Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).
The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals.
SUMMARY
Lack of sensitive single-cell analysis tools has limited the characterization of metabolic activity in cancer stem cells. By hyperspectral stimulated Raman scattering imaging of single living cells and mass spectrometry analysis of extracted lipids, we report here significantly increased levels of unsaturated lipids in ovarian cancer stem cells (CSCs) as compared to non-CSCs. Higher lipid unsaturation levels were also detected in CSC-enriched spheroids compared to monolayer cultures of ovarian cancer cell lines or primary cells. Inhibition of lipid desaturases effectively eliminated CSCs, suppressed sphere formation in vitro, and blocked tumor initiation capacity in vivo. Mechanistically, we demonstrate that NF-κB directly regulates the expression levels of lipid desaturases and that inhibition of desaturases blocks NF-κB signaling. Collectively, our findings reveal that increased lipid unsaturation is a metabolic marker for ovarian CSCs and a target for CSC-specific therapy.
Tumors are composed of non-homogeneous cell populations exhibiting varying degrees of genetic and functional heterogeneity. Cancer stem cells (CSCs) are capable of sustaining tumors by manipulating genetic and non-genetic factors to metastasize, resist treatment, and maintain the tumor microenvironment. Understanding the key traits and mechanisms of CSC survival provides opportunities to improve patient outcomes via improved prognostic models and therapeutics. Here, we review the clinical significance of CSCs and results of potential CSC-targeting therapies in various cancers. We discuss barriers to translating cues from pre-clinical models into clinical applications and propose new strategies for rational design of future anti-CSC trials.
Preclinical studies have shown that hypomethylating agents reverse platinum resistance in
ovarian cancer. In this phase II clinical trial, based upon the results of our phase I dose defining
study, we tested the clinical and biologic activity of low-dose decitabine administered before
carboplatin in platinum-resistant ovarian cancer patients. Among 17 patients with heavily pretreated
and platinum-resistant ovarian cancer, the regimen induced a 35% objective response rate
(RR) and progression-free survival (PFS) of 10.2 months, with nine patients (53%) free of
progression at 6 months. Global and gene-specific DNA demethylation was achieved in peripheral blood
mononuclear cells and tumors. The number of demethylated genes was greater (P <
0.05) in tumor biopsies from patients with PFS more than 6 versus less than 6 months (311 vs. 244
genes). Pathways enriched at baseline in tumors from patients with PFS more than 6 months included
cytokine–cytokine receptor interactions, drug transporters, and mitogen-activated protein
kinase, toll-like receptor and Jak-STAT signaling pathways, whereas those enriched in demethylated
genes after decitabine treatment included pathways involved in cancer, Wnt signaling, and apoptosis
(P < 0.01). Demethylation of MLH1, RASSF1A, HOXA10, and
HOXA11 in tumors positively correlated with PFS (P < 0.05).
Together, the results of this study suggest that low-dose decitabine altered DNA methylation of
genes and cancer pathways, restoring sensitivity to carboplatin in patients with heavily pretreated
ovarian cancer and resulting in a high RR and prolonged PFS.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.