Nitin T. TelangCancer Prevention Research Program Palindrome Liaisons Consultants, USA
Title: Triple-negative Breast Cancer: A model for Drug Discovery
Background: The triple-negative breast cancer (TNBC) subtype of clinical breast cancer lacks the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2). The TNBC subtype represents an aggressive cancer with high risk of fetal metastasis. Because of the lack of receptor expression, the therapeutic options for TNBC are restricted to conventional chemotherapy of cytotoxic anthracyclins, paclitaxels and cisplatin. Long-term chemotherapy is associated with intrinsic or acquired therapy resistance and emergence of chemo-resistant cancer initiating caner stem cell population that is endowed with cellular plasticity, epithelial-mesenchymal transition and high risk of metastatic progression. These limitations emphasize an unmet need to identify therapeutic alternatives. Natural products such as nutritional herbs, because of low systemic toxicity, documented human consumption and growth inhibitory efficacy in cancer stem cells, may represent testable alternatives. Bioactive agents present in nutritional herbs may provide novel drug candidates.
Experimental Models: ER/PR/HER-2 negative MDA-MB-231 cells and doxorubicin resistant MDA-MB-231/DOX-R cells represent cellular models for TNBC and drug-resistant cancer stem cells, respectively.
Experimental Modulation: Treatment of the parental MDA-MB-231 cells with select nutritional herbs results in anti-proliferative effects associated with downregulated RB, RAS, PI3K and AKT signaling pathways. Pro-apoptotic effects of the nutritional herbs are associated with reciprocal modulation in anti-apoptotic BCL-2 and pro-apoptotic BAX expression. The MDA-MB-231/DOX-R cells exhibit increased tumor spheroid formation and upregulated expression of stem cell specific CD44 cell surface protein, and NANOG and OCT-4 nuclear transcription factors.
Conclusion: Collectively, this evidence validates facile experimental approaches to identify and prioritize novel drug candidates as testable alternatives against therapy resistant TNBC stem cell population. Future investigations utilizing patient-derived tumor samples may minimize extrapolation and facilitate clinical relevance and translatability of preclinical evidence.
Dr. Nitin TELANG is the Director, Cancer Prevention Research Program at Palindrome Liaisons Consultants, New Jersey. He earned his Ph.D. degree in India (1974), and obtained the post-doctoral training at University of Nebraska, American Health Foundation, New York and Memorial Sloan-Kettering Cancer Center, New York (1976-1985). He has served as a faculty member at Memorial Sloan-Kettering Cancer Center, Weill-Cornell Medical College, and Strang Cancer Prevention Center, New York (1986-2007). Dr. TELANG has published more than 150 peer-reviewed papers in the areas of carcinogenesis, cancer prevention, and cancer stem cell biology. He has served on Grant Review Study Sections for National Cancer Institute (NCI) and US Department of Defense Breast Cancer Research Program (DOD-BCRP). He is on the editorial boards for Oncology Reports, International Journal of Oncology, World Academy of Sciences Journal and International Journal of Molecular Sciences- Molecular Pharmacology. His research has been funded by grants from NCI and DOD. He has received NCI FIRST Award, DOD-BCRP IDEA Award and AN Marquis Lifetime Achievement Award.