Development of miRNA-based approach for pediatric high-grade gliomas - ABSTRACT Primary high-grade gliomas (pHGGs) constitute the leading cause of cancer-related mortality in children and adolescents aged. Initial treatment strategies typically consist of gross total resection, when feasible, followed by focal radiotherapy and chemotherapy. However, the choice/use of chemotherapy remains uncertain. Although numerous therapeutic approaches have been tested, outcomes remain dismal. Since there is no standard chemotherapy for pHGGs, new treatments are urgently needed. To overcome the clinical challenges related to developing new treatments for pHGGs, our primary objective for this project is to develop a new tumor-targeting therapeutic agent that is specifically designed for pHGGs on a molecular basis. Recent studies revealed significant differences in the miRNA expression profiles between pHGGs and normal brain tissues, indicating that several sets of miRNA are oncogenic and highly overexpressed in pHGGs. Specifically, our preliminary data showed that miR20a is aberrantly expressed and has an oncogenic function in pHGGs including glioblastomas (pGBM) and diffuse intrinsic pontine glioma (DIPG, diffuse midline glioma). Although pGBM and DIPG are pathologically different types of highly lethal pHGGs, they share oncogenic molecular profiles, suggesting that we can attack the same molecular targets for both pGBM and DIPG. Given that aiming to diminish oncogenic miRNA expression by using antisense-miRNA is a promising strategy, delivery of antisense-miRNA is currently the major challenge [e.g., lack of tumor targeting, poor transport, and cellular penetration]. To overcome these challenges, we developed a cell-penetrating peptide (p28)-conjugated with antisense-miR20a (namely AmiR20-p28). Our preliminary results showed that systemically injected AmiR20-p28 preferentially accumulates at the tumor lesion in the brain, and induces apoptotic cell death by significantly silencing endogenous miR20a in tumors and blood (circulating miR20a as a potential biomarker), thereby extensively prolonging the survival of mice bearing pGBM. Based on our data, we hypothesize that the development of a pHGG tumor-targeting AmiR20-p28 will provide a novel therapeutic tool. To test our hypothesis, we set realistic aims; Aim1) Determine the pharmacological activities of AmiR20- p28 in pHGGs. Aim2) Establish biomarkers, pharmacokinetics, and toxicity of AmiR20-p28. Our experimental plans were designed with multiple validations and blinded conditions, and our multi-disciplinary team integrates expertise in basic, translational, and clinical brain cancer biology, molecular biology, pathology, and biostatistics. We seek to overcome current limitations by using AmiR20-p28 for pHGGs for which there is no cure. Upon completing our aims, our unique approach can provide a broad impact on developing CPP/miRNA- based agents for pHGGs. It can also potentially provide better treatment strategies for pHGGs patients, which is a major milestone and relevant to the NIH focus area.
