Abstract 5442: LP-184, a tumor site activated small molecule synthetic lethal therapeutic, is effective in central nervous system cancers

Abstract

Abstract Blood-brain barrier (BBB) permeable agents effective against recurrent, chemotherapy-resistant central nervous system (CNS) tumors are urgently needed, particularly in Glioblastoma multiforme (GBM) and atypical teratoid/rhabdoid tumors (ATRT). These represent 2 extremely aggressive and lethal types of CNS malignancies sharing a median overall survival of 12-18 months and 5-year survival rate of 5 to 30% in the US. LP-184 has received orphan drug designation for the treatment of malignant gliomas. LP-184 is activated to a highly labile metabolite by Prostaglandin Reductase 1 (PTGR1) and has potential to be a potent therapeutic as a single agent for PTGR1-expressing malignancies. LP-184 was found to have nanomolar range potency (IC50 30-400 nM) against multiple human GBM cell lines and patient-derived neurospheres in vitro. Intravenous LP-184 induced complete and durable regression of pre-established subcutaneous U87 and M1123 GBM xenografts and prolonged survival of mice bearing orthotopic U87 and M1123 xenografts (p<0.0001). Activated LP-184 creates covalent DNA adducts (e.g. N3 of adenine) that are selectively repaired via ERRC-dependent nucleotide excision repair or by homologous recombination. Consistent with this, we observed 2-5X increase in cytotoxicity in U87, Mayo39, M1123 GBM cells treated with LP-184 in combination with the ERCC3 inhibitor Spironolactone relative to LP-184 alone. This supports LP-184’s function as a synthetic lethal agent in the presence of DNA repair deficiencies. > 50% of newly diagnosed GBMs fail to respond to standard of care temozolomide (TMZ) due to MGMT expression (i.e.unmethylated mgmt promoter) and essentially all GBMs ultimately develop TMZ resistance. Our in silico analyses and type of DNA adduct generated by LP-184 indicate that sensitivity to LP-184 is independent of MGMT expression and potentially higher in MGMT unmethylated cancers. This is supported by in vitro toxicity assays showing LP-184 IC50s of 46 nM in LN-18 (unmethylated mgmt) and 203 nM in U87 (hypermethylated mgmt) cell lines. Analysis of genes associated with LP-184 sensitivity in solid tumor cell lines revealed that expression of SMARCB1 is significantly anti-correlated to LP-184 sensitivity, suggesting that LP-184 will be effective in ATRTs and other tumors with SMARCB1 loss. LP-184 treatment induced tumor regression in mice implanted with SMARCB1 deficient CHLA06 ATRT subcutaneous xenografts, with 2 of 10 treated mice being virtually tumor-free after 2 cycles over 22 days. Pharmacokinetic analyses showed favorable in vivo BBB permeability (mouse brain/blood ratio=0.112) comparable to that reported for TMZ. LP-184 was also active in vitro against models of brain metastases from primary lung and breast cancers. These findings identify LP-184 as a promising new agent and support its further development for treating CNS tumors in adult and pediatric populations. Citation Format: Aditya Kulkarni. LP-184, a tumor site activated small molecule synthetic lethal therapeutic, is effective in central nervous system cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5442.