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- W4387608059 abstract "<div>AbstractPurpose:<p>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 <i>MGMT</i> expression. LP-184 is an acylfulvene-derived prodrug activated by the oxidoreductase PTGR1 that alkylates at N<sup>3</sup>-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.</p>Experimental Design:<p>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.</p>Results:<p>LP-184 inhibited viability of multiple GBM cell isolates including temozolomide-resistant and MGMT-expressing cells at IC<sub>50</sub> = approximately 22–310 nmol/L. Pharmacokinetics showed favorable AUC<sub>brain/plasma</sub> and AUC<sub>tumor/plasma</sub> ratios of 0.11 (brain <i>C</i><sub>max</sub> = 839 nmol/L) and 0.2 (tumor <i>C</i><sub>max</sub> = 2,530 nmol/L), 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, which induces ERCC3 degradation, decreased LP-184 IC<sub>50</sub> 3 to 6 fold and enhanced GBM xenograft antitumor responses.</p>Conclusions:<p>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>" @default.
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- W4387608059 date "2023-10-13" @default.
- W4387608059 modified "2023-10-14" @default.
- W4387608059 title "Data from Preclinical Efficacy of LP-184, a Tumor Site Activated Synthetic Lethal Therapeutic, in Glioblastoma" @default.
- W4387608059 doi "https://doi.org/10.1158/1078-0432.c.6879402" @default.
- W4387608059 hasPublicationYear "2023" @default.
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