Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer

Shicheng Yang; Allen Green; Needa Brown; Alexis Robinson; Merline Senat; Bryanna Testino; Daniela M Dinulescu; Srinivas Sridhar

doi:10.3389/fonc.2023.1175617

Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer

Front Oncol. 2023 May 9:13:1175617. doi: 10.3389/fonc.2023.1175617. eCollection 2023.

Authors

Shicheng Yang¹, Allen Green², Needa Brown^{3

4

5}, Alexis Robinson⁴, Merline Senat⁴, Bryanna Testino^{2

4}, Daniela M Dinulescu², Srinivas Sridhar^{1

3

4

5

6}

Affiliations

¹ Department of Chemical Engineering, Northeastern University, Boston, MA, United States.
² Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
³ Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
⁴ Cancer Nanomedicine Co-ops for Undergraduate Research Experience (CaNCURE), Northeastern University, Boston, MA, United States.
⁵ Department of Physics, Northeastern University, Boston, MA, United States.
⁶ Department of Bioengineering, Northeastern University, Boston, MA, United States.

Abstract

Background: Ovarian cancer has long been known to be the deadliest cancer associated with the female reproductive system. More than 15% of ovarian cancer patients have a defective BRCA-mediated homologous recombination repair pathway that can be therapeutically targeted with PARP inhibitors (PARPi), such as Talazoparib (TLZ). The expansion of TLZ clinical approval beyond breast cancer has been hindered due to the highly potent systemic side effects resembling chemotherapeutics. Here we report the development of a novel TLZ-loaded PLGA implant (InCeT-TLZ) that sustainedly releases TLZ directly into the peritoneal (i.p.) cavity to treat patient-mimicking BRCA-mutated metastatic ovarian cancer (mOC).

Methods: InCeT-TLZ was fabricated by dissolving TLZ and PLGA in chloroform, followed by extrusion and evaporation. Drug loading and release were confirmed by HPLC. The in vivo therapeutic efficacy of InCeT-TLZ was carried out in a murine Brca2^-/-p53^R172H/-Pten^-/- genetically engineered peritoneally mOC model. Mice with tumors were divided into four groups: PBS i.p. injection, empty implant i.p. implantation, TLZ i.p. injection, and InCeT-TLZ i.p. implantation. Body weight was recorded three times weekly as an indicator of treatment tolerance and efficacy. Mice were sacrificed when the body weight increased by 50% of the initial weight.

Results: Biodegradable InCeT-TLZ administered intraperitoneally releases 66 μg of TLZ over 25 days. In vivo experimentation shows doubled survival in the InCeT-TLZ treated group compared to control, and no significant signs of toxicity were visible histologically in the surrounding peritoneal organs, indicating that the sustained and local delivery of TLZ greatly maximized therapeutic efficacy and minimized severe clinical side effects. The treated animals eventually developed resistance to PARPi therapy and were sacrificed. To explore treatments to overcome resistance, in vitro studies with TLZ sensitive and resistant ascites-derived murine cell lines were carried out and demonstrated that ATR inhibitor and PI3K inhibitor could be used in combination with the InCeT-TLZ to overcome acquired PARPi resistance.

Conclusion: Compared to intraperitoneal PARPi injection, the InCeT-TLZ better inhibits tumor growth, delays the ascites formation, and prolongs the overall survival of treated mice, which could be a promising therapy option that benefits thousands of women diagnosed with ovarian cancer.

Keywords: BRCA deficient mouse model; PARP inhibitor; Talazoparib loaded implant; metastatic ovarian cancer; sustained delivery.

Grants and funding

This work was supported by NIH grant 5 R25 CA174650-09 (SS), DOD W81XWH-20-1-0342 (DD), NIH/NCI 1U01CA233360-01 (DD), and NIH/NCI RO1 CA142746 (DD).