23 Dec The Wistar Institute Discovers New Therapeutic Strategy for Chemotherapy Resistance in Ovarian Cancer
MedicalResearch.com Interview with:
Rugang Zhang, Ph.D
Professor & Co-Leader, Gene Expression & Regulation Program
Deputy Director, The Wistar Institute Cancer Center
MedicalResearch.com: What is the background for this study?
Response: Although the majority of epithelial ovarian cancer (EOC) patients initially respond well to platinum therapy, relapse ultimately occurs, which remains a major challenge in the clinical management of EOC. Substantial evidence suggests that cancer stem-like cells (CSC) contribute to chemotherapy resistance and elimination of CSC prevents the therapeutic relapse including in EOCs. Thus, therapeutic elimination of EOC CSCs represents a promising approach to achieve a durable therapeutic outcome by preventing chemotherapy resistance.
Platinum-based chemotherapies are known to induce senescence that limits the propagation of cells subjected to insults such as cancer chemotherapeutics. In contrast to apoptosis, senescent cells remain viable. Senescent cells secrete a plethora of pro-inflammatory cytokines and chemokines, which is termed senescence-associated secretory phenotype (SASP). Therapy-induced inflammation promotes tumor progression and therapy resistance, and the SASP is known to promote cancer stem-like cells. However, clinically applicable approaches to target stemness associated with therapy-induced senescence remain to be explored.
MedicalResearch.com: What are the main findings?
Response: Our study shows that NAMPT inhibition selectively eliminates SASP during platinum-induced senescence of epithelial ovarian cancer cells. Indeed, inhibition of NAMPT activity using clinically applicable small molecule inhibitors eradicates EOC CSCs. Significantly, a combination of platinum treatment with pharmacological inhibepithelial ovarian cancerition of NAMPT suppresses the outgrowth of resistant cancer cells and prolongs survival in a preclinical EOC mouse model.
MedicalResearch.com: What should readers take away from your report?
Response: Our study provides scientific rationale for developing urgently needed novel therapeutic strategies for therapy-resistant ovarian cancer, a major challenge in the clinical management of ovarian cancer, using clinically applicable NAMPT inhibitors. Thus, these studies will lay the critical foundation for developing novel intervention strategies for ovarian cancer with a durable outcome.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: It is necessary to further investigate whether NAMPT inhibition can also eradicate therapy-induced cancer stem cells in additional cancer types and by different therapeutics such as radiation. In addition, NAD+-augmenting dietary supplements such as NMN are being clinically tested to alleviate age-related pathophysiological conditions. Because NAD+ precursors such as NMN enhance the NAMPT pathway, these supplements may have unintended side-effects of promoting CSCs. Further studies are warranted in this important interface between cancer and aging biology.
NAMPT inhibition suppresses cancer stem-like cells associated with therapy-induced senescence in ovarian cancer
Timothy Nacarelli, Takeshi Fukumoto, Joseph A. Zundell, Nail Fatkhutdinov, Stephanie Jean, Mark G. Cadungog, Mark E. Borowsky and Rugang Zhang
Cancer Res December 19 2019 DOI: 10.1158/0008-5472.CAN-19-2830
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