Epigenetic therapies: new strategies for the treatment of neuroblastoma

Carlos Jiménez Jiménez, Luz Jubierre Zapater

Pediatric cancer is the main cause of death by disease in children in developed countries. Although advances in therapy have increased the survival of affected children during the last decades, there is still a group of patients unable to respond to therapy and overcome the disease. This is the reason why research on new therapeutic approaches is a must. In our laboratory, we are focused specifically on pediatric tumors of the nervous system, mainly neuroblastoma. Neuroblastoma originates in the peripheral nervous system and is one of the most common solid tumors of the infancy. It is usually diagnosed at an average age of 18 months, and the patients classified as high risk show still poor survival rates: approximately 40% at five years after diagnose. This mortality is mostly caused by development of drug resistance.

In order to overcome this phenomenon, we propose to target proteins responsible for epigenetic events as an alternative therapeutic strategy, what is known as epigenetic therapies. The term epigenetics refers to all those chemical changes, that can be inherited through cell division and even generations, which regulate the expression of genes. This modifications lead to changes in the compaction of the DNA, regulating this way the gene expression. What is more, epigenetic regulators have the ability of regulate a variety of genes at the same time, hindering the appearance of resistant mechanisms in cancer cells.

We have identified two different epigenetic regulators as potential therapeutic targets in neuroblastoma. On the one hand, BRG1, which is part of one of the most important chromatin remodeling complexes in the cell, seems to be essential for the survival of neuroblastoma tumor cells. We have inhibited this protein in neuroblastoma cells on culture and in mice and we found a drastic reduction of tumor growth. We are also studying the role of ZRF1, an epigenetic regulator known to be involved in the embryonic development of the nervous system and also found to be a key factor of some cancers such as leukemia. We have also found that the expression of ZRF1 is determinant for the viability of neuroblastoma cells.

Our main goals in the laboratory are to delve in the study of these two proteins and to develop new drugs to inhibit them in order to improve the therapeutic options for neuroblastoma patients.