Universität zu Köln

Lampis, Silvia, Raieli, Salvatore, Montemurro, Luca, Bartolucci, Damiano ORCID: 0000-0001-9237-5376, Amadesi, Camilla, Bortolotti, Sonia, Angelucci, Silvia, Scardovi, Anna Lisa, Nieddu, Giammario, Cerisoli, Lucia, Paganelli, Francesca ORCID: 0000-0002-8694-2140, Valente, Sabrina, Fischer, Matthias, Martelli, Alberto Maria, Pasquinelli, Gianandrea, Pession, Andrea, Hrelia, Patrizia and Tonelli, Roberto (2022). The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma. J. Exp. Clin. Cancer Res., 41 (1). LONDON: BMC. ISSN 1756-9966

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lampis, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Raieli, Salvatore UNSPECIFIED UNSPECIFIED UNSPECIFIED Montemurro, Luca UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartolucci, Damiano UNSPECIFIED orcid.org/0000-0001-9237-5376 UNSPECIFIED Amadesi, Camilla UNSPECIFIED UNSPECIFIED UNSPECIFIED Bortolotti, Sonia UNSPECIFIED UNSPECIFIED UNSPECIFIED Angelucci, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Scardovi, Anna Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Nieddu, Giammario UNSPECIFIED UNSPECIFIED UNSPECIFIED Cerisoli, Lucia UNSPECIFIED UNSPECIFIED UNSPECIFIED Paganelli, Francesca UNSPECIFIED orcid.org/0000-0002-8694-2140 UNSPECIFIED Valente, Sabrina UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Martelli, Alberto Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasquinelli, Gianandrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Pession, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Hrelia, Patrizia UNSPECIFIED UNSPECIFIED UNSPECIFIED Tonelli, Roberto UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-681498
DOI:	10.1186/s13046-022-02367-5
Journal or Publication Title:	J. Exp. Clin. Cancer Res.
Volume:	41
Number:	1
Date:	2022
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1756-9966
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACUTE PROMYELOCYTIC LEUKEMIA; N-MYC; BONE-MARROW; EXPRESSION; CELLS; ACTIVATION; THERAPY; PATHWAY; PROGRESSION; ASSOCIATION Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68149