# Therapeutic enzyme depletion of L-serine for cancer treatment

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $598,635

## Abstract

PROJECT SUMMARY
Serine is an essential nutrient for tumor growth, and there is significant interest in starving cancer cells of
serine for cancer therapy. For example, we have recently found that luminal/ER+ breast tumors, which
account for approximately half of all breast cancer fatalities, are unable synthesize serine de novo (i.e., they
are auxotrophic for serine) and are therefore particularly vulnerable to serine deprivation. Dietary serine
starvation is currently the only method of reducing serine availability in vivo, but this approach will be difficult to
implement in humans due to the extreme dietary modifications it requires. Furthermore, dietary serine
starvation can only reduce circulating serine levels by 50%, which may not be sufficient to inhibit the growth of
many tumors. Therapeutic enzymes are an alternative method of manipulating nutrient levels in vivo that
have proven to be effective treatments for cancer and other diseases. We hypothesized that a therapeutic
serine degrading enzyme might be a more effective method of achieving in vivo serine starvation for cancer
therapy. To test this hypothesis, we have developed a novel therapeutic serine degrading enzyme, engineered
human serine dehydratase (eSDH), that is capable of reducing circulating serine levels by greater than 90% in
mice without the need for any dietary changes. Our preliminary data suggests that prolonged serine depletion
with eSDH is well-tolerated by mice and capable of inhibiting tumor growth in multiple mouse models. The
overarching goals of this proposal are to optimize eSDH to generate an enzyme that is suitable for
subsequent clinical development and to evaluate it as a potential cancer therapeutic in pre-clinical models. To
achieve these goals, we propose experiments that will 1) engineer a more selective and stable optimized eSDH
enzyme with enhanced pharmacological properties 2) assess the physiological impact and potential side-
effects of enzymatic serine depletion, 3) evaluate the efficacy of eSDH against tumors that are auxotrophic for
serine, and 4) further investigate our preliminary finding that eSDH treatment induces anti-tumor immunity. A
targeted therapeutic approach for serine auxotrophic tumors that also induces anti-tumor immunity could
provide an effective treatment modality for patients with luminal breast cancer and other malignancies.

## Key facts

- **NIH application ID:** 10809675
- **Project number:** 5R01CA280737-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Jonathan L. Coloff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $598,635
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809675

## Citation

> US National Institutes of Health, RePORTER application 10809675, Therapeutic enzyme depletion of L-serine for cancer treatment (5R01CA280737-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10809675. Licensed CC0.

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