Preclinical efficacy of lp-184, a tumor site activated synthetically lethal therapeutic, in glioblastoma

Abstract Temozolomide (TMZ) is currently the most effective standard-of-care chemotherapy based on its ability to prolong survival of patients with newly diagnosed MGMT-methylated GBM. Blood-brain barrier (BBB) permeable agents effective against TMZ-resistant GBMs (i.e. recurrent GBM, MGMT unmethylated GBM) are desperately needed. Lantern Pharma is advancing LP-184, an acylfulvene prodrug activated by the enzyme PTGR1, in GBM. In an MGMT expressing TMZ resistant GBM PDX model, LP-184 was found to be ~5000X more potent than TMZ. DNA damage induced by acylfulvenes is primarily repaired via transcription-coupled nucleotide excision repair (TC-NER) mediated by ERCC complexes and gene set variation analyses associate LP-184 cell sensitivity with low TC-NER. ERCC3 is a key NER factor that is proteolytically degraded in response to the FDA approved BBB permeable diuretic, spironolactone (SP). After verifying that spironolactone induces rapid ERCC3 degradation by up to 95% in GBM cells, we validated that SP-induced ERCC3 loss led to substantial increases in LP-184 response in vitro and in subcutaneous tumor xenografts. Co-treatment of GBM cells with LP-184 and 5 or 25 µM SP resulted in a 3-6 fold decrease in LP-184 IC50s in M1123, Mayo39 and U87 cultures in vitro. Mice bearing pre-established subcutaneous U87 xenografts were treated with SP alone, LP-184 alone or their combination. Tumors recurred after initial regression in 5/5 animals treated with LP-184 alone whereas tumors showed durable complete regression without recurrence in 4/5 animals treated with LP-184 + SP. LP-184 is a promising chemotherapeutic with potential clinical translation in GBM patients. Our results indicate that LP-184 is MGMT-agnostic and effective in TMZ-resistant pre-clinical GBM models. Our findings also identify ERCC3-dependent TC-NER activity as a determinant of LP-184 synthetic lethality predicting that LP-184’s therapeutic potential will be significantly enhanced in patients with intrinsic or spironolactone-induced NER deficient tumors.