A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models

PARP inhibitors are approved for treatment of cancers with or defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG carrier via a β-eliminative releasable linke...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2021-02, Vol.81 (4), p.1076-1086
Hauptverfasser: Fontaine, Shaun D, Ashley, Gary W, Houghton, Peter J, Kurmasheva, Raushan T, Diolaiti, Morgan, Ashworth, Alan, Peer, Cody J, Nguyen, Ryan, Figg, Sr, William D, Beckford-Vera, Denis R, Santi, Daniel V
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Sprache:eng
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Zusammenfassung:PARP inhibitors are approved for treatment of cancers with or defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG carrier via a β-eliminative releasable linker. A single injection of the PEG∼TLZ conjugate was as effective as ∼30 daily oral doses of TLZ in growth suppression of homologous recombination-defective tumors in mouse xenografts. These included the KT-10 Wilms' tumor with a mutation, the -deficient MX-1 triple-negative breast cancer, and the -deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type . Although the half-life of PEG∼TLZ and released TLZ in the mouse was only ∼1 day, the exposure of released TLZ from a single safe, effective dose of the prodrug exceeded that of oral TLZ given daily over one month. μPET/CT imaging showed high uptake and prolonged retention of an 89Zr-labeled surrogate of PEG∼TLZ in the MX-1 -deficient tumor. These data suggest that the long-lasting antitumor effect of the prodrug is due to a combination of its long , the high exposure of TLZ released from the prodrug, increased tumor sensitivity upon continued exposure, and tumor accumulation. Using pharmacokinetic parameters of TLZ in humans, we designed a long-acting PEG∼TLZ for humans that may be superior in efficacy to daily oral TLZ and would be useful for treatment of PARP inhibitor-sensitive cancers in which oral medications are not tolerated. SIGNIFICANCE: These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-20-1741