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.
Subject(s)
Antineoplastic Agents/pharmacology , Neuroblastoma/therapy , Protein Kinase Inhibitors/pharmacology , RNA, Small Interfering/metabolism , RNAi Therapeutics , Receptor Protein-Tyrosine Kinases , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , 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 , Neuroblastoma/genetics , Neuroblastoma/pathology , Protein Kinase Inhibitors/pharmacokinetics , RNA Interference , RNA, Small Interfering/genetics , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Signal Transduction/drug effects , Transfection , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Neuroblastoma (NB) is the most common extracranial solid tumor in children, accounting for about 8% of childhood cancers. Despite aggressive treatment, patients suffering from high-risk NB have very poor 5-year overall survival rate, due to relapsed and/or treatment-resistant tumors. A further increase in therapeutic dose intensity is not feasible, because it will lead to prohibitive short-term and long-term toxicities. New approaches with targeted therapies may improve efficacy and decrease toxicity. The use of drug delivery systems allows site specific delivery of higher payload of active agents associated with lower systemic toxicity compared to the use of conventional ("free") drugs. The possibility of imparting selectivity to the carriers to the cancer foci through the use of a targeting moiety (e.g., a peptide or an antibody) further enhances drug efficacy and safety. We have recently developed two strategies for increasing local concentration of anti-cancer agents, such as CpG-containing oligonucleotides, small interfering RNAs, and chemotherapeutics in NB. For doing that, we have used the monoclonal antibody anti-disialoganglioside (GD2), able to specifically recognize the NB tumor and the peptides containing NGR and CPRECES motifs, that selectively bind to the aminopeptidase N-expressing endothelial and the aminopeptidase A-expressing perivascular tumor cells, respectively. The review will focus on the use of tumor- and tumor vasculature-targeted nanocarriers to improve tumor targeting, uptake, and penetration of drugs in preclinical models of human NB.
