Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The critical role of angiogenesis in tumour growth and metastasis is now well established in the literature. Growing tumours stimulate neovascularisation through the secretion of pro-angiogenic growth factors, in particular, basic fibroblast growth factor and VEGF. Several lines of evidence have implicated VEGF in tumourigenesis, and understanding the role of VEGF in tumour angiogenesis has facilitated the development of novel targeting agents that specifically interfere with angiogenesis. Different approaches to disrupting tumour-induced angiogenesis encompass tyrosine kinase inhibitor, monoclonal antibodies, small-molecule inhibitors and transcription inhibitors. However, monoclonal antibody and tyrosine kinase inhibitors are the most advanced drug classes currently being investigated in clinical trials. So far, three anti-VEGF inhibitors, bevacizumab, sunitinib and sorafenib, have been approved for the treatment of solid human malignancies including colorectal cancer, gastrointestinal stromal tumours and renal cell carcinoma. Other antiangiogenic drugs are being investigated in various types of cancer. This review summarises the current literature on the use of these agents to interfere with VEGF, VEGF receptor, the matrix breakdown or other mechanisms involved in angiogenesis.
 ...
PMID:Therapeutic options to target angiogenesis in human malignancies. 1706 23

Recent data have expanded the concept that cancer-associated stromal fibroblasts (CAFs) play an important role in tumor invasion and angiogenesis. Here, we show that platelet-derived growth factor (PDGF) is a mitogen for human CAFs isolated from hepatic metastases of colorectal cancer. The tyrosine kinase inhibitor imatinib mesylate (1 microM) abrogated the PDGF-induced DNA synthesis, and furthermore counteracted an inhibitory effect of PDGF on the expression of alpha-smooth muscle actin (alpha-SMA). High-dose imatinib mesylate (10 microM) decreased the viability of CAFs in vitro independent from co-stimulation with PDGF. Interestingly, imatinib mesylate (10 microM) strikingly induced the expression of the pro-inflammatory and pro-angiogenic cytokines interleukin (IL)-6 and IL-8, and mildly stimulated the release of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Our results suggest that imatinib mesylate, due to its anti-proliferative activity, may be effective in combination with other substances for the treatment of colorectal metastasis progression.
 ...
PMID:Imatinib mesylate inhibits proliferation and modulates cytokine expression of human cancer-associated stromal fibroblasts from colorectal metastases. 1714 49

Colorectal cancer is an ideal model in which to study malignant progression from the molecular-genetic perspective because different stages of the same malignancy coexist within each patient. Approximately 75% of colorectal cancer cases are sporadic and the remaining are familial disease, yet genetic mutations that have been identified account for only 5% to 6% of inherited cases. The two major pathways by which mutational changes leading to colorectal cancer occur are chromosomal instability and microsatellite instability. This article discusses genes and signaling pathways involved in development of inherited disease, as well as the association of some of these pathways with sporadic cases. Furthermore, therapies targeting active pathways in colorectal carcinogenesis, including the vascular endothelial growth factor and epidermal growth factor receptor tyrosine kinase, have shown promising results in clinical trials are now included in standard recommended treatment.
 ...
PMID:Molecular biology of colorectal cancer: new targets. 1717 80

The discovery of epidermal growth factor receptor (EGFR) mutations in never-smokers has been the most relevant finding ever in non-small cell lung cancer. When patients whose tumors bear the sensitizing mutations are treated with the tyrosine kinase inhibitors gefitinib or erlotinib, we witness response rates and durations never before reported, including complete responses. At the same time, the presence of EGFR mutations has raised numerous new questions, tantalizing data, and new challenges for treatment. This is particularly true as we try to generalize the findings in lung cancer to other malignancies. The indiscriminate use of gefitinib or erlotinib in the general lung cancer population results in meager survival benefit for patients. Similarly, the tyrosine kinase inhibitors have limited activity in a variety of tumor types with EGFR overexpression. This has led to the question of whether EGFR remains a viable target in patients other than those whose tumors contain mutations, and whether the modest activity of cetuximab in colorectal cancer and head and neck cancer represents all that we can expect from inhibition of this pathway in the absence of mutation. Mechanisms of pathway activation other than mutation have been discovered in recent years, and include overexpression mediated by gene amplification or by amplification of a dinucleotide repeat in the EGFR promoter, mutation of an extracellular region on EGFR generating a mutant protein termed EGFRvIII, and enhanced signaling due to heterodimerization with other members of the EGFR family, particularly overexpression of HER2/HER3. The extent to which these paths to EGFR activation will confer sensitivity to the tyrosine kinase inhibitors or to EGFR monoclonal antibodies is being explored. Thus far, published clinical data suggest that there is little room for the administration of gefitinib or erlotinib in the absence of EGFR mutations. The five articles in this edition of CCR Focus will address the various mechanisms of EGFR pathway activation and provide insight into the potential for translation into clinical relevance.
 ...
PMID:Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway. 1718 93

Research on developing molecular diagnostics for hereditary cancers resulted in establishing diagnostic services for familiar polyposis and non-polyposis patients (mutation determination of APC, MYH, STK11, SMAD4, MLH1, MSH2). In familiar testicular cancers the role of gr/gr gene on Y chromosome was identified. Molecular diagnostic tool was established to monitor the progression of follicular lymphoma using Bcl-2/IgH fusion sequences. Molecular diagnostic tools were developed to monitor circulating endothelial precursor cells (CEP) as well and the technique was tested in lung cancer patients. In malignant melanoma we have tested several potential novel markers among which ryanodine receptor seems to be a promising one, while the functional P2X7 receptor may serve as a therapeutic target. We have determined the tyrosine kinase "kinome" profile of HER-2-amplified breast cancers. Furthermore, the "kinome" profile was found to be characteristic for head and neck cancers of various anatomical location. Based on previous studies on the anti-migratory and antimetastatic potential of low-molecular-weight heparins, we have identified short heparin-derived oligosaccharides with maintained antimetastatic- but non-anticoagulant potentials. Pharmacogenomic studies on the role of polymorphism of the serine-hydroxymethyl-transferase (SHMT) gene in the efficacy of 5-FU and FOLFIRI protocols of colorectal cancer patients revealed a significant effect resulting in altered overall survival as well.
 ...
PMID:[Developments in cancer management by innovative genomics. 2006 report of the National Cancer Consortium]. 1721 11

Lapatinib (GW 572016) is an oral inhibitor of the tyrosine kinase activity of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2), which are both frequently altered in human malignant tumors. Being a multitargeting agent, it has the theoretical ability to provide more efficient antitumor activity and delay the onset of tumor resistance. Based on promising preclinical results, lapatinib is being extensively studied in cancer patients. In Phase I clinical trials, the side effect profile of lapatinib results are favorable, with a few patients experiencing serious toxicity. Phase II studies showed that lapatinib has meaningful clinical activity in the setting of HER2-positive advanced breast cancer patients. Unfortunately, its activity in epidermal growth factor receptor-dominated cancers, such as colorectal cancer or squamous cell carcinoma of the head and neck, is modest. An extensive program is now ongoing in breast cancer patients to establish the correct role of lapatinib in this clinical setting. Studies in breast cancer, as well as in other solid tumors are also collecting a large amount of biological data. Correlative studies will hopefully clarify predictive factors of lapatinib efficacy that can be applied in clinical practice in order to select patients for treatment.
 ...
PMID:Lapatinib: a dual inhibitor of EGFR and HER2 tyrosine kinase activity. 1725 Apr 63

The licensing of bevacizumab in patients with metastatic colorectal cancer has fueled research in angiogenesis. Vatalanib (PTK787/ZK 222584), a potent oral tyrosine kinase inhibitor with a selective range of molecular targets, has been extensively investigated and has shown promising results in patients with colorectal cancer in early trials. Dynamic contrast-enhanced MRI has been useful as a pharmacodynamic tool to define the dose that has a biological effect. The primary objectives of the Phase III CONFIRM (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in First-line) studies were not met. However, an interesting pre-planned subset analysis in both studies showed that patients with high lactate dehydrogenase derived clinical benefit. Although this type of analysis should always be considered with caution, the Phase III clinical programme of vatalanib is continuing with further innovative studies looking at other indications and schedules for vatalanib.
 ...
PMID:Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours. 1730 31

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal cancer of teh gastrointestinal tract. They are characterized by the expression of KIT. Therapeutically, metastatic GISTs are effectively treated by imatinib, a tyrosine kinase inhibitor (TKI) with activity against KIT and platelet-derived growth factor receptor. Gastrointestinal stromal tumors refractory to standard therapy with imatinib are a clinical challenge. This has lead to the clinical testing of a variety of agents used alone or in combination with other TKIs. Sunitinib, a multitargeted TKI, is the first drug available fort eh treatment of these patients. Additional trials are ongoing, evaluating the efficacy of the novel KIT TKIs AMG 706 and AMN 107 (nilotinib). RAD001, PKC412, and bavacizumab are being tested in conjunction with imatinib. Lastly, the heat-shock protein-90 inhibitor IPI-540 is also in phase I evaluation in imatinib-refractory patients with GIST. The future management of GIST is likely to be altered by the availability of more agents and by better biologic understanding of the patient populations each agent best treats.
Clin Colorectal Cancer 2006 Nov
PMID:Beyond imatinib: second generation c-KIT inhibitors for the management of gastrointestinal stromal tumors. 1741 50

Since the mid-1980s, it has been known that the epidermal growth factor receptor, an immunoglobulin G cytoplasmic membrane protein and member of the type I subfamily of tyrosine kinase receptors, plays a key role in tumor growth and metastasis. Cetuximab is the first immunoglobulin G1 monoclonal antibody that blocks the epidermal growth factor receptor, resulting in an inhibition of tumor growth, angiogenesis, tumor spread and metastasis. Cetuximab is active in heavily pretreated colorectal cancer, as a single agent or in combination with irinotecan, a conclusion that is strongly suggested by the Bowel Oncology with Cetuximab Antibody (BOND) study in terms of response rate (11% monotherapy vs 23% in combination; p < 0.007) and time to progression (1.5 vs 4.1 months; p < 0.001). The main adverse event related to cetuximab is skin reaction, the intensity of which is correlated with efficacy. The Monoclonal Antibody Erbitux in a European Pre-License (MABEL) study has confirmed these results, recently generating a median survival of 9.2 months, comparable to 8.6 months achieved in the BOND study. Cetuximab has shown efficacy (with or without irinotecan) as second-line treatment in patients who have failed irinotecan in combination with bevacizumab, an antivascular endothelial growth factor monoclonal antibody. The combination is currently being tested in the first-line management of advanced colorectal cancer, as well as in the adjuvant setting. The evaluation of other combinations either with oxaliplatin or capecitabine, is ongoing, with preliminary reports of promising activity.
 ...
PMID:Cetuximab plus irinotecan in refractory colorectal cancer patients. 1742 61

Vascular endothelial growth factor (VEGF) is one of the most important factors involved in tumor angiogenesis and has become an important target for anticancer treatment. In 2004, this approach was validated in a randomized, controlled phase III clinical trial. It was shown that the addition of bevacizumab, a humanized monoclonal antibody against VEGF-A, to conventional chemotherapy prolonged survival over chemotherapy alone in patients with metastatic colorectal cancer. In this review, we discuss the results of the clinical trials that have led to the incorporation of antiangiogenic agents into the treatment of patients with advanced colorectal cancer. We limit ourselves to the two agents that have been tested extensively in phase III trials: bevacizumab and vatalanib, a small molecule tyrosine kinase inhibitor against VEGF receptors. In addition, we discuss the adverse effects of bevacizumab and vatalanib and the clinical management of the side effects.
 ...
PMID:Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. 1747 Jun 87


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