Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of critical importance in tumor invasion and metastasis. Based on this evidence, the pharmaceutical industry produced several well tolerated, orally active MMP inhibitors (MMPIs) which demonstrated efficacy in mouse cancer models. Phase III clinical trials initiated in 1997-98 using marimastat, prinomastat (AG3340), and BAY 12-9566 alone or in combination with standard chemotherapy in patients with advanced cancers (lung, prostate, pancreas, brain, GI tract) have recently been reported; no clinical efficacy was demonstrated. Bayer and Agouron have discontinued their ongoing Phase III drug trials of MMPIs in advanced cancer. In retrospect, the failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs appear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have been established. Our understanding of MMP pathophysiology in cancer has expanded considerably in the past 10 years. Current views indicate that: (1) most MMPs in tumors are made by stromal cells, not carcinoma cells; (2) cancer cells induce stromal cells to synthesize MMPs using extracellular matrix metalloproteinase inducer (EMMPRIN) and cytokine stimulatory mechanisms; and (3) MMPs promote cell migration and the release of growth factors sequestered in the extracellular matrix. MMPs have a dual function in tumor angiogenesis: MMP-2 and MT1-MMP are required in breaking down basement membrane barriers in the early stage of angiogenesis, while other MMPs are involved in the generation of an angiogenic inhibitor, angiostatin. In spite of considerable recent progress in identifying multiple roles of MMPs in disease, our understanding of MMP function in cancer is far from complete (see Table 1). Based on accumulated data, it is recommended that future MMPI trials focus on: (1) patients with early stage cancer; (2) the use of MMPIs along with chemotherapy; (3) the measurement of MMPs in tumor tissue and blood as a means of identifying patients who are more likely to respond to MMPI therapy; and (4) identification of biomarkers that reflect activation or inhibition of MMPs in vivo.
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PMID:Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. 1142 50

Since the approval of the multityrosine kinase inhibitor (TKI) sorafenib (Nexavar, Bayer and Onyx) as the standard of care for intermediate to advanced stages of hepatocellular carcinoma (HCC), there has been considerable interest in developing more potent TKIs to improve morbidity and mortality for patients with HCC. Much of the research on TKIs targets pathways implicated in angiogenesis, given that HCC is a highly vascularized cancer type. It was theorized that the efficacy of sorafenib is primarily attributable to its angiogenesis targets-namely, vascular endothelial growth factor receptors, platelet-derived growth factor receptors, FLT-3, and RAF kinases. Over the past 2 years, several pivotal phase 3 trials of newer TKIs targeting similar pathways have failed to meet criteria for superiority or noninferiority to sorafenib. Reasons for this may stem from the genetic and biologic heterogeneity of HCC. Genomic studies of tumor samples have shown scarce uniformity in kinase mutations, underscoring the variability that exists in HCC. This beckons the question of whether efforts should shift to other potential targets, either within the realm of TKIs or other targets entirely. Receptor tyrosine kinases, such as those encoded by the MET proto-oncogene, are expressed in certain individuals and have shown to be susceptible to targeted TKIs. As researchers continue to investigate therapies, the goal is to further research efforts into culprit oncogenes that mediate tumor progression, which will likely lead to more personalized and targeted regimens.
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PMID:The role of tyrosine kinase inhibitors in hepatocellular carcinoma. 2500 Mar 14