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Fenretinide via NOXA induction, enhanced activity of the BCL-2 inhibitor venetoclax in high BCL-2-expressing neuroblastoma preclinical models

Recurrent high-risk neuroblastoma is a childhood cancer that often fails to respond to therapy. Fenretinide (4-HPR) is a cyototoxic retinoid with cliical activity in recurrent neuroblastoma and venetoclax (ABT-199) is a selective inhibitor of the anti-apoptotic protein BCL-2. We evaluated activity of 4-HPR + ABT-199 in preclinical models of neuroblastoma. Patient-derived cell lines and xenografts from progresssive neuroblastoma were tested. Cytotoxicity was evaluated by DIMSCAN, apoptosis by flow cytometry, gene expression by RNA sequencing, RT-PCR, and immunoblotting. 4-HPR + ABT-199 was highly synergistic against high BCL-2 expressing neuroblastoma cell lines and significantly improved event-free survival of mice carrying high BCL-2 expressing patient-derived xenografts (PDXs). In 10 matched-pair cell lines (established at diagnosis (DX) and relapse (PD) from the same patients), BCL-2 expression in the DX and PD lines were comparable, suggesting that BCL-2 expression at diagnosis may provide a biomarker for neuroblastomas likely to respond to 4-HPR + ABT-199. In a pair of DX (COG-N-603x) and PD (COG-N-623x) PDXs established from the same patient, COG-N-623x was less responsive to cyclophosphamide + topotecan than COG-N-603x, but both DX and PD PDXs were responsive to 4-HPR + ABT-199. Synergy of 4-HPR + ABT-199 was mediated by induction of NOXA via 4-HPR stimulation of reactive oxygen species (ROS) that induced expression of ATF4 and ATF3, transcription factors for NOXA. Thus, fenretinide + ventoclax is a synergistic combination that warrants clinical testing in high BCL-2 expressing neuroblastoma.

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Cat.No. Product Name Information
S8048 Venetoclax (ABT-199) Venetoclax (ABT-199, GDC-0199) is a Bcl-2-selective inhibitor with Ki of <0.01 nM in cell-free assays, >4800-fold more selective versus Bcl-xL and Bcl-w, and no activity to Mcl-1. Venetoclax is reported to induce cell growth suppression, apoptosis, cell cycle arrest, and autophagy in triple negative breast cancer MDA-MB-231 cells. Phase 3.

Related Targets

Bcl-2