# Context-Dependent Effects of PARP Inhibitors on Breast Cancer Bone Metastasis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $370,575

## Abstract

Bone metastasis is a frequent, debilitating and essentially incurable cancer complication. More than 70% of
patients with advanced breast cancer have metastatic bone disease, leading to severe bone pain, pathological
fracture, life-threatening hypercalcemia, spinal cord compression, limited mobility and increased mortality.
During bone metastasis, cancer cells and osteoclasts form a vicious cycle so that cancer cells promote
osteoclast differentiation and osteoclasts in turn facilitate cancer cell seeding and proliferation in the skeletal
environment. Nonetheless, the current understanding of the intricate mechanisms underlying this malicious
cycle is still limited, and the existing osteoclast inhibitor drugs confer no survival benefit. Our overarching goal
is to discover new and better treatment for cancer bone metastasis that simultaneously suppresses both
cancer cell and osteoclast. In December 2014, an inhibitor of Poly (ADP-ribose) polymerase (PARP), Olaparib,
was approved by the FDA for treating elapsed BRCA-defective ovarian cancer. Since then, two more PARP
inhibitors have also received FDA approval. Several PARP1/2 dual inhibitors are also currently in clinical trials
as breast cancer therapy. Despite these clinical efforts on PARP inhibitors in cancer treatment, little is known
about the roles of PARPs in metastasis. Moreover, it is unclear whether and how different PARP family
members display distinct functions. In our preliminary studies, we have found that PARP2 loss, but not PARP1
loss, promotes bone metastasis by acting in both osteoclast and tumor cell to enhance osteoclastogenesis;
olaparib treatment exacerbates bone metastasis in a manner that is dependent on modifiers such as BRCA
status and drug resistance. We hypothesize that PARP2 is a powerful dual suppressor of bone metastasis by
regulating key targets in osteoclast and tumor cell to synergistically impede breast cancer malignancy. Here we
propose to perform a series of comprehensive analyses to test this hypothesis, combining genetic and
pharmacological, gain- and loss-of-function, in vitro and in vivo strategies. In Aim 1, we will determine how
PARPs in osteoclast regulate bone metastasis. In Aim 2, we will determine how PARPs in cancer cell regulate
bone metastasis. In Aim 3, we will elucidate the molecular and biochemical mechanisms for PARP regulation
of bone metastasis by identifying and functionally characterizing key PARP targets. This investigation is highly
significant and clinically relevant because it will identify PARP2 as a novel dual suppressor of breast cancer
bone metastasis, uncover potential deleterious yet context-dependent effects of current PARP1/2 dual inhibitor
cancer drugs to exacerbate skeletal metastasis, reveal important functional distinctions between PARP2 and
PARP1, suggest PARP1-specific inhibitors as possibly safer options, highlight the exciting therapeutic potential
of PARP2 activation to mitigate breast cancer bone metastasis, and provid...

## Key facts

- **NIH application ID:** 9987293
- **Project number:** 5R01CA229487-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** WILLIAM Lee KRAUS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,575
- **Award type:** 5
- **Project period:** 2018-08-10 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987293

## Citation

> US National Institutes of Health, RePORTER application 9987293, Context-Dependent Effects of PARP Inhibitors on Breast Cancer Bone Metastasis (5R01CA229487-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9987293. Licensed CC0.

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