Gallium maltolate for the treatment of difficult-to-treat high-grade pediatric brain tumors

About This Grant

PROJECT ABSTRACT/SUMMARY Neoplasms of the central nervous system (CNS) are the most frequently encountered solid tumors of childhood and remain one of the top causes of death in children. Pediatric high-grade gliomas (pHGGs) and atypical teratoid rhabdoid tumor (ATRT) are particularly aggressive pediatric CNS (pedCNS) tumors associated with poor outcome. Therapy consists of extremely burdensome multi-modal treatment protocols with toxic profiles that cause patients to suffer from detrimental effects, which significantly impact the quality of life during their already limited lifespan. New therapeutic strategies are badly needed to increase the survival benefit and quality of life of patients with pHGG and ATRT. To address this need, we performed initial studies that demonstrated that primary CNS cancers display dysregulated iron homeostasis and that gallium maltolate (GaM), an iron mimetic metallocompound, inhibits the growth of pHGG and ATRT cells in vitro and in an orthotopic rat model, extending overall survival. Cancer iron metabolism is an attractive target for therapeutical intervention. Iron plays a vital role in the pathobiology of many cancers, including brain cancer. Gallium acts as an iron mimetic, enabling it to hijack common iron trafficking pathways to enter cancer cells. However, unlike iron, gallium cannot take part in cellular redox reactions, thus disrupting critical iron-dependent processes and resulting in cell death. Our group has demonstrated the effectiveness of gallium maltolate (GaM), a newer generation compound with high oral bioavailability and therapeutic index, both in vitro and in vivo. In animal studies of adult glioblastoma, the most aggressive type of primary brain tumors, we demonstrated a slower tumor growth rate, a doubling of survival, and an improved quality of life with treatment. Preliminary studies in pHGGs and ATRTs suggest similar benefits. Despite this promising initial step, questions regarding the efficacy of GaM remain. Specifically, we intend to address the knowledge gap as to what drives response to GaM therapy. Therefore, our overall goal is to be able to offer a new treatment strategy to brain tumor patients with few therapeutic options. In Specific Aim 1, we propose a sophisticated multi-pronged approach leveraging behavioral assessments, state-of-the-art MRI-guided biopsy, cellular bioenergetics, and induction coupled plasma mass spectrometry (ICP-MS), to develop a tissue sensitivity profile. In Specific Aim 2, we propose to explore the synergistic potential of combining GaM with radiation therapy, the backbone of many treatment protocols. Preliminary data suggest a potentiating cytotoxic effect, which requires confirmation in vivo. Collectively, these investigations will provide insights regarding how to maximize antineoplastic therapy with GaM to improve both the quality of life and extend survival in children with primary brain tumors.