# Nucleotide inhibitors as precision medicine in breast cancer

> **NIH NIH R41** · RECOMBINATION THERAPEUTICS, LLC · 2020 · $399,757

## Abstract

Breast cancer is the most frequently diagnosed cancer in women, and 15-20% of patients have triple negative
breast cancer (TNBC) which results in a 70% mortality rate within 5 years of diagnosis. 10-15% of TNBC patients
possess heritable mutations in the BRCA1/BRCA2 tumor suppressor genes which promote homologous
recombination (HR) of DNA double-strand breaks (DSBs). BRCA-mutated cells are highly susceptible to DNA
damage and DNA repair inhibitors. Although Poly (ADP) ribose polymerase inhibitors (PARPi) cause synthetic
lethality in BRCA-deficient cells by suppressing DNA repair and inducing DNA damage, resistance has become
a major problem in the clinic. Thus, there is an urgent need for developing additional druggable targets. The DNA
repair protein DNA polymerase theta (Polq) is a promising drug target since it is essential for the proliferation of
BRCA-mutated cancer cells, but is dispensable for normal cells and mice. Moreover, high Polq expression levels
correspond to a poor clinical outcome for the majority (70%) of breast cancer patients. Hence, Polq represents
an ideal drug target for eradicating BRCA-mutated breast cancer cells.
 Nucleoside analog chain terminators have been widely used as FDA approved prodrugs to successfully
target polymerases for the treatment of viruses (i.e. HIV and Hepatitis C). Once these analogs are incorporated
by the target polymerase (as their triphosphate active metabolite), nucleic acid synthesis becomes terminated.
Here, we discovered 2’,3’-dideoxyribonucleoside triphosphates (ddNTPs; chain terminators) as potent nucleotide
Polq inhibitors (NPolqi). Remarkably, ddNTPs show absolutely no inhibition of replicative Pols d and e or repair
Pols k and h, and show a ~3-fold selectivity for Polq over mitochondrial Polg. These data demonstrate the
unexpected finding that replicative Pols are completely resistant to ddNTPs, whereas Polq prefers these chain
terminators over canonical dNTPs. Cellular data demonstrate that 2’,3’-dideoxycytosine (ddC), an FDA approved
HIV prodrug (Zalcitabine), preferentially kills BRCA1-mutated TNBC cells, with little toxicity in BRCA1-wild-type
(WT) cells. ddC also acts in combination with FDA approved olaparib to kill PARPi resistant BRCA1-WT TNBC
cells. ddC therefore serves as an initial scaffold for developing novel NPolqi. Recombination Therapeutics, LLC
(RTx), a start-up company focusing on precision oncology, will further develop ddC as a novel, potent and
selective NPolqi by developing the following Aims: 1. To optimize the potency and selectivity of NPolqi; 2. To test
the efficacy of optimized prodrug NPolqi in breast cancer xenograft models. In summary, we expect that these
Phase I studies will develop a novel Polq nucleotide inhibitor for provisional patent filing, and demonstrate its
ability to halt/slow the growth of breast cancer tumors exhibiting BRCA1 mutations and PARPi resistance.

## Key facts

- **NIH application ID:** 10138548
- **Project number:** 1R41CA257002-01
- **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:** $399,757
- **Award type:** 1
- **Project period:** 2020-09-18 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138548

## Citation

> US National Institutes of Health, RePORTER application 10138548, Nucleotide inhibitors as precision medicine in breast cancer (1R41CA257002-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10138548. Licensed CC0.

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