Sustained, local delivery of the PARP inhibitor talazoparib prevents the development of mammary gland hyperplasia in Brca1-deficient mice

Di Zhang,Karen T Liby,Jessica Moerland,Srinivas Sridhar,Bijay Singh,Owen Mitchell,Lizbeth Lockwood,Sarah Carapellucci

doi:10.1038/s41598-020-79663-7

Di Zhang, Karen T Liby + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-79663-7

Copy DOI

Abstract

Mutations in BRCA genes are the leading cause of hereditary breast cancer. Current options to prevent cancer in these high-risk patients, such as anti-estrogen drugs and radical mastectomy, are limited by lack of efficacy, undesirable toxicities, or physical and emotional challenges. We have previously shown that PARP inhibitors can significantly delay tumor development in BRCA1-deficient mice. Here, we fabricated the PARP inhibitor talazoparib (TLZ) into spacer implants (InCeT-TLZ) for localized and sustained delivery. We hypothesized that this novel formulation will provide an effective chemopreventive strategy with minimal toxicity. TLZ was released gradually over 30 days as implants degraded. InCeT-TLZ significantly decreased proliferation and increased DNA damage in the mammary glands of BRCA1-deficient mice. Notably, the number of mice that developed hyperplasia in the mammary glands was significantly lower with InCeT-TLZ treatment compared to the control group. Meanwhile, InCeT-TLZ was also better tolerated than oral TLZ, without loss of body weight or anemia. This study provides proof of concept for a novel and safe chemopreventive strategy using localized delivery of a PARP inhibitor for high-risk individuals. Future studies will directly evaluate the effects of InCeT-TLZ for preventing tumor development.

Highlights

Mutations in BRCAgenes are the leading cause of hereditary breast cancer
We developed a localized delivery platform for the PARP inhibitor talazoparib as a novel strategy for chemoprevention
We fabricated talazoparib into a spacer implant which can be inserted into the target tissue as a sustained drug release depot

Summary

Introduction

Mutations in BRCAgenes are the leading cause of hereditary breast cancer. Current options to prevent cancer in these high-risk patients, such as anti-estrogen drugs and radical mastectomy, are limited by lack of efficacy, undesirable toxicities, or physical and emotional challenges. We have previously shown that PARP inhibitors can significantly delay tumor development in BRCA1-deficient mice. We fabricated the PARP inhibitor talazoparib (TLZ) into spacer implants (InCeT-TLZ) for localized and sustained delivery. We hypothesized that this novel formulation will provide an effective chemopreventive strategy with minimal toxicity. Abbreviations ATM Ataxia telangiesctasia mutated gene ATR Ataxia telangiectasia and Rad[3] related BPM Bilateral prophylactic mastectomy BRCA Breast cancer-associated gene CHK1/2 Checkpoint kinase 1/2 FANCA FA Complementation Group A FANCD2 FA Complementation Group D2 HR Homologous recombination InCeT-TLZ Talazoparib (TLZ) spacer implants SERMs Selective estrogen receptor modulators PARP Poly (ADP-ribose) polymerase PCNA Proliferating cell nuclear antigen PLGA Poly (lactic-co-glycolic) acid. Accumulating evidence has suggested that better dietary choices[8], eliminating the use of tobacco[9], maintaining physical activity and proper body weight[10] can reduce cancer risk

Objectives

Methods

Results

Conclusion