Development of a novel, CNS-penetrant synthetic triterpenoid for pediatric high-grade glioma. - PROJECT ABSTRACT This application is focused development of a new therapeutic for pediatric high-grade glioma (HGG), including a rare subset known as Diffuse Intrinsic Pontine Glioma (DIPG). DIPG is a rare brain cancer primarily affecting children, with approximately 200-300 new annual cases in the United States, less than 2 percent survival at 2 years, and with a limited response to therapeutic radiation (RT). Recently published studies in preclinical glioma models have revealed that RT results in a progressive accumulation of monocyte derived macrophages (MDMs) and activated microglia, and that inhibition of the recruitment of MDMs delays glioma recurrence. There is substantial evidence demonstrating a key role for chemokine (C-C motif) ligand 2 or ‘CCL2’ also known as monocyte chemoattractant protein-1 (MCP-1) in RT-induced inflammation, including the recruitment of MDMs into the brain and tumor microenvironment (TME). These studies not only show that RT induces a transient and selective upregulation of CCL2 within hours of exposure, but also demonstrate disruption of CCL2 signaling during this time frame alone is sufficient to attenuate chronic microglial activation and to allow the recovery of neurogenesis in the weeks following radiation. However, there is a desperate need for new agents that are not only potent inhibitors of CCL2 production and signaling, but that are also safe for administration in combination with RT. The synthetic oleanane triterpenoids (SOTs) evaluated in this application meet these criteria. The research team pursues ground-breaking, high-risk, high-gain studies that address our central hypothesis that chronic, systemic oral administration of a newly developed SOT (CDDO-2P-Im or ‘2P-Im’) will enhance the radiation response of DIPG through mechanisms that include suppression of RT-induced recruitment and activation myeloid cells in the brain, with potential to also limit RT-related toxicity. Preliminary data show 900 nanomoles of 2P-Im/kg of brain at 6 hours after a 1 µmole dose, given either by intraperitoneal injection or by oral gavage in mice, and that 2P-Im inhibits CCL2 production by activated human macrophages at picomolar concentrations in vitro. The project is organized around three specific aims that: (1) define the effect of 2P-Im (both alone and in combination with RT) on in vitro clonogenic survival of DIPG cell lines, including those harboring the histone H3.3 Lys 27-to-methionine (K27M) mutation, and the relationship to direct molecular targets of 2P-Im (AIM 1); (2) determine the dose- and time-dependent effects of 2P-Im on RT-induced recruitment of MDMs and on microglial activation (AIM 2); and (3) demonstrate the in vivo efficacy and activity of 2P-Im (administered in rodent diet) in established, orthotopic PDX models of DIPG, including the capacity of 2P-Im to enhance the radiation response of DIPG xenografts in vivo, (AIM 3). Data generated in this proposal will position 2P-Im for advancement to critical, IND-enabling studies, and as a novel, orally bioavailable therapy for a highly aggressive, refractory rare childhood cancer.
