Research Papers:

New therapeutic strategies in neuroblastoma: combined targeting of a novel tyrosine kinase inhibitor and liposomal siRNAs against ALK

Daniela Di Paolo _, D. Yang, Fabio Pastorino, Laura Emionite, Michele Cilli, Antonio Daga, Elisa Destefanis, Annarita Di Fiore, Francesca Piaggio, Chiara Brignole, Xiaobao Xu, Chris Liang, James Gibbons, Mirco Ponzoni and Patrizia Perri

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Oncotarget. 2015; 6:28774-28789. https://doi.org/10.18632/oncotarget.4342

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Daniela Di Paolo1, D. Yang2, Fabio Pastorino1, Laura Emionite3, Michele Cilli3, Antonio Daga4, Elisa Destafanis1,6, Annarita Di Fiore1, Francesca Piaggio1, Chiara Brignole1, Xiaobao Xu2, Chris Liang5, James Gibbons5, Mirco Ponzoni1,*, Patrizia Perri1,*

1Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy

2Sundia MediTech Company, Ltd., Shangai, China

3Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

4Laboratorio Trasferimento Genico, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

5Xcovery LLC, West Palm Beach, FL, USA

6Present address: Centre for Inherited Cardiovascular, IRCCS Politecnico San Matteo, Pavia, Italy

*These authors have contributed equally to this work

Correspondence to:

M. Ponzoni, e-mail: [email protected]

P. Perri, e-mail: [email protected]

Keywords: neuroblastoma, ALK-inhibitor, X-396, RNA-interference, targeted nanoliposomes

Received: March 10, 2015     Accepted: June 09, 2015     Published: June 20, 2015


Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients.

We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models.

X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner.

In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents.

Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors.

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