The Tyrosine Kinase Inhibitor E-3810 Combined with Paclitaxel Inhibits the Growth of Advanced-Stage Triple-Negative Breast Cancer Xenografts

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. On the basis of its histopathology and molecular-genomic changes, ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC xenografts that recapitulate the molecular and biologic heterogeneity of human ovarian cancer. Thirty-four EOC xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive, and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient-derived EOC xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor-specific molecular markers, and develop novel treatment modalities. Cancer Res; 74(23); 6980-90. Ó2014 AACR.

show abstract

“…20 mg/kg Q4 Â 3 or Q7 Â 3. All these schedules are reported to be effective in different experimental models (22,48 …”

Section: Discussionmentioning

confidence: 99%

Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, recent studies demonstrated that a novel inhibitor, E-3810, inhibits VEGFR1, VEGFR2, VEGFR3, FGFR1 and colony stimulating factor 1 receptor (CSF1R) with inhibition of FGFR2 at higher concentrations [81]. Studies using an MDA-MB-231 xenograft model demonstrated that treatment with E-3810 alone led to tumor stabilization [81]. Furthermore, combination treatment with paclitaxel led to tumor regression and was well-tolerated [81].…”

Section: Overview Of Fgf/fgfr In Breast Cancermentioning

confidence: 99%

The FGF/FGF receptor axis as a therapeutic target in breast cancer

Brady

Chuntova

Bade³

et al. 2013

Expert Review of Endocrinology & Metabolism

View full text Add to dashboard Cite

Fibroblast growth factor receptor (FGFR) signaling is a vital component of both embryonic and postnatal mammary gland development, which has prompted researchers to investigate both its relevance to breast cancer and its potential as a therapeutic target. Deregulated FGFR signaling during breast cancer occurs through various mechanisms, including amplification of the receptor genes, aberrant ligand expression, receptor mutations and translocations. Recent experimental outcomes involving both animal models and human breast cancer cell lines have led to the initiation of multiple early clinical trials investigating the safety and efficacy of small molecule FGFR inhibitors. In this article we review both the most recent discoveries and the need for further investigation of the mechanisms through which FGF/FGFR signaling has emerged as an oncogenic driver.

show abstract

“…While triple-negative breast cancer represents only 10-20% of breast cancers (7), this is still a large number of women. Only a minority of women with metastatic triple-negative breast cancer survive past 5 years, even with aggressive chemotherapy (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

View full text Add to dashboard Cite

Please cite this article as: Amith Schammim Ray, Fliegel Larry.Na+/H+ exchangermediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics.Seminars in Cancer Biology http://dx.doi. org/10.1016/j.semcancer.2017.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abstract (250 words):Breast cancer is the leading cause of cancer-related death in women in Europe and North America, and metastasis is the primary cause of fatality in patients with breast cancer. While some breast cancers are quite treatable, the triple-negative breast cancers are more metastatic and resistant to chemotherapy. There is clearly an urgent need for better treatments for this form of the disease. Breast cancer is characterized by genetically complex intra-tumour heterogeneity, particularly within the triple-negative clinical subtype. This complicates treatment options, so the development of specifically targeted chemotherapy for less treatable forms is critical.Dysregulation of pH homeostasis is a common factor in breast tumour cells. This occurs in concert with a metabolic switch to aerobic glycolysis that occurs at the onset of oncogenic transformation. The Na + /H + exchanger isoform 1 (NHE1) is the major pH regulatory protein involved in the increased proton extrusion of breast cancer cells. Its increased activity results in intracellular alkalinisation and extracellular acidification that drives cancer progression. The acidification of the extracellular tumour microenvironment also contributes to the development of chemotherapy resistance. In this review, we outline the role of H + as a carcinogenic signal and the role and regulation of NHE1 as a trigger for metastasis. We review recent evidence supporting the use of pharmacological inhibitors of NHE1 as a viable treatment option for triplenegative breast cancer.

show abstract

The Tyrosine Kinase Inhibitor E-3810 Combined with Paclitaxel Inhibits the Growth of Advanced-Stage Triple-Negative Breast Cancer Xenografts

Cited by 39 publications

References 43 publications

Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

The FGF/FGF receptor axis as a therapeutic target in breast cancer

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Contact Info

Product

Resources

About