Projects
The HCC SPORE in Brain cancer consists of three projects. Each project exists to improve the standard of care for adult and pediatric gliomas through the use of targeted therapies.
SPORE
Brain Cancer
Specialized Programs of Research Excellence
Targeted therapeutics for pediatric low-grade glioma
PROJECT SUMMARY
Project one targets pediatric low-grade gliomas (pLGGs), the most common subtype of glioma in children. Nearly 75% of pLGGs are driven by truncation/fusion variants of the BRAF protein kinase. Type 1 RAF inhibitors (developed for the amino acid substitution mutations of BRAF commonly expressed in malignant melanoma) are ineffective on these truncation/fusion variants. Only about one third of patients with pLGGs who receive standard of care progress to become candidates for RAF inhibitors such as tovorafenib. However, almost all patients with pLGG undergo long term follow up with MRIs, which are stressful for children and parents alike.
We have three specific aims:
- Aim 1: Enhanced efficacy and tolerability of targeted inhibition for pLGG.
- Aim 2: A genomic “audit” of RAF expression in pLGG.
- Aim 3: Non-invasive “child friendly” predictors of children with pLGG most likely to require and respond to RAF antagonists.
Project Co-Leaders
Druggable dependencies in diffuse midline gliomas
PROJECT SUMMARY
Project two targets diffuse midline gliomas (DMGs) — the deadliest brain tumor of children. DMGs are unresectable and refractory to conventional therapeutic modalities. Moreover, the prevalent oncogenic drivers (a set of recurrent H3K27M substitutions) are undruggable. Various workarounds and surrogate targets for drug development have thus far shown no clear clinical benefit. Against this backdrop, the project two team has conducted a genome-wide CRISPR screen for DMG-specific metabolic vulnerabilities. The screen reveals that DMGs are critically dependent on the alternative end-joining (alt-EJ) pathway for repair of DNA double-strand breaks (DSBs). Three separate components of the alt EJ pathway are viable targets for drug development and the team has identified brain-penetrant, clinical-stage antagonists for each of these three components. One of the drugs identified by the team is orludodstat — a brain-penetrant inhibitor of de novo pyrimidine biosynthesis that was identified.
We have three specific aims:
- Aim 1: Brain penetrance and target engagement in a phase 0, target validation clinical trial of orludodstat for DMG.
- Aim 2: Pre-clinical development of POLQ and ATR kinase antagonists.
- Aim 3: A 3-dimensional (3D) reference map of DMG architecture.
Project Co-Leaders
Targeting IDH mutant gliomas
PROJECT SUMMARY
Project three addresses the early-stage (lower-grade) IDH mutant gliomas (IDHM) of young adults. We have demonstrated that the IDHM oncoprotein sensitizes progressive (WHO grade 4) IDHM gliomas to inhibitors of de novo pyrimidine synthesis or NAD+ metabolism — a pair of “synthetic lethal” vulnerabilities created by the IDHM-generated (R)-2HG oncometabolite. Importantly, these vulnerabilities can be exploited by orludodstat, a clinical stage, brain-penetrant inhibitor of the de novo pathway for pyrimidine biosynthesis, or with temozolomide and poly (ADPribose) glycohydrolase (PARG) inhibitor combination therapy, respectively. IDH-mutant gliomas eventually progress to high-grade disease and become refractory to these treatments. As such, there is an unmet clinical need for new therapies tailored to the unique pathobiology and the clinical course of IDH-mutant gliomas. Recently, pharmacological inhibitors of mutant IDH (IDHi) have been tested in several clinical trials for brain tumor therapy.
We have three specific aims:
- Aim 1: Define the impact of IDHi acquired resistance on orludodstat activity in IDH-mutant glioma.
- Aim 2: Define the impact of IDHi acquired resistance on the activity of PARG inhibitor and TMZ combination therapy in IDH-mutant glioma.
- Aim 3: Evaluate orludodstat activity in patients who have progressed on IDHi therapy.
Project Co-Leaders
- Samuel McBrayer, Ph.D. (Basic Co-Lead)
- Luis Nicholas Gonzalez Castro, M.D., Ph.D. (Clinical Co-Lead)