scholarly journals Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: current status and future perspectives

2013 ◽  
Vol 7 (1) ◽  
pp. 3 ◽  
Author(s):  
Meizhong Jin ◽  
Elizabeth Buck ◽  
Mark J. Mulvihill
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Signaling Network ◽  
Current Status ◽  
Insulin Like Growth Factor ◽  
Signaling Mechanisms ◽  
Epidermal Growth ◽  
Complex Signaling

Based on over three decades of pre-clinical data, insulin-like growth factor-1 receptor (IGF-1R) signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF-1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF- 1R targeted therapies (<em>e.g. </em>monoclonal antibodies) and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor. Such findings have helped to guide the design rationale of numerous drug combinations that are currently being evaluated in clinical trials.

scholarly journals Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: current status and future perspectives

2013 ◽  
pp. e3
Author(s):  
Meizhong Jin ◽  
Elizabeth Buck ◽  
Mark J. Mulvihill
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Signaling Network ◽  
Current Status ◽  
Insulin Like Growth Factor ◽  
Signaling Mechanisms ◽  
Epidermal Growth ◽  
Complex Signaling

Based on over three decades of pre-clinical data, insulin-like growth factor-1 receptor (IGF-1R) signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF-1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF- 1R targeted therapies (e.g. monoclonal antibodies) and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor. Such findings have helped to guide the design rationale of numerous drug combinations that are currently being evaluated in clinical trials.

scholarly journals Research on new drugs in the therapy of bladder cancer (BC)

2018 ◽  
Vol 72 ◽  
pp. 442-448 ◽  
Author(s):  
Karolina Jurkowska ◽  
Anna Długosz
Keyword(s):  
Bladder Cancer ◽  
Clinical Trials ◽  
Epidermal Growth Factor Receptor ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
New Drugs ◽  
Muscle Invasive Bladder Cancer ◽  
Epidermal Growth ◽  
Muscle Invasive

New, more effective and safer therapies in bladder cancer are being developed. Most attention is focused on monoclonal antibody therapies, targeted therapies and immunotherapy. Numerous pre-clinical and clinical studies on the use of the new drugs in bladder cancer are currently in progress. The great hope is associated with monoclonal antibodies, which are immune checkpoint inhibitors. Last year, two drugs from this group (Atezolizumab and Nivolumab) have been approved by Food and Drug Administration (FDA) for the treatment of muscle invasive bladder cancer (MIBC). Other monoclonal antibodies in this group such as Pembrolizumab are also in clinical trials. Much attention is also focused on targeted therapies. Inhibitors of: VEGF (vascular endothelial growth factor), EGFR (epidermal growth factor receptor), HER-2 (human epidermal growth factor receptor 2) and mTOR kinase are examined in bladder cancer. These drugs are often studied as a combination therapy with chemioterapeutic agents. Alternatives for BCG (Bacillus Calmette-Guérin) therapy in non muscle invasive bladder cancer (NMIBC) are also being developed. Research on the use of new vaccines and other immunotherapies (e.g. IL-12 therapy) are underway. The aim of this paper is to present the direction of current trends in bladder cancer treatment and what changes in therapy we can expect in the future. The drugs in clinical trials and those already registered in other countries have been reviewed. The latest drug-based therapeutic solutions have been described, which can replace traditional chemotherapy in the future.

scholarly journals Generation and Characterization of Rat Monoclonal Antibodies Against Epidermal Growth Factor Receptor

2015 ◽  
Vol 34 (6) ◽  
pp. 418-422 ◽  
Author(s):  
Tomohiro Osaki ◽  
Cai-Xia Wang ◽  
Taro Tachibana ◽  
Masayuki Azuma ◽  
Masaya Kitamura ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Epidermal Growth

scholarly journals Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers

2011 ◽  
Vol 29 (2) ◽  
pp. 166-173 ◽  
Author(s):  
Bhuvanesh Dave ◽  
Ilenia Migliaccio ◽  
M. Carolina Gutierrez ◽  
Meng-Fen Wu ◽  
Gary C. Chamness ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Epidermal Growth

Purpose Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

Phosphorylation of Nck in response to a variety of receptors, phorbol myristate acetate, and cyclic AMP

1992 ◽  
Vol 12 (12) ◽  
pp. 5816-5823
Author(s):  
D Park ◽  
S G Rhee
Keyword(s):  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Immunoglobulin M ◽  
Rat Tissues ◽  
A431 Cells ◽  
Sh3 Domains ◽  
Epidermal Growth ◽  
Stimulation Of

The 47-kDa protein coimmunoprecipitated with phospholipase C (PLC)-gamma 1 by anti-PLC-gamma 1 monoclonal antibodies is proved to be Nck, a protein composed almost exclusively of one SH2 and three SH3 domains. Nck and PLC-gamma 1 are recognized by certain anti-PLC-gamma 1 monoclonal antibodies because Nck and PLC-gamma 1 share an epitope that likely is located in their SH3 domains. Nck is widely distributed in rat tissues, with an especially high level of expression in testes. The expression levels of Nck remains unchanged during the development of rat brain, whereas PLC-gamma 1 decreases during the same developmental period. Stimulation of A431 cells with epidermal growth factor elicits the tight association of Nck with the epidermal growth factor receptor and phosphorylation of Nck on both serine and tyrosine residues. The phosphorylation of Nck is also enhanced in response to stimulation of the nerve growth factor receptor in PC12 cells, the T-cell receptor complex in Jurkat cells, the membrane immunoglobulin M in Daudi cells, and the low-affinity immunoglobulin G receptor (Fc gamma RII) in U937 cells. The phosphorylation of Nck was also enhanced following treatment of A431 cells with phorbol 12-myristate 13-acetate or forskolin. These results suggest that Nck is a target for a variety of protein kinases that might modulate the postulated role of Nck as an adaptor for the physical and functional coordination of signalling proteins.

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