Bioreducible LiPBAE miR-590-3p nanomiRs inhibit recurrent glioblastoma growth and prolong survival

Abstract:

Despite aggressive therapy consisting of surgery followed by radio/chemotherapy Glioblastoma (GBM) recurs in almost all patients and, currently, there are no proven therapies to treat recurrent GBM (rGBM). Recent developments in nanomedicine provide new and promising opportunities to develop new targeted therapeutics to treat brain tumors. In this study we combine bioinformatics, forward-thinking understanding of miRNA biology and cutting-edge nucleic acid delivery vehicles to advance targeted therapeutics for rGBM. Bioinformatic analysis of RNA sequencing from GSCs and clinical rGBM specimens identified TGF-beta receptor II (TGFBR2) signaling as a targetable pathway in rGBM. Mechanistically, we show that alterations in chromatin state driven by stem-cell driving events are conducive to a therapy-resistant state induced by TGFBR2. We show that blocking TGFBR2 via molecular and pharmacological approaches decreases the stem cell capacity, cell viability and re-sensitizes clinical rGBM isolates to temozolomide (TMZ) in vitro. miRNA-based network analysis uncovered miR-590-3p as a tumor suppressor that efficiently simultaneously inhibits multiple oncogenic nodes downstream of TGFBR2 reducing self-renewal capacity of therapy-resistant GSCs. To translate these in vitro finding, we developed novel bioreducible Lipophilic poly(β-amino ester) nanoparticles (LiPBAEs) for in vivo miRNA delivery. Following direct intratumoral infusion, these nanomiRs efficiently distribute through the tumors and mir-590-3p nanomiRs inhibited the growth and extended survival of animals bearing orthotopic human rGBM xenografts, with apparent curative effects in 3 of 10 treated mice. These results show that miRNA-based targeted therapeutics provide new opportunities to treat rGBM and bypass the resistance that is developed to standard of care. 

Audience Take Away Notes:

• General background about GBM
• Advanced approaches to target cancer stem cells as anti-tumor therapeutics
• General background on bioinformatics and polymeric nanoparticle design
• Novel concept about leveraging miRNAs as cancer therapeutics

Biography:

Hernando Lopez Bertoniwas born in Paraguay, South America and moved to the United States after completing high school to pursue a career in science in the United States of America. The long-term goal of my research is to understand the molecular mechanisms involved in regulating stemness and differentiation in neoplastic and non-neoplastic neural cells. We want to better understand Glioblastoma Multiforme (GBM) by studying the molecular mechanism by which these cells acquire a stem-like phenotype and use this knowledge to develop new ways to treat and diagnose the disease.