PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma

Vanessa Del Pozo, Andrew J. Robles, Shaun D. Fontaine, Qianqian Liu, Joel E. Michalek, Peter J. Houghton, Raushan T. Kurmasheva

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Current therapy is ineffective for relapsed and metastatic Ewing sarcoma (EwS) owing to development of drug resistance. Macromolecular prodrugs potentially lead to lower drug exposure in normal tissues and reduced toxicity. We evaluated the efficacy of PEGylated talazoparib (PEG∼TLZ), a PARP1 inhibitor, alone or in combination with the DNA-alkylating agent temozolomide (TMZ) in EwS and other pediatric tumors using conventional testing or single-mouse trial (SMT). A single dose of PEG∼TLZ (10 μmol/kg on day 0) combined with 5 daily doses of TMZ (40 mg/kg starting on day 3/4) produced minimal toxicity, and the combination achieved maintained complete response in EwS and glioblastoma models. The SMT trial with the 3-day interval between PEG∼TLZ and TMZ resulted in objective responses in EwS and other xenografts. Thus, PEG∼TLZ + TMZ demonstrated a broad range of activity in pediatric solid tumor models. Furthermore, the therapeutic window of PEG∼TLZ + TMZ was enhanced compared with the free-TLZ combination.

Original languageEnglish (US)
Article number103725
JournaliScience
Volume25
Issue number2
DOIs
StatePublished - Feb 18 2022

Keywords

  • Molecular medicine
  • Oncology
  • Pharmacology

ASJC Scopus subject areas

  • General

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