Preclinical Efficacy of LP-184, a Tumor Site Activated Synthetic Lethal Therapeutic, in Glioblastoma

Clin Cancer Res. 2023 Oct 13;29(20):4209-4218. doi: 10.1158/1078-0432.CCR-23-0673.

Abstract

Purpose: Glioblastoma (GBM) is the most common brain malignancy with median survival <2 years. Standard-of-care temozolomide has marginal efficacy in approximately 70% of patients due to MGMT expression. LP-184 is an acylfulvene-derived prodrug activated by the oxidoreductase PTGR1 that alkylates at N3-adenine, not reported to be repaired by MGMT. This article examines LP-184 efficacy against preclinical GBM models and identifies molecular predictors of LP-184 efficacy in clinical GBM.

Experimental design: LP-184 effects on GBM cell viability and DNA damage were determined using cell lines, primary PDX-derived cells and patient-derived neurospheres. GBM cell sensitivities to LP-184 relative to temozolomide 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 GBM cells and tumors to LP-184 responsiveness.

Results: LP-184 inhibited viability of multiple GBM cell isolates including temozolomide-resistant and MGMT-expressing cells at IC50 = approximately 22-310 nmol/L. Pharmacokinetics showed favorable AUCbrain/plasma and AUCtumor/plasma ratios of 0.11 (brain Cmax = 839 nmol/L) and 0.2 (tumor Cmax = 2,530 nmol/L), respectively. LP-184 induced regression of GBM xenografts and prolonged survival of mice bearing orthotopic xenografts. Bioinformatic analyses identified PTGR1 elevation in clinical GBM subtypes and associated LP-184 sensitivity with EGFR signaling, low nucleotide excision repair (NER), and low ERCC3 expression. Spironolactone, which induces ERCC3 degradation, decreased LP-184 IC50 3 to 6 fold and enhanced GBM xenograft antitumor 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.

MeSH terms

  • Animals
  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Damage / drug effects
  • DNA Modification Methylases / antagonists & inhibitors
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • Glioblastoma* / drug therapy
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Mice
  • Prodrugs / pharmacology
  • Synthetic Lethal Mutations
  • Temozolomide / pharmacology
  • Temozolomide / therapeutic use
  • Xenograft Model Antitumor Assays*

Substances

  • Temozolomide
  • DNA Repair Enzymes
  • DNA Modification Methylases
  • Prodrugs