# Next-generation precision medicine for targeting recombination-deficient cancers

> **NIH NIH R41** · RECOMBINATION THERAPEUTICS, LLC · 2020 · $298,959

## Abstract

Precision medicine is a revolutionary therapeutic approach in which therapies are designed and selected
based on genetic mutations present in certain cancers. For example, treating patients with BRCA-deficient
cancers with a medicine that inhibits a particular DNA repair pathway can result in selective killing of these cancer
cells. This approach is based upon the concept of synthetic lethality whereby inactivation of a particular gene
product selectively kills cells based on their genetic mutation, while sparing normal cells. Synthetic lethality has
been used to target cancer cells mutated or deficient in the BRCA1 or BRCA2 tumor suppressor proteins which
promote the homologous recombination (HR) DNA double-strand break (DSB) repair pathway. Because BRCA-
deficient cancer cells are impaired in HR, they are susceptible to drugs that cause DNA damage and/or block
DNA repair. Approximately 5-10% of breast cancers and ~50% of epithelial ovarian cancers are defective in the
BRCA pathway. Thus, these cancer types have been used to develop first-generation personalized medicines
that kill BRCA-deficient cells by inactivating Poly-ADP ribose polymerase 1 (PARP1) which promotes base
excision repair. Despite the initial success of PARP inhibitors (PARPi), drug resistance has become a major
problem in the clinic. Thus, it is important to identify and develop alternative drug targets involved in DNA repair
as next-generation personalized medicines for BRCA-deficient cancers that increase patient survival rates and
potentially reduce drug resistance.
 Recent studies have identified DNA polymerase theta (Polq) as a promising new precision medicine drug
target in BRCA-deficient breast and ovarian cancers. We have identified selective Polq inhibitors (Polqi) that
preferentially kill BRCA-deficient breast cancer cells and BRCA-deficient leukemia cells. These data demonstrate
proof of concept that selective Polqi can be developed as pre-clinical drug leads that target BRCA-deficient
cancer cells for killing. In Phase I research, we plan to optimize the potency and drug-like properties of our
leading Polqi via structure-activity relationship (SAR) studies, and test the efficacy of our lead drug candidate as
monotherapy and as combination therapy with PARPi in BRCA-deficient breast cancer xenografts in vivo. In
summary, we anticipate that optimized Polqi will preferentially kill BRCA-mutated breast cancer cells in vitro and
in vivo, while having little or no effects in normal cells.

## Key facts

- **NIH application ID:** 9909705
- **Project number:** 1R41CA239983-01A1
- **Recipient organization:** RECOMBINATION THERAPEUTICS, LLC
- **Principal Investigator:** Richard T Pomerantz
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $298,959
- **Award type:** 1
- **Project period:** 2020-03-10 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9909705

## Citation

> US National Institutes of Health, RePORTER application 9909705, Next-generation precision medicine for targeting recombination-deficient cancers (1R41CA239983-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9909705. Licensed CC0.

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