Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.
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PMID:[Angiogenesis inhibitors for the systemic treatment of metastatic renal cell carcinoma: sunitinib, sorafenib, bevacizumab and temsirolimus]. 1838 Mar 84

c-Src is a proto-oncogene involved in the genesis of and invasion by many cancers. This non-receptor tyrosine kinase also plays a crucial role in bone homeostasis, since inhibition or deletion of c-Src impairs the function of osteoclasts, the bone resorbing cells. It is thus conceivable that c-Src could be a suitable target for the pharmacological treatment of cancers, skeletal metastases and diseases of bone loss, such as osteoporosis. The pyrrolo-pyrimidines CGP77675 and CGP76030 proved to be effective in preventing bone loss in animal models, while the effect of AZD0530, a dually active inhibitor of c-Src and Bcr-ABL, on bone resorption, has been tested in a Phase I clinical trials with promising results. As far as the metastatic bone disease is concerned, c-Src inhibitors could potentially have inhibitory effects both on osteoclasts and on tumour cells, and could disrupt the vicious circle established between these cell types in the bone microenvironment. In accord with this idea, CGP76030 is able to reduce the incidence of osteolytic lesions and of visceral metastases, and to suppress morbidity and lethality in a bone metastasis mouse model without obvious adverse effects. The purine-based c-Src inhibitor AP23451 and the dual c-Src/Abl inhibitors AP22408 and AP23236 proved efficacious in reducing bone metastases in preclinical studies. These results open a new avenue for the development of innovative therapies for the treatment of bone metastatic disease.
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PMID:Inhibition of protein kinase c-Src as a therapeutic approach for cancer and bone metastases. 1839 92

The c-Met proto-oncogene encodes a receptor tyrosine kinase (TK) that promotes invasive tumor growth and metastasis. Recent studies show that the presence of c-Met gene amplification is predictive for selective c-Met TK inhibitors in gastric cancer and lung cancer. In this study, we utilized a highly quantitative PCR/ligase detection reaction technique to quantify c-Met gene copy number in primary colorectal cancer (CRC) (N=247), liver metastases (N=147), and paired normal tissues. We identified no differences in c-Met gene copy number between normal colonic mucosa and liver tissue. However, mean c-Met gene copy number was significantly elevated in CRC compared with normal mucosa (P<0.001), and in liver metastases compared with normal liver (P<0.001). Furthermore, a significant increase in c-Met was seen in liver metastases compared with primary CRC (P<0.0001). c-Met gene amplification was observed in 2% (3/177) of localized cancers, 9% (6/70) of cancers with distant metastases (P<0.02), and 18% (25/147) of liver metastases (P<0.01). Among patients treated by liver resection, there was a trend toward poorer 3-year survival in association with c-Met gene amplification (P=0.07). Slight increases in c-Met copy number can be detected in localized CRCs, but gene amplification is largely restricted to Stage IV primary cancers and liver metastases. c-Met gene amplification is linked to metastatic progression, and is a viable target for a significant subset of advanced CRC.
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PMID:c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. 1839 71

Gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal neoplasm of the gastrointestinal tract. Now, there is widespread scientific and clinical interest in GIST because of identifying in principal pathogenetic defects and development of a specific molecular inhibitor of GIST. GISTs have a gain-of-function mutation in the c-kit protooncogene. Mutation results in constitutive activation of the Kit receptor tyrosine kinase, which induces malignant cell proliferation. Imatinib (gleevec) is an oral agent that selectively inhibits c-Kit, whose efficacy proves that a specific inhibitor can counteract the effects of a genetic defect responsible for cancer. Although STI571 was first applied to GIST, it has already revolutionized the treatment of patients with metastases. Now so many molecular target agents are under development in clinical trials.
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PMID:[GIST]. 1848 9

Gastrointestinal stromal tumour (GIST) is the commonest mesenchymal tumour to affect the gastrointestinal tract. Appropriate management requires accurate diagnosis and the skills of a multidisciplinary team. Surgery is the only curative treatment option and should be performed whenever feasible, by experienced personnel. For patients with advanced unresectable or metastatic disease, the receptor tyrosine kinase inhibitor imatinib offers effective therapy and can provide effective palliation for the majority of patients with this disease. The background to this recent development and a guideline for the management of GIST is proposed.
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PMID:A Guideline for the Management of Gastrointestinal Stromal Tumour (GIST). 1852 37

Gastrointestinal stromal tumors (GISTs) generally arise from primary activating mutations in the KIT or PDGFRA genes that result in constitutive activation of receptor tyrosine kinase activity. Imatinib provides targeted therapy for GIST by inhibiting the KIT and PDGFR-alpha tyrosine kinases. Clinical benefit is achieved in approximately 85% of patients with unresectable or metastatic disease, with a median progression-free survival of 20 to 24 months. The mechanisms of acquired resistance to imatinib are heterogeneous, with most involving the emergence of secondary mutations in KIT exons 13, 14, or 17. In patients failing or intolerant to imatinib, the multitargeted agent sunitinib achieves durable disease control in approximately 50% of cases. Experimental treatment options beyond those currently available consist of other KIT-targeting tyrosine kinase inhibitors, such as nilotinib, or agents targeting alternative pathways, such as antiangiogenic agents, mammalian target of rapamycin, RAF kinase, and chaperone inhibitors.
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PMID:Novel approaches to imatinib- and sunitinib-resistant GIST. 1877 61

Approximately 80% of advanced metastatic gastrointestinal stromal tumors (GISTs) respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, the majority of patients suffer disease progression at a median of 2 years due to drug resistance. In general, progressing GISTs retain their typical morphology. Herein, we report 5 cases of progressing metastatic GIST with heterologous rhabdomyoblastic differentiation after TKI treatment. Histologic, immunohistochemical, and mutational analyses were performed on histologically classic GISTs and components with rhabdomyoblastic differentiation. There were 3 men and 2 women (ranging from 35 to 66 y of age). Three tumors were localized at presentation (2 stomach and 1 small bowel) and 2 presented with metastases. All localized primary tumors were high risk. Two tumors showed spindle cell morphology and 3 were epithelioid, including 1 with marked pleomorphism. After resection of the 3 localized primary tumors, intra-abdominal (2 patients) and liver (1 patient) metastases developed. All patients were treated with imatinib and showed partial clinical responses (4 patient) or stable disease (1 patient). Four patients subsequently progressed; 2 patients were treated with sunitinib after progression with minor responses. Four patients underwent surgical debulking. At last follow-up (range: 20 to 87 mo), 2 patients died of disease, 2 were alive with metastatic disease resistant to TKIs, and 1 was alive without evidence of disease. In all cases, rhabdomyoblastic differentiation was identified adjacent to areas with classic GIST morphology in at least 1 metastatic site; in 1 case, the primary tumor (after treatment with TKIs) showed heterologous differentiation. The rhabdomyoblastic components showed strong and diffuse positivity for desmin and expressed myogenin, whereas KIT was negative in the rhabdomyoblastic component in all cases. Primary KIT mutations were detected in both the conventional GIST and rhabdomyoblastic components from all patients: KIT exon 11 mutations in 4 cases and a platelet-derived growth factor receptor alpha gene exon 18 deletion in 1 case. No secondary mutations of the type associated with TKI resistance were identified in the rhabdomyoblastic areas. This is the first report of rhabdomyoblastic differentiation occurring in GISTs that progressed on TKI therapy. It is associated with loss of KIT expression, but retention of the receptor tyrosine kinase mutation of the precursor GIST. The rhabdomyoblastic differentiation can represent a diagnostic pitfall. The molecular mechanisms for this form of TKI-resistant clonal evolution remain to be determined.
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PMID:Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: a novel form of tumor progression. 1883 Jan 21

Gastrointestinal stromal tumors (GISTs) are a rare and heterogeneous group of spindle cell neoplasms that have also been reported outside of gastrointestinal (GI) tract. These tumors are characterized by somatic mutations of c-KIT (CD117), a proto-oncogene that encodes a receptor tyrosine kinase normally expressed in the interstitial cell of Cajal that control the GI smooth muscle peristalsis, and an exquisite sensitivity to the action of the tyrokinase inhibitor imatinib mesylate (STI571; Gleevec). We report two cases of gastrointestinal stromal tumor identified on prostatic biopsies, where a primary prostatic sarcoma was considered in the differential diagnosis. In one of the cases, there was extensive local disease involving prostate, rectum, and pelvic wall, as well as metastatic disease that quickly lead to the patient's death despite aggressive treatment with imatinib mesylate and conventional chemotherapy. In the other case, the tumor was mostly confined to the rectum but also focally extended into the prostate capsule. The patient underwent resection and was alive without disease 18 months after surgery. In both cases, tissue samples from prostate and the rectum showed a malignant spindle cell neoplasm, which was positive for CD117 (c-kit). Given their unique clinical management, gastrointestinal stromal tumors should be considered in the differential diagnosis of spindle cell lesions on prostatic needle biopsies and CD117 should be added to the immunohistochemical panel in the work-up of such lesions to avoid misinterpreting them as primary prostatic neoplasms.
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PMID:Gastrointestinal stromal tumors presenting as a prostatic mass. 1922 92

The most common cause of death of cancer sufferers is through the occurrence of metastases. The metastatic behaviour of tumour cells is regulated by extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, and aberrant expression/activation of the c-Met receptor is closely associated with metastatic progression. Nk4 (also known as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and inhibits c-Met signalling and tumour metastasis. Nk4 has an additional anti-angiogenic activity independent of its HGF-antagonist function. Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects make the Nk4 sequence an attractive candidate for gene therapy of cancer. This study investigates the inhibition of tumour metastasis by gene therapy mediated production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is vital in order to achieve the highest therapeutic responses. Non-viral plasmid delivery methods have the advantage of safety and ease of production, providing immediate transgene expression, albeit short-lived in most tumours. Sustained presence of anti-angiogenic molecules is preferable with anti-angiogenic therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) might represent a more appropriate delivery in this respect. However, the incubation time required by AAV vectors to reach appropriate gene expression levels hampers efficacy in many fast-growing murine tumour models. Here, we describe murine trials assessing the effects of Nk4 on the spontaneously metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced the highest therapeutic response with significant reduction in both primary tumour growth and incidence of lung metastases. Plasmid-mediated therapy also significantly reduced metastatic growth, but with moderate reduction in primary subcutaneous tumour growth. Overall, this study demonstrates the potential for Nk4 gene therapy of metastatic tumours, when delivered by AAV or non-viral methods.
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PMID:Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours. 1927 40

The receptor tyrosine kinase EphB2 is expressed by colon progenitor cells; however, only 39% of colorectal tumors express EphB2 and expression levels decline with disease progression. Conversely, EphB4 is absent in normal colon but is expressed in all 102 colorectal cancer specimens analyzed, and its expression level correlates with higher tumor stage and grade. Both EphB4 and EphB2 are regulated by the Wnt pathway, the activation of which is critically required for the progression of colorectal cancer. Differential usage of transcriptional coactivator cyclic AMP-responsive element binding protein-binding protein (CBP) over p300 by the Wnt/beta-catenin pathway is known to suppress differentiation and increase proliferation. We show that the beta-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the beta-catenin-p300 complex. Gain of EphB4 provides survival advantage to tumor cells and resistance to innate tumor necrosis factor-related apoptosis-inducing ligand-mediated cell death. Knockdown of EphB4 inhibits tumor growth and metastases. Our work is the first to show that EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage.
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PMID:Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression. 1936 6


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