LP-184 + spironolactone

LP-184 + spironolactone is an investigational **combination therapy** for central nervous system (CNS) cancers, including glioblastoma and atypical teratoid rhabdoid tumor (ATRT). LP-184 is a next-generation small molecule in the acylfulvene class, developed as a prodrug activated by prostaglandin reductase 1 (PTGR1), which is highly expressed in some CNS cancers. Upon activation, LP-184 induces **irreparable DNA damage** by generating cytotoxic DNA adducts, leading to tumor cell death. Spironolactone, a mineralocorticoid receptor antagonist, is used as a chemosensitizer in this combination: it induces **degradation of ERCC3**, a protein required for nucleotide excision repair (NER), thereby rendering cancer cells more vulnerable to the DNA-damaging effects of LP-184. Mechanistically, this combination exploits synthetic lethality by targeting DNA repair-deficient tumor cells, and preclinical studies demonstrate synergistic antitumor activity. The combination is being developed by Lantern Pharma and its subsidiary Starlight Therapeutics for pediatric and adult CNS tumor indications, including ongoing clinical trials and FDA rare pediatric disease and fast track designations[1][3][5][7].