R01HD103638

Theranostics for Pediatric Brain Cancer - Theranostics for Pediatric Brain Cancer

Glioblastoma (GBM) is the most frequently diagnosed primary malignant brain tumor in children, with a median survival of less than one year. Disease recurrence is common and is caused by the presence of glioma-initiating cells (GICs) that are unresponsive to conventional therapies, underscoring the urgent need for new therapeutic options.

We aim to develop a novel strategy to specifically disrupt the lifeline of GICs without causing toxic effects to the normal brain. The highly vascularized nature of GBMs and the critical function of the perivascular niche for nutritional supply of GICs have spurred much interest in novel vascular-disruptive agents (VDAs).

Intravenously administered VDAs easily reach GBM vessels and do not rely on the enhanced permeability and retention effect, which can limit the delivery of macromolecules to the tumor tissue. VDA-mediated blood vessel disruption causes efficient drug delivery to the GIC niche and starvation of many tumor cells. In contrast to classical anti-angiogenesis drugs, VDAs not only disrupt the tumor vasculature but also cause significant GIC apoptosis through direct cytotoxic effects.

While being highly effective for cancer treatment, initial VDA formulations also caused significant toxicity to the normal brain. This is particularly concerning for children, as the developing brain is more vulnerable to toxic side effects compared to the adult brain. To solve this problem, we developed novel VDA-loaded theranostic (combined therapeutic and diagnostic) nanoparticles, which are specifically activated in brain tumors by matrix metalloproteinases 14 (MMP-14). The normal brain does not express MMP-14 and therefore does not activate the theranostic drug, thereby creating highly effective cancer therapy without side effects.

The major goal of our project is to develop MMP-14-activatable theranostic nanoparticles (TNPs) for curative treatment of GBM without causing toxicity to the normal brain. The approach relies on the high prevalence of MMP-14 in GBM, a proven MMP-14-activatable prodrug strategy, and a nanocarrier platform based on FDA-approved iron oxide nanoparticles.

We hypothesize that our TNPs will be converted to an active therapeutic agent only within MMP-14-expressing tumors, releasing the therapeutic drug azademethylcolchicine and causing significant antitumor effects. In addition, we postulate that the iron oxide nanoparticle moiety will allow real-time monitoring of drug accumulation and localization at tumors with magnetic resonance imaging (MRI).

In Aim 1, we will evaluate whether TNP dose and VDA payload affect VDA-mediated vascular disruption, blood-brain barrier (BBB) breakdown, and cancer-specific toxicity. In Aim 2, we will investigate the link between VDA-mediated tumor microvessel disruption, microvascular endothelial cell death, and GIC death.

TNPs hold the potential to substantially improve therapeutic efficacy while simultaneously reducing dose-limiting toxicities. Realizing our goal will uncover new targets and mechanisms for successful GBM therapy, eliminate or substantially reduce off-target toxicities, and provide children with brain cancers with a much-needed new treatment option.

The Leland Stanford Junior University

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

California United States

State-Wide

Development of Appropriate Pediatric Formulations and Pediatric Drug Delivery Systems (R01) (PAR-17-193)

Amendment Since initial award the total obligations have increased 387% from $677,761 to $3,299,320.