Monday, May 6, 2024
5/6/2024
Glioblastoma multiforme (GBM) is associated with poor prognosis due to its highly invasive and drug-resistant phenotype. Recurrence is a common phenomenon in GBM patients due to the presence of chemo- and radio- resistant Brain Tumor-Initiating Cells (BTICs). Consequently, current therapies including surgery followed by radiation or chemotherapy with Temozolomide (TMZ) failed to improve patient median overall survival emphasizing the necessity of novel treatment strategies for drug-resistant GBM. Interestingly, Neuroplin-1 (NRP1) has been shown to be implicated in the drug-resistance and stemness in multiple types of cancer. Recently, we showed that depletion of NRP1 improved survival compared to that of vascular endothelial growth factor (VEGF-A) depletion in mice bearing patient-derived GBM xenografts. NRP1 depletion also improved sensitivity to TMZ and enhanced the overall survival when combined with TMZ. Our preliminary data further showed that a proprietary tumor-targeted liposomal (TTL) formulation combining a first generation small- molecule NRP1 inhibitor (EG00229; G in short) with Everolimus (E) provided significant survival advantage in TMZ resistant glioma cells as compared to that of TMZ alone. However, EG00229 is poorly water soluble, and its liposomal formulation is not stable for long term storage. Hence, we developed a new generation of small- molecule NRP1 inhibitors (NRP1i, Ni in short) with better solubility in order to create a stable liposomal formulation. The central hypothesis of our proposal is that NRP1i combined with everolimus in a single payload using TTL, either as a systemic therapy or delivered locally in a hydrogel-based system, will reduce drug- resistance and stemness and augment radiation sensitivity in GBM, leading to better therapeutic outcomes. To validate our hypothesis, we propose three major aims. In Aim 1, we will combine the most effective NRP1i with everolimus as a single payload in TTL formulation (TTL-ENi) for evaluating in vitro efficacy in inhibiting stemness and drug-resistance signaling pathways and in vivo studies using multiple therapy resistance BTICs animal models including immune-competent mice models. Further, the additive effect of radiotherapy and chemotherapy (e.g. TMZ) in combination with the TTL-ENi will be evaluated. We will also analyze the effect of our proposed therapy on the tumor immune microenvironment using two state-of-the-art techniques namely mass cytometry (CyTOF) and digital spatial profiling (DSP). In Aim 2, we will assess the efficacy of the local administration of TTL-ENi-hydrogel in a resection and recurrence model of GBM. Moreover, the additive effect of radiotherapy and chemotherapy (e.g. TMZ) in combination with the TTL-ENi-hydrogel will be evaluated. Aim 3 will focus on the comparative pharmacokinetics, pharmacodynamics, and preliminary toxicity studies of the most potent formulation for future clinical trials. We expect that a successful execution of our proposed research will lead to clinical trial in near future for a better therapeutic strategy to override the drug-resistance in GBM patients as well as patients suffering from other drug-resistant cancers.
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