EXTH-28. Targeting DNA repair mechanisms with spironolactone to enhance LP-184 CNS pharmacodynamics and efficacy

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Abstract Limited CNS bioavailability and on-target pharmacodynamics are major obstacles to developing new effective systemic therapies for GBM and other brain tumors. Strategies to overcome these obstacles include blood-brain barrier (BBB) disruption to enhance CNS penetration and brain penetrant drug combinations that enhance tumor cell chemosensitivity through synthetic lethality. LP-184 is a synthetic acylfulvene class small molecule alkylator that induces DNA damage and inhibits GBM cell viability agnostic of MGMT status with IC50 range ~20-300 nM. LP-184 improves survival in orthotopic GBM xenograft models with pre-clinical brain Cmax ~840 nM and tumor Cmax ~2,500 nM. Pre-clinical brain/plasma and tumor/plasma ratios are 0.11 and 0.2, respectively. Pharmacokinetics from a first-in-human Phase 1a study (NCT05933265) show plasma Cmax ~1000 nM at likely RDE, predicting ≥IC50-range brain and tumor concentrations based on in vitro and in vivo pre-clinical data. Transcription-coupled nucleotide excision repair (TC-NER) reverses LP-184 DNA damage and GSEA coupled with LP-184 sensitivity screens identified ERCC3, a TC-NER complex helicase, as a target for sensitizing GBM cells to LP-184. Spironolactone, an FDA-approved BBB-permeable aldosterone inhibitor, is predicted to sensitize GBM to LP-184 via multiple molecular targets including ERCC3. Treating GBM models including PDX-derived cells with spironolactone (25 µM) induces ERCC3 protein degradation by up to 95% and sensitizes cells to LP-184 in vitro (~5-fold IC50 reduction). Kinetic analysis of spironolactone-induced (35 mg/kg daily) ERCC3 degradation in orthotopic GBM PDX xenografts revealed ~50%, 56% and 79% degradation on LP-184 treatment days -2, -1, and 0, respectively. Furthermore, spironolactone enhances orthotopic GBM PDX responses to LP-184. Machine learning approaches also associate spironolactone-induced GBM cell sensitization to LP-184 with down-regulation of the TC-NER complex endonuclease ERCC1 and the DNA damage sensor CETN2. These findings provide a rationale and framework for a planned Phase 1b/2a trial to evaluate LP-184 + spironolactone therapy against recurrent GBM.

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