Yuying Tan

Preclinical Evaluation of NTX-301, a Novel DNA Hypomethylating Agent in Ovarian Cancer

Abstract Purpose: DNA methylation causes silencing of tumor-suppressor and differentiation-associated genes, being linked to chemoresistance. Previous studies demonstrated that hypomethylating agents (HMA) resensitize ovarian cancer to chemotherapy. NTX-301 is a highly potent and orally bioavailable HMA, in early clinical development. Experimental Design: The antitumor effects of NTX-301 were studied in ovarian cancer models by using cell viability, stemness and ferroptosis assays, RNA sequencing, lipidomic analyses, and stimulated Raman spectroscopy. Results: Ovarian cancer cells (SKOV3, IC50 = 5.08 nmol/L; OVCAR5 IC50 = 3.66 nmol/L) were highly sensitive to NTX-301 compared with fallopian tube epithelial cells. NTX-301 downregulated expression of DNA methyltransferases 1–3 and induced transcriptomic reprogramming with 15,000 differentially expressed genes (DEG, P < 0.05). Among them, Gene Ontology enrichment analysis identified regulation of fatty acid biosynthesis and molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase, known features of cancer stem cells. Low-dose NTX-301 reduced the ALDH(+) cell population and expression of stemness-associated transcription factors. Stearoyl-coenzyme A desaturase 1 (SCD), which regulates production of unsaturated fatty acids (UFA), was among the top DEG downregulated by NTX-301. NTX-301 treatment decreased levels of UFA and increased oxidized lipids, and this was blunted by deferoxamine, indicating cell death via ferroptosis. NTX-301–induced ferroptosis was rescued by oleic acid. In vivo, monotherapy with NTX-301 significantly inhibited ovarian cancer and patient-derived xenograft growth (P < 0.05). Decreased SCD levels and increased oxidized lipids were detected in NTX-301–treated xenografts. Conclusions: NTX-301 is active in ovarian cancer models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death.

Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells

AbstractIncreased glycolysis is considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during therapeutic resistance development is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we find that cisplatin-resistant cells exhibit increased fatty acids (FA) uptake, accompanied by decreased glucose uptake and lipogenesis, indicating reprogramming from glucose to FA dependent anabolic and energy metabolism. A metabolic index incorporating glucose derived anabolism and FA uptake correlates linearly to the level of cisplatin resistance in ovarian cancer (OC) cell lines and primary cells. The increased FA uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing beta-oxidation. Consequently, blocking beta-oxidation by a small molecule inhibitor combined with cisplatin or carboplatin synergistically suppresses OC proliferation in vitro and growth of patient-derived xenografts in vivo. Collectively, these findings support a rapid detection method of cisplatin-resistance at single cell level and a strategy for treating cisplatin-resistant tumors.

Survival outcomes of neoadjuvant chemotherapy-related strategies compared with concurrent chemoradiotherapy for locally advanced cervical cancer: a meta-analysis of randomized controlled trials

The survival benefits of neoadjuvant chemotherapy (NAC) compared with those of concurrent chemoradiotherapy (CRT) for locally advanced cervical cancer (LACC) patients remain uncertain. Meta-analysis was used to compare NAC and CRT. A systematic search was performed up to 9 September 2020. Survival outcomes were analyzed based on event frequency or hazard ratios (HRs). Multilevel mixed-effects logistic regression was applied to analyze the effect of regimen variables on survival outcomes. Analysis based on Cox regression showed that CRT was better than NAC + radical hysterectomy (RT) (HR 1.25; 95% confidence interval (CI)) 1.02-1.54; p = 0.034) in terms of overall survival (OS). According to multilevel mixed-effects model analysis comparing NAC + RT and CRT, LACC patients who used cisplatin instead of carboplatin had a better Progression-free survival (PFS) (odds ratio (OR) 1.54; 95% CI 1.08-2.20; p = 0.016). When NAC + CRT and CRT were compared, gemcitabine administration was associated with a decrease in PFS (OR 0.47; 95% CI 0.22-0.99; p = 0.047). Increased doses of cisplatin and paclitaxel were associated with survival improvement. Based on traditional meta-analysis, CRT was better than NAC + RT in terms of OS. Carboplatin instead of cisplatin as part of the NAC + RT strategy or gemcitabine use in NAC + CRT may not be a good choice. An increased total dosage of paclitaxel and/or cisplatin as part of NAC + CRT and CRT strategies may improve the survival outcome of LACC patients.