Nanoformulation of Talazoparib Increases Maximum Tolerated Doses in Combination With Temozolomide for Treatment of Ewing Sarcoma

Paige Baldwin; Rostislav Likhotvorik; Nabeela Baig; Jodie Cropper; Ruth Carlson; Raushan Kurmasheva; Srinivas Sridhar

doi:10.3389/fonc.2019.01416

Nanoformulation of Talazoparib Increases Maximum Tolerated Doses in Combination With Temozolomide for Treatment of Ewing Sarcoma

Front Oncol. 2019 Dec 17:9:1416. doi: 10.3389/fonc.2019.01416. eCollection 2019.

Authors

Paige Baldwin¹, Rostislav Likhotvorik², Nabeela Baig², Jodie Cropper², Ruth Carlson², Raushan Kurmasheva^{2

3}, Srinivas Sridhar^{1

4

5}

Affiliations

¹ Department of Bioengineering, Northeastern University, Boston, MA, United States.
² Greehey Children's Cancer Research Institute, San Antonio, TX, United States.
³ Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
⁴ Department of Physics, Northeastern University, Boston, MA, United States.
⁵ Division of Radiation Oncology, Harvard Medical School, Boston, MA, United States.

Abstract

The Pediatric Preclinical Testing Program previously identified the PARP inhibitor talazoparib (TLZ) as a means to potentiate temozolomide (TMZ) activity for the treatment of Ewing sarcoma. However, the combination of TLZ and TMZ has been toxic in both preclinical and clinical testing, necessitating TMZ dose reduction to ~15% of the single agent maximum tolerated dose. We have synthesized a nanoparticle formulation of talazoparib (NanoTLZ) to be administered intravenously in an effort to modulate the toxicity profile of this combination treatment. Results in Ewing sarcoma xenograft models are presented to demonstrate the utility of this delivery method both alone and in combination with TMZ. NanoTLZ reduced gross toxicity and had a higher maximum tolerated dose than oral TLZ. The dose of TMZ did not have to be reduced when combined with NanoTLZ as was required when combined with oral TLZ. This indicated the NanoTLZ delivery system may be advantageous in decreasing the systemic toxicity associated with the combination of oral TLZ and TMZ.

Keywords: Ewing sarcoma; combination therapy; nanoparticle; talazoparib; temozolomide.