iScience: PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma (Kurmasheva & Houghton Labs)

Vanessa del Pozo
Andrew J.Robles
Shaun D.Fontaine
QianqianLiu
Joel E.Michalek
Peter J.Houghton
Raushan T.Kurmasheva

Highlights

• Nanoparticle-formulated drugs minimize drug-induced toxicity
• PEG∼TLZ enhances in vivo activity of TMZ in pediatric tumor xenografts
• A 3-day interval between each drug’s administration widens the therapeutic window
• A single IV dose of PEG∼TLZ is advantageous for treating infants/young children

Summary

Current therapy is ineffective for relapsed and metastatic Ewing sarcoma (EwS) owing to the 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.

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