title: New therapeutic strategies in neuroblastoma: combined targeting of a novel tyrosine kinase inhibitor and liposomal siRNAs against ALK.
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.
authors: Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
authors: Daniela
authors: D
authors: Di Paolo
authors: Sundia MediTech Company, Ltd., Shangai, China.
authors: D
authors: D
authors: Yang
authors: Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
authors: Fabio
authors: F
authors: Pastorino
authors: Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors: Laura
authors: L
authors: Emionite
authors: Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors: Michele
authors: M
authors: Cilli
authors: Laboratorio Trasferimento Genico, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors: Antonio
authors: A
authors: Daga
authors: Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.|Present address: Centre for Inherited Cardiovascular, IRCCS Politecnico San Matteo, Pavia, Italy.
authors: Elisa
authors: E
authors: Destafanis
authors: Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
authors: Annarita
authors: A
authors: Di Fiore
authors: Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
authors: Francesca
authors: F
authors: Piaggio
authors: Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
authors: Chiara
authors: C
authors: Brignole
authors: Sundia MediTech Company, Ltd., Shangai, China.
authors: Xiaobao
authors: X
authors: Xu
authors: Xcovery LLC, West Palm Beach, FL, USA.
authors: Chris
authors: C
authors: Liang
authors: Xcovery LLC, West Palm Beach, FL, USA.
authors: James
authors: J
authors: Gibbons
authors: Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
authors: Mirco
authors: M
authors: Ponzoni
authors: Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
authors: Patrizia
authors: P
authors: Perri
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D008081:Liposomes; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D053758:Nanoparticles; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D000067492:RNAi Therapeutics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK-inhibitor; RNA-interference; X-396; neuroblastoma; targeted nanoliposomes