An emerging and radically different strategy for molecular therapy is the targeting of genomic deletions, which conventionally have not been considered to be therapeutically actionable. However, it has now been demonstrated that genes that are adjacent or in close proximity to lost tumor suppressor genes, so called ?passenger? or ?collaterally deleted? genes, expose pharmacologically targetable vulnerabilities if these passenger genes have critical functions. For example, gliomas with passenger deletions in the glycolytic gene Enolase 1 (ENO1) are exquisitely sensitive to agents that inhibit mitochondrial Oxidative Phosphorylation (OxPhos), including a new drug developed at MD Anderson by the Institute of Applied Cancer Science (IACS), called IACS-010759, which inhibits OxPhos by binding mitochondrial Complex I with nM affinity. Hypersensitivity to OxPhos inhibition derives from impaired glycolysis, because ENO1-deleted tumor cells are unable to initiate compensatory upregulation of glycolysis in the face of inhibition of OxPhos, while normal cells do not share this metabolic vulnerability. This provides a therapeutic window. Equally important, we have also shown in pre-clinical tumor models that inhibition of OxPhos by IACS-010759 can be non-invasively imaged with the PET redox/hypoxia probe, 18F-fluoroazomycin-arabinoside ([18F]FAZA), because inhibiting OxPhos reverses tumor hypoxia. We thus hypothesize that IACS-010759 constitutes a novel molecular targeted therapeutic agent for the treatment of GBMs with loss of ENO1 or of other genes that impair glycolysis, and that PET/CT imaging with [18F]FAZA can be used as a noninvasive marker of target engagement. We will test this hypothesis by determining drug-penetration and target engagement with [18F]FAZA PET/CT and biochemical response to IACS-010759 in patients with GBM. IACS-010759 has received IND-approval and is currently undergoing phase I dose escalation in a liquid tumor setting, AML (NCT02882321) at MDACC. IND approval was granted for an expansion cohort of IACS- 010759 into solid tumor, including GBM, with phase I solid tumor testing anticipated to begin in the summer, 2018. We have already received a first-in-USA IND approval for clinical [18F]FAZA PET (MDACC; IND#135054), and an approved IRB activated on September 22, 2017 (MDACC#2016-0847) for baseline Test-Retest [18F]FAZA PET/CT analysis at MDACC. In the context of the continuation phase I trial of IACS-010759 to include GBM patients, we further propose a first-in-GBM companion trial with an amended protocol for Test-Drug-Retest [18F]FAZA PET/CT to measure target engagement and correlate with biological endpoints. Success of this proposal will validate a novel PET companion diagnostic for target engagement of IACS- 010759, corroborate collateral genomic deletions as targetable entities that will dramatically extend what may be considered ?druggable? genetic alterations, and increase the clinical utility of PET in precision medicine.
Genes that are adjacent to lost tumor suppressor genes, so called ?passenger? or ?collaterally deleted? genes, expose pharmacologically targetable vulnerabilities if these passenger genes have critical functions. Consistent with this idea, ENO1-deleted glioma cells, deficient in a critical glycolysis enzyme, are exceptionally sensitive to inhibition of mitochondrial Oxidative Phosphorylation (OxPhos), of which IACS-010759, a novel high affinity active-site inhibitor of mitochondrial Complex I, blocks the electron transport chain, reverses tumor hypoxia and is entering extended Phase 1 trials. We propose a companion imaging trial to quantify drug penetration and target engagement of IACS-010759 non- invasively by repeated PET/CT with the hypoxia/redox tracer [18F]FAZA in GBM patients, a study that will extend what may be considered ?druggable? genetic alterations and increase the clinical utility of PET in precision medicine.
