Oncotarget

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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Abstract

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: mircoponzoni@ospedale-gaslini.ge.it

P. Perri, e-mail: patriziaperri@ospedale-gaslini.ge.it

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

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

ABSTRACT

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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