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 ¼ 5.08 nmol/L; OVCAR5 IC50 ¼ 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(þ) 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1175-1188 |
| Number of pages | 14 |
| Journal | Clinical Cancer Research |
| Volume | 30 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 15 2024 |
Funding
D. Matei reports grants from PinotBio during the conduct of the study; personal fees from GOG Foundation, GSK, Elsevier, and CVS Health; grants from Merck; and other support from Astex Inc. outside the submitted work. No disclosures were reported by the other authors. Funding and drug for this study was contributed by PinotBio to D. Matei, the NCI R01 CA224275 to D. Matei and J.-X. Cheng, and the U.S. Department of Veterans Affairs IO1BX000792 to D. Matei. Flow cytometry analyses were performed in the Northwestern University Flow Cytometry Core Facility supported by the Cancer Center Support Grant NCI CA060553. PDX experiments were performed in the Center for Developmental Therapeutics (CDT) partly supported by Cancer Center Support Grant NCI CA060553.
ASJC Scopus subject areas
- General Medicine
