Abstract A021: Exosome delivered combinatorial treatment for malignant brain tumors

Abstract

Abstract Glioblastoma (GBM), a World Health Organization (WHO) Grade IV astrocytoma, is a highly aggressive brain tumor with poor prognosis. Current therapeutic approaches, which include surgery, chemotherapy, and radiation therapy, are largely ineffective and often result in tumor recurrence. Several characteristics of the tumors make them challenging to treat, including their protection by the blood-brain barrier, which hinders effective treatment delivery. Our research addresses this issue by using exosomes, which are small cell-derived vesicles, as delivery vehicles for microRNA (miR) therapies. Dysregulation of miR expression has been implicated in tumorigenesis, and targeting these dysregulated miRs is emerging as a promising approach to tumor treatment. In particular, miR-7 and miR-124 have been identified as tumor-suppressive miRs that are downregulated in various tumors, including GBM. In this study, stem cell-derived exosomes loaded with miR-7 and miR-124 have been evaluated as a combinatorial approach for treating GBM. In our work, human adipose stem cells (ADSCs) were transduced with the target miR-7 and miR-124 plasmids and cultured in exosome-depleted FBS. The miR-containing exosomes from the ADSCs were then isolated, purified, quantified, and characterized for use in subsequent studies. Murine and human GBM cells as well as primary patient-derived primary GBM cells were treated with miR-7 and miR-124 exosomes, and the efficacy of exosome treatment was determined using cell viability assays and microscopy. The mechanisms of miR modulation of cell proliferation and cell death pathways were analyzed with time-course western blot analysis. Orthotopic animal models of GBM will be used to assess the effectiveness of our methods in vivo. Our results have demonstrated successful delivery of miR-7 and miR-124 to GBM cells via stem cell-derived exosomes. Data show that treatment with these tumor-suppressive miRs halts GBM growth in vitro by modulating multiple pathways involved in tumor growth and progression. While we await results of our in vivo studies, our preliminary data demonstrate that delivery of miR-7 and miR-124 via stem cell-derived exosomes is a promising therapeutic approach for treating GBM. Citation Format: Sydney Thomas, Karthik Gourishetti, Karthik Rangavajhula, Deepak Bhere. Exosome delivered combinatorial treatment for malignant brain tumors [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A021.