# Novel Prostate cancer therapy based on m-aconitase inhibition

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2022 · $235,035

## Abstract

ABSTRACT
Treatment options for patients with early-stage prostate cancer include mostly watchful waiting, radical
prostatectomy or radiation therapy, whereas for patients with advanced disease hormone therapy followed by
chemotherapy/radiotherapy are the preferred options. However, all of these options suffer from very serious side
effects. While early-stage cancers can be addressed with radical prostatectomy, this is not the case for advanced
cancers at hormone refractory and/or metastatic stages. Approaches with lesser side effects and more
effectiveness are needed, especially for the latter scenarios.
Our proposed approach takes advantage of the innate property of the prostate gland, which is accumulation of
enormously high levels of citrate and zinc by the prostate glandular epithelial cells. Zinc serves as an inhibitor of
m-aconitase, the enzyme, which controls the first reaction for the entry of citrate into the Krebs cycle. The Krebs
cycle in these cells is truncated, and synthesized citrate accumulates for secretion into prostatic fluid. However,
in prostate cancer cells the ability to accumulate zinc is lost due to downregulation of zinc transporter. This
deficiency leads to normalization of m-aconitase activity and oxidation of citrate via a functional Krebs cycle
resulting in 38 ATP/glucose compared to 14 ATP/glucose produced from the aerobic oxidation of glucose in
normal prostate cells. Thus, the malignant cells become energy-efficient in contrast to the energy-inefficient,
specialized citrate-producing prostate epithelial cell and change their phenotype to a “citrate-oxidizing”.
In this study we propose to inhibit m-aconitase with the goal to reverse the “citrate-oxidizing” phenotype in
prostate cancer. This will be done by delivering zinc to tumors in vivo using prostate specific membrane antigen
(PSMA)-targeted image-guided liposomes loaded with zinc. We expect that inhibition of m-aconitase by zinc will
cause a dramatic decrease in energy production by cancer cells, which will ultimately lead to energy deprivation
and cell death. Since monitoring the delivery of Zn-containing liposomes will provide us with opportunity to alter
formulation in the course of investigation and adjust treatment regimen, the proposed liposomes will contain
imaging reporters for magnetic resonance and optical imaging. We propose to synthesize and test Zn-containing
PSMA-specific image-guided liposomes first in vitro and then in pilot studies in vivo in non-metastatic and
metastatic mouse models of prostate cancer. The latter is of high significance since it is the advanced stage that
causes high mortality in prostate cancer patients.

## Key facts

- **NIH application ID:** 10435673
- **Project number:** 1R21CA245343-01A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** ANNA MOORE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $235,035
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435673

## Citation

> US National Institutes of Health, RePORTER application 10435673, Novel Prostate cancer therapy based on m-aconitase inhibition (1R21CA245343-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10435673. Licensed CC0.

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