DNA aptamers as tools for toxin delivery to glioblastoma

Title: DNA aptamers as tools for toxin delivery to glioblastoma Despite recent advances in understanding the pathophysiology of glioblastoma (GBM), translation into improved clinical outcomes is absent. With a 5-year survival rate of less than 5%, nearly every patient with GBM will experience recurrence and succumb to the disease. Therapeutic efficacy is hindered by obstacles including the highly selective blood brain barrier (BBB), and inherent tumor characteristics such as high intratumor heterogeneity, which enables therapeutic resistance and recurrence. Aptamers are short, synthetic, single strands of DNA or RNA. Folding into three-dimensional shapes inherent to oligonucleotides, aptamers act as nucleic acid antibodies, binding ligands with equilibrium dissociation constants in the nanomolar region, comparable to antibodies. Aptamers are also ~6-fold smaller than antibodies and some have the potential to cross the BBB. Aptamers are identified through Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and preliminary experiments suggest that for aptamers to be developed as successful aptamer drug conjugates (ApDCs), training of drug conjugates to properly localize and release the free drug must be included in the SELEX process itself. Thus, this study seeks to optimize approaches to identify DNA aptamers that can be used as GBM-specific ApDCs. Overall question: Can we develop new drug conjugates that deliver therapy to GBM tumors otherwise resistant to treatment due to the blood-brain-barrier and intratumoral heterogeneity? Central Hypothesis: DNA aptamer-drug conjugates can be selected from a vast random library for their ability to home to human GBM patient-derived xenograft (PDX) tumors in mice. Aim 1 will identify GBM-specific MMAE- conjugated DNA aptamers in PDX models. Aim 2 will select ApDCs for intracellular MMAE toxin delivery. Long term goal: Develop a diverse library of therapeutically effective anti-GBM ApDCs from which personalized ApDCs cocktails could be selected to treat GBM patients. Completion of this study will impact the fields of both aptamer technology development and neuro-oncology, while potentially identifying novel therapeutic modalities. Additionally, the research aims of this proposal, coupled with my education plan, provide a unique training opportunity for me to translate my preliminary basic science data into a potential GBM therapy. Not only will the proposed fellowship train me to become an expert in the field of ApDCs, but the project and training environment will also take me one step closer to becoming an effective physician scientist.