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: Daniela Di Paolo, D Yang, Fabio Pastorino, Laura Emionite, Michele Cilli, Antonio Daga, Elisa Destafanis, Annarita Di Fiore, Francesca Piaggio, Chiara Brignole, Xiaobao Xu, Chris Liang, James Gibbons, Mirco Ponzoni, Patrizia Perri
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 30 Pg. 28774-89 (Oct 06 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26299615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Liposomes
• Protein Kinase Inhibitors
• RNA, Small Interfering
• ALK protein, human
• Alk protein, mouse
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases

Topics

• Anaplastic Lymphoma Kinase
• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Biological Availability
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Combined Modality Therapy
• Dose-Response Relationship, Drug
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Half-Life
• Humans
• Liposomes
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Targeted Therapy
• Mutation
• Nanoparticles
• Neuroblastoma (enzymology, genetics, pathology, therapy)
• Protein Kinase Inhibitors (pharmacokinetics, pharmacology)
• RNA Interference
• RNA, Small Interfering (genetics, metabolism)
• RNAi Therapeutics
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Transfection
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays