Article by Disease – Critical Roles of EGFR Family Members in Breast Cancer and Breast Cancer Stem Cells – Current Pharmaceutical Design



The roles of the epidermal growth factor receptor (EGFR) signaling pathway in various cancers including breast, bladder, brain, colorectal, esophageal, gastric, head and neck, hepatocellular, lung, neuroblastoma, ovarian, pancreatic, prostate, renal and other cancers have been keenly investigated since the 1980’s. While the receptors and many downstream signaling molecules have been identified and characterized, there is still much to learn about this pathway and how its deregulation can lead to cancer and how it may be differentially regulated in various cell types. Multiple inhibitors to EGFR family members have been developed and many are in clinical use. Current research often focuses on their roles and other associated pathways in cancer stem cells (CSCs), identifying sites where therapeutic resistance may develop and the mechanisms by which microRNAs (miRs) and other RNAs regulate this pathway. This review will focus on recent advances in these fields with a specific focus on breast cancer and breast CSCs. Relatively novel areas of investigation, such as treatments for other diseases (e.g., diabetes, metabolism, and intestinal parasites), have provided new information about therapeutic resistance and CSCs.

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Press Release for EurekAlert! Preclinical studies involving resistance to antiangiogenic therapies


New blood vessel growth, or angiogenesis, is critical for cancer to grow and spread throughout the body. Drugs that target vascular endothelial growth factor (VEGF) — a key driver of angiogenesis — are now approved for the treatment of several metastatic cancers. However, not all patients respond and many more eventually become resistant after initial treatment benefits.

While researchers have sought to identify possible mechanisms to explain drug resistance the methods to study have proven complex. Preclinical studies seeking to identify reasons for antiangiogenic treatment failure have relied on animal models of cancer because the complex interaction between the tumor and the “normal” blood vessels that the treatment targets is difficult to reproduce in a petri dish. But the use of animal models can also increase the varience in results.

In a review published in the journal Current Drug Targets, researchers at Roswell Park Cancer Institute in Buffalo, New York, examined this variability and found that the many mechanisms of resistance identified in laboratory models are based on inconsistent definitions of treatment failure. “Most studies involve only a few drugs and animal models that do not fully recapitulate clinically relevant metastatic disease,” said Dr. John Ebos, Assistant Professor at the Departments of Cancer Genetics and Medicine at Roswell Park. “Many excellent studies have been performed; however, it is difficult to determine which are most applicable to patients.”

The literature considered in this new review highlights the challenges of studying resistance to inhibitors of tumor angiogenesis in preclinical models and the need to improve methodology to help qualify and quantify treatment failure to predict alternative strategies that will be of greatest benefit to patients.

Reference: Mastri, M.; et al (2016). The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy., DOI: 10.2174/1389450117666151209123544


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Most Cited Article ::: Persistent Current Blockers of Voltage-Gated Sodium Channels: A Clinical Opportunity for Controlling Metastatic Disease

Author(s): Mustafa B.A. Djamgoz and Rustem Onkal.

Abstract: A range of experimental and clinical data suggests strongly (i) that metastatic progression in carcinomas is accompanied (maybe even preceded) by upregulation of functional voltage-gated sodium channels (VGSCs) and (ii) that VGSC activity enhances cancer cell invasiveness. First, this review outlines the available in vitro and in vivo evidence for the VGSC expression and its proposed pathophysiological role. Second, we question the mechanism(s) whereby VGSC activity can induce such a cancer-promoting effect. We advance the hypothesis that it is the hypoxia-sensitive persistent component of the VGSC current (INaP) that is central to the phenomenon. Indeed, blockers of INaP are very effective in suppressing cancer cell invasiveness in vitro. Based upon these data, UK and international patent applications have been filed which describe the use of INaP blockers, like ranolazine (“Ranexa”) and riluzole (“Rilutex”), as anti-metastatic agents. Importantly, since these drugs are already in clinical use, against conditions like cardiac angina and amyotrophic lateral scelerosis, there are no issues of dosage, unacceptable side effects or long-term use. Thus, INaP blockers have the potential to turn cancer into a chronic condition.

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This article is from the journal Recent Patents on Anti-Cancer Drug Discovery

Chinese authors contributions to Bentham’s iournal ‘Current Alzheimer Research’

Pan-Amyloid Oligomer Specific scFv Antibody Attenuates Memory Deficits and Brain Amyloid Burden in Mice with Alzheimer’s Disease

Current Alzheimer Research, 11(1): 69-78.

Author(s): Min Zhao, Shao-wei Wang, Yu-jiong Wang, Ran Zhang, Ya-nan Li, Ya-jing Su, Wei-wei Zhou, Xiao-lin Yu and Rui-tian Liu

Abstract: Amyloid oligomers have a critical function in the pathologic processes of various amyloidoses, such as Alzheimer’s disease (AD), Parkinson disease (PD), Huntington’s disease, prion-related diseases, type 2 diabetes, and hereditary renal amyloidosis. Our previous reports demonstrated that a conformation-dependent oligomer-specific single-chain variable fragment (scFv) antibody, W20, isolated from a naïve human scFv library, can recognize oligomers assembled from α -synuclein, amylin, insulin, A β40/42, prion peptide 106–126, and lysozyme, inhibit the aggregation of various amyloid, and attenuate amyloid oligomer-induced cytotoxicity In vitro. Furthermore, W20 recognized the amyloid oligomers in all types of plaques, Lewy bodies, and amylin deposits in the brain tissues of AD and PD patients and in the pancreas of type 2 diabetes patients. In the current study, we showed that W20 blocked the binding of Aβ oligomers to SH-SY5Y cells, did not bind to heat shock protein, rescued cognitive impairments in APP/PS1 transgenic mice, and interfered with Aβ levels and deposits in mouse brain. These results suggest that W20 may be a promising therapeutic for the treatment of AD.

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Contributions by Chinese Authors in Bentham Science Journal; Anti-Cancer Agents in Medicinal Chemistry

Baicalin Suppresses Migration, Invasion and Metastasis of Breast Cancer via p38MAPK Signaling Pathway

Author(s): Xiu- Feng Wang, Qian- Mei Zhou, Jia Du, Hui Zhang, Yi- Yu Lu and Shi- Bing Su

Affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai 201203, PR China.

Abstract: Metastasis is the major cause of death in breast cancer patients. In this study, we investigated the effects of baicalin, a natural compound, on cell migration, invasion and metastasis using human breast cancer MDA-MB-231 cell line as model system. Baicalin not only dose-dependently inhibited MDA-MB-231 cells migration and in vitro invasion, but also suppressed the tumor outgrowth and the pulmonary metastasis of MDA-MB-231 cells in xenograft model. Importantly, treatment of baicalin caused little change in body weight, liver and kidney function of recipient animals. Tumorigenesis-inhibitory effect is likely linked to the capability of baicalin to downregulate metalloproteinase (MMP)-2, MMP-9, urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) expression in MDA-MB-231 cells. As baicalin blocked p38 mitogen-activated protein kinase (MAPK) activity and treatment of p38MAPK inhibitor SB203580 led to the reduction of MMP-2, MMP-9, uPA and uPAR expressions, we concluded that baicalin suppresses the tumorigenecity of MDA-MB-231 cells by down-regulating MMP-2, MMP-9, uPA and uPAR expressions through the interruption of p38MAPK signaling pathway.

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