The Mir-15 Family Members Are Therapeutic Candidates To Treat Chemoresistant Neuroblastomas

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Neuroblastoma (NBL) is the most common solid tumor in infants and accounts for approximately 15% of cancer deaths in children. Neuroblastomas are very heterogeneous, with prognosis ranging from spontaneous regression to aggressive clinical course, and often become refractory to all current forms of treatment. While low and intermediate-risk patients have good prognosis, high-risk patients have poor prognosis and need intense chemotherapy. Despite the aggressive treatment, 60-70% of patients will die, mainly due to resistance to therapy and metastasis. Owing to the multiple different mechanisms that confer NBL resistance to therapy, targeting single components of a pathway may not suffice to restore chemosensitivity. In this respect, it is desirable to find molecules that can regulate multiple cellular processes or different component of the same pathways, thereby overcoming MDR and improving the therapeutic response. Our strategy is aimed to use microRNAs (miRNAs) to target the oncogenic properties of MDR neuroblastomas and render them vulnerable to treatment. The mRNA expression of genes related to multidrug resistance was analyzed in multiple neuroblastoma data sets. The 3′UTR of the genes differentially expressed in the highest-risk neuroblastoma group (Stage 4, MYCN amplified) was scanned with miRNA-binding sites prediction algorithms (TargetScan, PicTar, miRANDA). MicroRNAs predicted to regulate the expression of 2 or more overexpressed genes were selected for functional validation. Thirty-six miRNAs mimetics were transfected in two different chemoresistant neuroblastoma cell lines and effects on cell proliferation were evaluated. We have found a substantial number of genes implicated in the DNA damage response deregulated in high-risk NBL. MicroRNA-binding prediction algorithms revealed that most of them could potentially be regulated by microRNAs. Functional analysis in chemoresistant NBL cell lines identified several microRNAs that regulate proliferation, the best of which were the miR-15 family members. The overexpression of miR-497 reduces de proliferation of chemoresistant NBL cell lines and induces apoptotic cell death only in MYCN-amplified cell lines. Moreover, conditional overexpression of miR-497 in neuroblastoma xenografts led to a reduction in tumor growth. CONCLUSIONS: A substantial number of genes implicated in the MDR phenotype are deregulated in high-risk NBL and can be simultaneously targeted with miRNAs, providing a new therapeutic approach for chemoresistant neuroblastomas. This work is supported by Instituto de Salud Carlos III (CP11/00052, RD12/0036/0016 and PI11/00740) cofinanced by the European Regional Development Fund (ERDF) and Asociacion Espanola Contra el Cancer-Junta de Barcelona. Citation Format: Aroa Soriano, Laia Paris-Coderch, Luz Jubierre, Ana Almazan-Moga, Carla Molist, Josep Roma, Soledad Gallego, Jose Sanchez de Toledo, Miguel F. Segura. The miR-15 family members are therapeutic candidates to treat chemoresistant neuroblastomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4380. doi:10.1158/1538-7445.AM2014-4380