The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma.

Autor: Lampis S; R&D Department, BIOGENERA SpA, Bologna, Italy., Raieli S; R&D Department, BIOGENERA SpA, Bologna, Italy., Montemurro L; Pediatric Unit, S. Orsola IRCCS, University of Bologna, Bologna, Italy., Bartolucci D; R&D Department, BIOGENERA SpA, Bologna, Italy., Amadesi C; R&D Department, BIOGENERA SpA, Bologna, Italy., Bortolotti S; R&D Department, BIOGENERA SpA, Bologna, Italy., Angelucci S; R&D Department, BIOGENERA SpA, Bologna, Italy., Scardovi AL; R&D Department, BIOGENERA SpA, Bologna, Italy., Nieddu G; R&D Department, BIOGENERA SpA, Bologna, Italy., Cerisoli L; R&D Department, BIOGENERA SpA, Bologna, Italy., Paganelli F; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.; CNR Institute of Molecular Genetics 'Luigi Luca Cavalli-Sforza', Unit of Bologna, Bologna, Italy., Valente S; Biotechnology and Methods in Laboratory Medicine, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy., Fischer M; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany; and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Martelli AM; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy., Pasquinelli G; Biotechnology and Methods in Laboratory Medicine, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.; Subcellular nephro-vascular diagnostic program, Pathology Unit S. Orsola IRCCS, University of Bologna, Bologna, Italy., Pession A; Pediatric Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Hrelia P; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy., Tonelli R; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy. roberto.tonelli@unibo.it.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2022 Apr 30; Vol. 41 (1), pp. 160. Date of Electronic Publication: 2022 Apr 30.
DOI: 10.1186/s13046-022-02367-5
Abstrakt: Background: Neuroblastoma is a deadly childhood cancer, and MYCN-amplified neuroblastoma (MNA-NB) patients have the worst prognoses and are therapy-resistant. While retinoic acid (RA) is beneficial for some neuroblastoma patients, the cause of RA resistance is unknown. Thus, there remains a need for new therapies to treat neuroblastoma. Here we explored the possibility of combining a MYCN-specific antigene oligonucleotide BGA002 and RA as therapeutic approach to restore sensitivity to RA in NB.
Methods: By molecular and cellular biology techniques, we assessed the combined effect of the two compounds in NB cell lines and in a xenograft mouse model MNA-NB.
Results: We found that MYCN-specific inhibition by BGA002 in combination with RA (BGA002-RA) act synergistically and overcame resistance in NB cell lines. BGA002-RA also reactivated neuron differentiation (or led to apoptosis) and inhibited invasiveness capacity in MNA-NB. Moreover, we found that neuroblastoma had the highest level of mRNA expression of mTOR pathway genes, and that BGA002 led to mTOR pathway inhibition followed by autophagy reactivation in MNA-NB cells, which was strengthened by BGA002-RA. BGA002-RA in vivo treatment also eliminated tumor vascularization in a MNA-NB mouse model and significantly increased survival.
Conclusion: Taken together, MYCN modulation mediates the therapeutic efficacy of RA and the development of RA resistance in MNA-NB. Furthermore, by targeting MYCN, a cancer-specific mTOR pathway inhibition occurs only in MNA-NB, thus avoiding the side effects of targeting mTOR in normal cells. These findings warrant clinical testing of BGA002-RA as a strategy for overcoming RA resistance in MNA-NB.
(© 2022. The Author(s).)
Databáze: MEDLINE
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