The goal of this Fast Track STTR project is to determine proof-of-principle and efficacyof a novel blood brain barrier (BBB) penetrating therapeutic nanoparticle for the potentialtreatment of otherwise intractable brain tumors like glioblastoma multiforme (GBM). Thisproject seeks to demonstrate that novel, targetable nanoparticles can deliverytherapeutic substances to human brain tumor cells and reduce tumor burden in braincancer and prolong patient survival. The therapeutic cargos are encapsulated cytotoxicdrugs for otherwise intractable brain tumors. After exiting the brain vasculature, uponrecognition by the tumor cell, the nanoparticle binds, gets taken into the cell(endocytosed) and the nanoparticle cargo is released, ultimately allowing availability ofthe drug to kill the cancer cell. This project fits well within the mission of the NCI, todevelop new nanotechnology-based therapeutics, especially for high-risk tumors.Historically successful cancer chemotherapy, while vastly increasing survival in non-CNS tumors, has failed to do so for brain tumors in children and adults alike. GBMremains the most malignant primary central nervous system tumor, where the medianoverall survival is 15-23 months and 5-year survival is less than 6%. The incidence ofbrain metastases is increasing with an estimated 69, 950 adults age 40+ in 2021 in theUS alone. Brain tumors represent the highest per-patient initial cost of care for anycancer group. Estimations from Surveillance, Epidemiology, and End Results (SEER) onannualized mean net cost of care approach $150, 000 per patient. These patients havethe highest annualized mean net costs for last-year-of-life care, relative to other cancers, at $135, 000 to $210, 000 (depending on age and gender). There us thus dramatic unmetneed to prevent morbidity and mortality while improving an otherwise dismal survival rate.Treatment-resistant metastases are the ultimate cause of death in most cancer patients.For brain cancer treatment, systemic therapy for metastases is generally ineffective dueto the inability to get therapeutic doses across the blood brain barrier. A reliable, low-toxic, highly effective therapy is urgently needed to treat patients with primary tumorsand treatment-resistant metastases. The specific aims of this proposal are thereforeefficient encapsulation cancer drugs inside the targeted HPLNs that cross the bloodbrain barrier, demonstrate safety and efficacy in killing cancer cells in a spectrum ofhumanized xenograft mouse models of human GBM. NanoValent's goal, at theconclusion of the Fast Track proposal is to have a promising optimized formulation thatcan be that can ultimately be GMP manufactured and submitted for IND approval withthe FDA.
Public Health Relevance Statement: Project Narrative
Toxicity of drugs used to treat cancer is the major limiting factor in effective
chemotherapy; collateral damage to bone marrow and other normal tissues limits the
amount of chemotherapeutic agent a patient can receive and often precludes
administration of curative doses. This project seeks to develop a method to encapsulate
chemotherapeutic drugs inside tiny, nano-scale particles that can cross the blood brain
barrier and efficiently treat otherwise fatal brain tumors like glioblastoma multiforme
(GBM). Success in doing so will be a first in class demonstration of the potential of this
powerful drug for targeted and potentially curative treatment of brain tumors.
