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miRNA-based therapeutics to treat Glioblastoma at Johns Hopkins Medical Institute in Baltimore

Dr Hernando Lopez-Bertoni discusses the development of innovative molecular therapeutics using miRNAs to treat high-grade brain tumours at the Department of Neurology, Johns Hopkins School of medicine

Dr Hernando Lopez-Bertoni is an Assistant Professor in the Department of Neurology, Division of Neuro-Oncology at the Johns Hopkins School of Medicine. Dr Lopez-Bertoni completed his PhD training at University of Nebraska medical Center in Omaha, NE in 2012 under the mentorship of Dr Xu Luo. His PhD work built upon his interest in cell death mechanisms as he studied how Bcl-2 family proteins regulate cell death in response to different chemotherapeutic agents.

These were one of the first studies to show that simultaneously targeting more than one anti-apoptotic protein is required to efficiently kill tumour cells and helped solidify the concept of combinatorial pro-apoptotic therapeutics.

Diagnosis and treatment of brain cancer

Dr Lopez-Bertoni moved to Baltimore, MD in May 2012 to pursue a post-doctoral fellowship in neuro-oncology under the mentorship of Dr John Laterra at the Johns Hopkins School of Medicine. His work as a fellow focused on studying the molecular mechanisms involved in establishing and promoting brain tumour formation and understanding the contribution of stem-like cells to this process with the goal of using this knowledge to develop new approaches that will ultimately impact the diagnosis and treatment of brain cancer.

Dr Lopez-Bertoni has established himself as an exceptional researcher and educator. He published extensively on DNA methylation, miRNAs, the GBM cancer stem cell phenotype. He also worked on the DNA damage response in glial cells and participated in research looking at how the tumour microenvironment and receptor-tyrosine kinase inhibition affect the GBM tumour phenotype.

His work on in vivo miRNA delivery is serving as the foundation for sophisticated, mechanism-based, rational approaches to designing molecular therapeutics for GBM. Dr Lopez-Bertoni was at the forefront of identifying a role for the Yamanka factors in controlling the tumour-propagating phenotype of GBM stem-like cells.

In novel and original studies, he uncovered a molecular circuit by which Oct4/Sox2 drives GSC cellular transitions and tumour propagation, in part, by repressing miRNAs that regulate two distinct epigenetic mechanisms: (1) changes in chromatin architecture through the action of HMGA1, and (2) DNMT-dependent DNA methylation events.

Despite major advances in our understanding of cancer at the molecular level, mechanism-based treatment modalities remain limited. Dr Lopez-Bertoni’s work is at the forefront of tackling this important challenge. He has active collaborations exploring ways to translate the concept of miRNA network normalization in vivo. His efforts already identified a promising nanocarrier that allows for facile delivery of multiple miRNA types to GBM cells.

Using a technique that closely resembles clinically translatable convection-enhanced delivery (CED) Dr Lopez-Bertoni showed, for the first time, miRNA-loaded nanoparticles penetrate an established brain tumour in vivo, inhibiting the growth of established GBM xenografts, and prolong survival with an apparent 60% cure rate in mouse models.

His work highlights how novel developments in mechanisms of cell fate regulation can combine with nanomedicine to provide new avenues to develop innovative pre-clinical molecular therapeutics for GBM.

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