# Optimizing PARP inhibitor therapy through novel approaches to resolve the molecular mechanisms of response

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $382,637

## Abstract

Poly(ADP-ribose) polymerases (PARP) are a family of enzymes involved with multiple facets of
cellular function including DNA damage repair (DDR) and chromatin stability, along with others
that are just being discovered. The importance of PARP in DDR, specifically non-homologous
end joining, makes it an ideal therapeutic target in cancer where DDR deficiencies are
prominent. Clinical targeting of PARP was first performed in patients harboring BRCA mutations,
and thus defects in homologous recombination, where PARP inhibition is synthetically lethal.
Although effective, PARP inhibitors (PARPi) did not prove as ground breaking as hoped due to
several resistance mechanisms and the complexity of DDR. Currently there are 3 approved
PARP inhibitors for treatment of patient with ovarian cancer and two more in late stage clinical
trials. However, our understanding of molecular biology underlying PARP efficacy remains
limited. Intriguingly, knocking out PARP does not produce the cellular lethality found with PARP
inhibitor, which was recently explained by the discovery that PARP inhibitors trap PARP to sites
of DNA damage. However, even though they bind into the same protein pocket and have similar
affinities, some PARP inhibitors are much more potent trappers, the reason remains unknown.
Thus, PARP inhibitors function through both trapping and and enzymatic inhibition. Our
preliminary analysis of cell line response databases demonstrates wide differences in cell line
susceptibility to different PARP inhibitors, with some cell lines more sensitive to low trapping
inhibitors and other more sensitive to high trapping inhibitors. Determining the mechanisms of
differential PARP inhibitor sensitivity would provide insight into clinical selection among the
PARP inhibitors to drive more effective therapies. Here we will address three specific aims
through novel approaches of single cell protein expression and dynamics: 1) determine PARPi-
specific drivers of cellular response to select optimal PARPi treatment, 2) elucidate the
molecular mechanism of PARPi sensitivity to optimize combination therapy, and 3) optimally pair
PARPi to increase efficacy and minimize toxicity. Resolving the mechanisms of PARP inhibitor
efficacy will enable optimal clinical use and combination trial design. We expect to determine
biomarkers of response for each of the clinical PARP inhibitors that will guide clinical selection of
PARPi treatment.

## Key facts

- **NIH application ID:** 10212344
- **Project number:** 5R01CA241179-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** John Dubach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,637
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212344

## Citation

> US National Institutes of Health, RePORTER application 10212344, Optimizing PARP inhibitor therapy through novel approaches to resolve the molecular mechanisms of response (5R01CA241179-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10212344. Licensed CC0.

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