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ABSTRACT: The use of monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) pathway has been a significant addition to cancer therapy. One of the VEGF family members, VEGF-A (commonly referred to as VEGF), has been demonstrated to be important in angiogenesis. Although the mechanism of action of these antibodies is still under study, the anti-VEGF antibody bevacizumab has been approved for treatment of various solid cancers including colorectal, lung, and breast cancers as well as glioblastoma and renal cell carcinoma. Addition of bevacizumab to chemotherapy as adjuvant therapy in colorectal cancer did not improve disease-free survival. Bevacizumab is being tested in other clinical settings such as adjuvant therapy, maintenance therapy, and in combination with both chemotherapy and other targeted agents such as the epidermal growth factor receptor kinase inhibitor erlotinib. In addition to bevacizumab, other antibody-based therapies targeting the VEGF pathway are being tested. Ramucirumab and IMC-18F1 are monoclonal antibodies that target the VEGF receptors VEGFR-2 and VEGFR-1, respectively. Aflibercept (VEGF-Trap), a peptide-antibody fusion targeting VEGF ligand, is being tested in clinical trials. Much research is focused on identifying biomarkers to predict which patients will benefit from anti-VEGF therapy. Recent results suggest that VEGF single nucleotide polymorphisms may be predictive of patient response to bevacizumab. Improved imaging modalities such as dynamic contrast-enhanced MRI (DCE-MRI) can better characterize the efficacy of anti-angiogenic agents. As anti-VEGF treatments such as bevacizumab have been integrated into the treatment of many different types of cancers, the development of bevacizumab-resistant tumors has become more common. Recent studies show that targeting other angiogenesis signaling pathways such as platelet-derived growth factor-C (PDGF-C), Bombina variagata peptide 8 (Bv8, also known as prokineticin-2), and VEGFR-3 may lead to enhanced response in anti-VEGF resistant tumors. In the future, tailored treatments consisting of combinations of chemotherapy, other targeted therapies, and anti-angiogenesis agents will hopefully result in better patient outcomes.
BioDrugs 01/2009; 23(5):289-304. · 3.44 Impact Factor
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ABSTRACT: Pemetrexed disodium is a multitargeted antifolate cytotoxic chemotherapy agent approved by the U.S. Food and Drug Administration (FDA) initially for the treatment of malignant pleural mesothelioma, and in August 2004 for second-line treatment of non-small cell lung cancer (NSCLC). In September 2008, the FDA also approved pemetrexed and cisplatin as first-line therapy for NSCLC. Pemetrexed is also no longer recommended for treatment of NSCLC with squamous cell carcinoma histology. Pemetrexed is currently being tested in clinical trials as part of second-line combination, first-line, adjuvant and maintenance therapies.
Drugs of today (Barcelona, Spain: 1998) 10/2008; 44(9):669-78. · 1.28 Impact Factor
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ABSTRACT: The fidelity of cell division is dependent on the accumulation and ordered destruction of critical protein regulators. By triggering the appropriately timed, ubiquitin-dependent proteolysis of the mitotic regulatory proteins securin, cyclin B, aurora A kinase, and polo-like kinase 1, the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase plays an essential role in maintaining genomic stability. Misexpression of these APC/C substrates, individually, has been implicated in genomic instability and cancer. However, no comprehensive survey of the extent of their misregulation in tumors has been performed. Here, we analyzed more than 1600 benign and malignant tumors by immunohistochemical staining of tissue microarrays and found frequent overexpression of securin, polo-like kinase 1, aurora A, and Skp2 in malignant tumors. Positive and negative APC/C regulators, Cdh1 and Emi1, respectively, were also more strongly expressed in malignant versus benign tumors. Clustering and statistical analysis supports the finding that malignant tumors generally show broad misregulation of mitotic APC/C substrates not seen in benign tumors, suggesting that a "mitotic profile" in tumors may result from misregulation of the APC/C destruction pathway. This profile of misregulated mitotic APC/C substrates and regulators in malignant tumors suggests that analysis of this pathway may be diagnostically useful and represent a potentially important therapeutic target.
American Journal Of Pathology 06/2007; 170(5):1793-805. · 4.89 Impact Factor
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ABSTRACT: The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that controls the cell cycle by directing the ubiquitin-dependent proteolysis of S-phase and mitosis promoting factors. Emi1 is an E2F transcriptional target that drives cell cycle progression from G1/S through early mitosis by inhibiting the APC/C's ubiquitin ligase activity, and thus facilitates accumulation of APC/C substrates. Using cell culture model systems, we found that Emi1 overexpression leads to proliferation, tetraploidy and genome instability of cells deficient for p53. We propose that loss of pRb repression of E2F-mediated transcription causing misregulation of Emi1 and APC/C substrates results in the generation of tetraploidy and proliferation of genomically unstable cells in the absence of normal p53 function. This represents a potentially important mechanism by which pRb and p53 dysfunction may contribute to tumorigenesis through the generation of genomic instability.
Cell cycle (Georgetown, Tex.) 08/2006; 5(14):1569-73. · 5.36 Impact Factor
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ABSTRACT: Progression through mitosis occurs because cyclin B/Cdc2 activation induces the anaphase promoting complex (APC) to cause cyclin B destruction and mitotic exit. To ensure that cyclin B/Cdc2 does not prematurely activate the APC in early mitosis, there must be a mechanism delaying APC activation. Emi1 is a protein capable of inhibiting the APC in S and G2. We show here that Emi1 is phosphorylated by Cdc2, and on a DSGxxS consensus site, is subsequently recognized by the SCF(betaTrCP/Slimb) ubiquitin ligase and destroyed, thus providing a delay for APC activation. Failure of betaTrCP-dependent Emi1 destruction stabilizes APC substrates and results in mitotic catastrophe including centrosome overduplication, potentially explaining mitotic deficiencies in Drosophila Slimb/betaTrCP mutants. We hypothesize that Emi1 destruction relieves a late prophase checkpoint for APC activation.
Developmental Cell 07/2003; 4(6):813-26. · 14.03 Impact Factor
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Oncogene 10/2002; 21(40):6209-21. · 6.37 Impact Factor
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ABSTRACT: Emi1 promotes mitotic entry in Xenopus laevis embryos by inhibiting the APC(Cdc20) ubiquitination complex to allow accumulation of cyclin B. We show here that human Emi1 (hEmi1) functions to promote cyclin A accumulation and S phase entry in somatic cells by inhibiting the APC(Cdh1) complex. At the G1-S transition, hEmi1 is transcriptionally induced by the E2F transcription factor, much like cyclin A. hEmi1 overexpression accelerates S phase entry and can override a G1 block caused by overexpression of Cdh1 or the E2F-inhibitor p105 retinoblastoma protein (pRb). Depleting cells of hEmi1 through RNA interference prevents accumulation of cyclin A and inhibits S phase entry. These data suggest that E2F can activate both transcription of cyclin A and the hEmi1-dependent stabilization of APC(Cdh1) targets, such as cyclin A, to promote S phase entry.
Nature Cell Biology 06/2002; 4(5):358-66. · 19.49 Impact Factor
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ABSTRACT: Emi1 promotes mitotic entry in Xenopus laevis embryos by inhibiting the APCCdc20 ubiquitination complex to allow accumulation of cyclin B. We show here that human Emi1 (hEmi1) functions to promote cyclin A accumulation and S phase entry in somatic cells by inhibiting the APCCdh1 complex. At the G1–S transition, hEmi1 is transcriptionally induced by the E2F transcription factor, much like cyclin A. hEmi1 overexpression accelerates S phase entry and can override a G1 block caused by overexpression of Cdh1 or the E2F-inhibitor p105 retinoblastoma protein (pRb). Depleting cells of hEmi1 through RNA interference prevents accumulation of cyclin A and inhibits S phase entry. These data suggest that E2F can activate both transcription of cyclin A and the hEmi1-dependent stabilization of APCCdh1 targets, such as cyclin A, to promote S phase entry.
Nature Cell Biology 04/2002; 4(5):358-366. · 19.49 Impact Factor
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ABSTRACT: Recently, many new examples of E3 ubiquitin ligases or E3 enzymes have been found to regulate a host of cellular processes. These E3 enzymes direct the formation of multiubiquitin chains on specific protein substrates, and – typically – the subsequent destruction of those proteins. We discuss how the modular architecture of E3 enzymes connects one of two distinct classes of catalytic domains to a wide range of substrate-binding domains. In one catalytic class, a HECT domain transfers ubiquitin directly to substrate bound to a non-catalytic domain. Members of the other catalytic class, found in the SCF, VBC and APC complexes, use a RING finger domain to facilitate ubiquitylation. The separable substrate-recognition domains of E3 enzymes provides a flexible means of linking a conserved ubiquitylation function to potentially thousands of ubiquitylated substrates in eukaryotic cells.
Trends in Cell Biology 11/2000; · 12.35 Impact Factor
