Data from Preclinical efficacy of LP-184, a tumor site activated synthetic lethal therapeutic, in glioblastoma

<div>Abstract<p>Purpose: Glioblastoma (GBM), is the most common brain malignancy with median survival <2 yrs. Standard-of-care temozolomide (TMZ) has marginal efficacy in ~70% of patients due to <i>MGMT </i>expression. LP-184 is an acylfulvene-derived prodrug activated by the oxidoreductase PTGR1 that alkylates at N³-adenine, not repaired by MGMT. This paper examines LP-184 efficacy against preclinical GBM models and identifies molecular predictors of efficacy in clinical GBM. Experimental Design: LP-184 effects on GBM cell viability and DNA damage were determined using cell lines, primary patient-derived cells and neurospheres. GBM cell sensitivities to LP-184 relative to TMZ and MGMT expression were examined. Pharmacokinetics and CNS bioavailability were evaluated in mice with GBM xenografts. LP-184 effects on GBM xenograft growth and animal survival were determined. Machine learning, bioinformatic tools and clinical databases identified molecular predictors of LP-184 responsiveness. Results: LP-184 inhibited viability of multiple GBM cell isolates including TMZ-resistant and MGMT-expressing cells at IC₅₀ = ~22-310 nM. Pharmacokinetics showed favorable AUC_brain/plasma and AUC_tumor/plasma ratios of 0.11 (brain C_max=839 nM) and 0.2 (tumor C_max= 2,530 nM), respectively. LP-184 induced regression of GBM xenografts and prolonged survival of mice bearing orthotopic xenografts. Bioinformatic analyses identified <i>PTGR1</i> elevation in clinical GBM subtypes and associated LP-184 sensitivity with EGFR signaling, low nucleotide excision repair (NER) and low <i>ERCC3</i> expression. Spironolactone, that induces ERCC3 degradation, decreased LP-184 IC₅₀ 3-6 fold and enhanced GBM xenograft anti-tumor responses. Conclusions: These results establish LP-184 as a promising chemotherapeutic for GBM with enhanced efficacy in intrinsic or spironolactone-induced TC-NER deficient tumors.</p></div>