Glioblastoma (GBM), the most common and deadly adult primary brain tumor, is notoriously resistant to therapy, not only because of its unique biology, including Glioma Stem-like Cells (GSCs), but also because of the delivery challenges imposed by the blood-brain and blood-tumor barriers. Thus, there is an urgent need to identify effective GBM-specific therapeutics and to elucidate strategies for delivering these new agents. A promising new approach is treatment with microRNAs (miRs), which are small, noncoding RNAs that are powerful regulators of gene expression. We have shown that restoration of tumor suppressor miRs is capable of killing GSCs and, therefore, treatment with miRs is potentially a new paradigm in GBM therapy. However, it is currently unknown which miRs will be most effective against GBMs and how these miRs should be delivered. This grant is significant because it directly addresses both of these problems by identifying the most effect anti-GBM miRs and by developing exosomes derived from bone marrow mesenchymal stem cells (MSCs) as a new delivery strategy for these miRs. Exosomes are naturally occurring nanovesicles that function as intercellular transport vehicles. We hypothesize that miRs can be used as effective therapeutics against GBMs, and that exosomes derived from cultured MSCs can be used to systemically deliver these antiglioma miRs.
Aim 1 will identify miRs that are most effective against GSCs. In an in vitro high-throughput screen (HTS) of 578 miRs against a panel of GSCs, we have already identified 50 antiglioma miRs that effectively kill GSCs in vitro.
This aim will use an in vivo HTS to determine which of the 50 top candidates is most effective against orthotopic GSCs in mice, and it will define the most effective miR combinations. Mechanistic studies will identify the target(s) responsible for the anti-GBM effects.
Aim 2 will develop MSC-derived exosomes as novel delivery vehicles of antiglioma miRs. We have shown that after transduction with lentiviruses containing antiglioma miRs, MSCs package the miRs into exosomes (called Exos-miRs) and secrete the Exo-miRs into the culture medium. These Exo-miRs can be isolated and delivered systemically, after which they home to GSCs and inhibit target genes.
This aim will define the optimal dose/schedule of Exos-miRs using bioluminescence imaging and a novel TET-reporter system. This dose/schedule will be used to test the efficacy and safety of the best antiglioma miRs or miR combinations identified in Aim 1.
Aim 3 will elucidate the mechanisms underlying the ability of Exos-miRs to home to GBMs. By using proteomic analyses to compare strongly homing exosomes (MSC-Exos) with poorly homing ones (fibroblast-Exos), we have identified candidate homing proteins. In this aim, we will perform functional analyses to determine the extent to which the identified proteins mediate the homing of Exo-miRs to GBMs. Successful completion of this grant will result in a new and integrated agent/delivery paradigm that uses miRs to treat GBMs and MSC-derived exosomes to deliver these miRs, and that has the potential to improve the survival of the estimated 15,000 people who die of GBM each year due to the current lack of effective therapy for this disease.

Public Health Relevance

This proposal explores a new paradigm for treating malignant brain tumors that is centered on using therapeutic microRNAs to treat GBMs and on delivering these microRNAs with MSC-derived exosomes. Successful completion of this grant will establish the necessary evidence that this new strategy is effective against brain tumors and overcomes the major hurdles that currently prevent cure of this disease. The translation of this approach to the clinic is relevant to public health because this new strategy has the potential to improve the prospects of the estimated 15,000 people who die of GBM each year due to lack of effective therapy for this disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Welch, Anthony R
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University of Texas MD Anderson Cancer Center
United States
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