treatment modification. Although the precise mechanism for development of rash is not well defined, it is related to inhibition of EGFR-signaling pathways in the skin, and may serve as visible markers of anti-tumor activity and therapeutic efficacy. Secondary adverse reactions seen with anti-EGFR therapy include xerosis, pruritus, paronychia, hair abnormality, and mucositis.
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PMID:Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. 1701 Jul 47

Panitumumab (formerly known as ABX-EGF) is the first fully human monoclonal antibody to epidermal growth factor receptor to enter clinical trials for the treatment of solid tumors. Like cetuximab (Erbitux; BMS), it is directed against the extracellular ligand-binding domain of the receptor and results in blockade of the essential downstream signaling pathways that are known to govern apoptosis, proliferation and differentiation of both normal and neoplastic cell types in a wide array of tissues. It has a very high affinity for epidermal growth factor receptor and has been generally well tolerated and associated with very few infusion reactions. As a fully human agent, panitumumab has not been associated with the formation of any antibodies directed against it that has been evidenced by a very reliable pharmacokinetic profile with possible dosing schedules ranging from 1 to 3 weeks. Similar to other agents targeting the epidermal growth factor receptor pathway, a rash has been the primary toxicity and is dose dependent up to 2.5 mg/kg at which dose 100% of all patients have been affected. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal. It has been efficacious and well tolerated both as monotherapy and in combination with other chemotherapeutic agents. Several phase I trials, two phase II trials and most recently a phase III trial in pretreated colorectal cancer have been carried out to date. Currently, there is also a randomized phase III trial (Panitumumab Advanced Colorectal Cancer Evaluation Study) investigating the role of panitumumab in the first-line treatment of colorectal cancer. No unfavorable drug-drug interactions have been observed nor has there been any effect on the pharmacokinetics of drugs with which it is being used. Recent progress in preclinical and clinical studies of panitumumab is reviewed.
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PMID:Panitumumab the first fully human monoclonal antibody: from the bench to the clinic. 1715 97

There are a large number of tumor antigens, which may either be specific to the tumor or inappropriately expressed or processed (tumor-associated antigen, TAA). Over the last few years, hundreds of new TAAs have been identified. Some of these represent good targets for both passive (antibody based) and active (vaccine based) therapies. Antibody treatments targeted on tumor-specific antigens, such as Herceptin and Cetuximab, have been effective in clinical trials and are now licensed. In addition, TAAs act as good surrogate markers for use in both the diagnosis and assessment of treatment in cancer patients.
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PMID:Tumor antigens as surrogate markers and targets for therapy and vaccines. 1716 80


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