Nanotherapeutic enhancement of interstitial thermal therapy for glioblastoma

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Project Summary Brain invasion, limited drug delivery, and treatment resistance render glioblastoma (GBM) virtually untreatable with current surgical, chemo- and radiation therapy approaches. Tumor recurrence is nearly universal, and the median patient survival (~15 months) has not changed significantly in 20 years. Radical new ideas and approaches are needed to change the course of this devastating disease. New neurosurgical approaches to treating GBM are emerging with the FDA approval of minimally invasive and image-guided technologies that now enable access to and treatment of previously unresectable and complex recurrent tumors. A major advance has been the development of magnetic resonance imaging (MRI)-guided and monitored, robotically controlled laser probes for intra-tumoral thermal treatments (e.g., laser interstitial thermal therapy [LITT]). LITT is increasingly used to treat deep-seated, unresectable tumors through both direct thermal ablation and priming to sensitize the tumor to radiation. Such thermal priming of solid tumors, including GBM, has been known for decades to increase the efficacy of radiation treatment. However, tools to safely and effectively accomplish this in neurosurgery have been lacking. Our clinical research team is leading two Phase I trials (NCT04181684, NCT04699773) investigating LITT-based priming of GBM for enhanced radiation. While the preliminary results in GBM patients have been promising, many patients (~40%) experience usually temporary adverse effects, such as brain edema and seizures. We predict that improving the heat transfer within the tumor and reducing thermal effects on surrounding brain tissues will reduce side effects and accelerate the clinical translation and efficacy of this new approach. Gold nanoparticle (AuNP)-enhanced photothermal ablation can increase thermal conductance and capacitance within the tumor and reduce heat transfer to surrounding normal tissues. Combining AuNPs and LITT offers the opportunity to improve the efficacy and safety of LITT. Our multidisciplinary team of experts in surgical neuro-oncology (Woodworth), DART nanotechnology (Kim), GBM Fn14 biology (Winkles), and plasmonic nanoparticles for photothermal therapy (Huang), is developing an advanced local drug delivery strategy that bypasses the blood-brain barrier and leverages a novel Decreased nonspecific-Adhesivity, Receptor-Targeted (DART) NP formulation. We have shown that DART nanoparticles, targeted to the tumor necrosis factor receptor superfamily member fibroblast growth factor-inducible 14 (Fn14), can penetrate tumor tissues to provide more uniform dispersion and selectively bind to and enter GBM cells, including those in the invasive margin. The central hypothesis is that controlled, monitored intratumoral delivery of Fn14-targeted DART AuNPs will significantly enhance LITT for GBM with fewer side effects on surrounding brain tissues. We will test this hypothesis in Fn14+ or Fn14- GBM patient-derived xenograft (PDX) models using immunodeficient rats and in an RCAS/tv-a-based transgenic rat model of Fn14+ human GBM.