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

Abstract

PARP inhibitors are approved for treatment of cancers with BRCA1 or BRCA2 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 PEG40kDa 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 PALB2 mutation, the BRCA1-deficient MX-1 triple-negative breast cancer, and the BRCA2-deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type BRCA2. 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 BRCA1-deficient tumor. These data suggest that the long-lasting antitumor effect of the prodrug is due to a combination of its long t1/2, 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.

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

“…We previously showed that PEG$TLZ maintains a controlled and slow release of TLZ over $1 week in mice (Fontaine et al, 2021). Furthermore, the long elimination half-life, high tumor uptake, and very low efflux rates from tumors have been validated by PET imaging of PEG 40kDa -89 Zr conjugates (Beckford Vera et al, 2020).…”

“…Recent preclinical and clinical trials of the experimental combination of talazoparib (TLZ), the most potent of the approved PARP1 inhibitors, and TMZ in Ewing sarcoma demonstrated notable antitumor activity, but the combination was toxic both in patients and in mice (Schafer et al, 2020;Smith et al, 2015). As an alternative therapeutic approach to reducing toxicity and improving efficacy of the drug combination, we evaluated a novel PEGylated conjugate of TLZ (PEG$TLZ) that allows sustained, controlled release of the inhibitor within the tumor microenvironment (Fontaine et al, 2021). Nanocarrier-linked drugs increase uptake into tumor tissue and reduce permeability to normal vasculature, leading to lower dose exposure in normal tissues and reduced toxicity (Van De Ven et al, 2017, Caster et al, 2015Tsouris et al, 2014;Maeda et al, 2000;Baldwin et al, 2019;Chauhan and Jain, 2013;Chauhan et al, 2012;Matsumura and Maeda, 1986;Yang et al, 2021).…”

“…In this PEGylated prodrug, the release of TLZ is determined by the modulator group. TLZ was released with an in vitro t 1/2 $160 h at pH 7.4, 37 C (Fontaine et al, 2021).…”

Evaluation of Hedgehog Pathway Inhibitors as a Therapeutic Option for Uterine Leiomyosarcoma Using the Xenograft Model

“…The mice were handled according to the approved protocol (18-174) and all mice were maintained in a 12-h light/dark cycle and provided with water and standard diet ad libitum in a pathogen-free facility under climate control. 2 × 10 7 of the human LMS cells were inoculated into the right flank of mice with 1:1 Matrigel (Corning, Corning NY, USA) and fetal bovine serum (FBS) according to the previous publications [42][43][44][45][46]. After the tumor development, the animals were randomized separately into three groups, SMO inhibitor LDE225 (n = 5), GLI inhibitor Gant61 (n = 6 × 2), and control (n = 6 × 2).…”

Recent Developments in Nanomedicine for Pediatric Cancer

“…Bisphosphonates such as zoledronic acid can inhibit cancer angiogenesis, and because of their affinity to bone, nanoparticles conjugated with bisphosphonates showed an increased uptake and cell toxicity compared to pegylated PGLA nanoparticles [87,88]. Fontaine et al showed that long-acting PEGylated talazoparib has promising anti-tumor activity in Ewing sarcoma [89]. One approach to Ewing sarcoma involves silencing the miRNA that drives CD99, a hallmark surface antibody in the disease.…”