# Targeting Mitochondrial One-Carbon Metabolism in Epithelial Ovarian Cancer

> **NIH NIH F31** · WAYNE STATE UNIVERSITY · 2020 · $42,826

## Abstract

Project Summary/Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Even though most patients initially
respond to platinum-based therapy, the likelihood of reoccurrence is virtually 100%. Clearly, an urgent need
exists for developing tumor-selective therapeutics for EOC. One such option involves targeting EOCs via the
folate receptor alpha (FRα) which is overexpressed in up to 90% of cases. C1 metabolism is critical to cancer cell
survival and aberrant C1 metabolism in the mitochondria is frequently associated with malignancy. Current C1
inhibitors (e.g., pemetrexed) are plagued by problems of resistance and toxicity due to transport by the
ubiquitously expressed reduced folate carrier (RFC). Mitochondrial C1 metabolism of serine beginning with
serine hydroxymetyltransferase 2 (SHMT2) provides the majority of C1 units for biosynthesis of nucleotides in
the cytosol and approximately 85% of endogenous glycine. Mitochondrial C1 metabolism also provides C1 donors
required for translation of mitochondrial oxidative phosphorylation proteins and is critical to tumor metabolic
adaption by protecting cells from hypoxia-induced cell death through production of NADPH and glutathione to
maintain redox balance. There are no clinical inhibitors of SHMT2. We discovered a series of novel 5-substituted
pyrrolo[3,2-d]pyrimidine analogs that inhibit mitochondrial C1 metabolism, specifically SHMT2, with secondary
inhibition at cytosolic de novo purine biosynthesis, resulting in broad-spectrum antitumor activity. We propose
to extend our studies to EOC including identification of next-generation analogs of this series with specificity for
tumor-selective uptake by FRα and to refine our structure-activity-relationships for mitochondrial C1 targeting,
leading to a new and highly selective therapy for EOC based on FRα expression and drug uptake. In aim 1, we
will interrogate prospective inhibitors for FRα-specificity and drug efficacy in engineered Chinese hamster
ovarian (CHO) cells which individually express the major transport systems (e.g. FRα and RFC) and cisplatin
sensitive and resistant EOC cells expressing a range of FRα. Additional studies will measure plasma membrane
transport properties for FRα-targeted lead analogs vis á vis other transporters. In aim 2, we will determine the
targeted pathways/enzymes of novel analogs in EOC through glycine/nucleoside “rescue” from inhibition of cell
proliferation, targeted metabolomics and studies with isolated enzymes targets. We will assay MFT uptake of
lead analogs into mitochondria and measure mitochondrial oxidative stress and depolarization as a read-out of
mitochondrial targeting. In aim 3, we will determine in vivo efficacies of the lead inhibitors of mitochondrial and
cytosolic C1 metabolism in human EOC cell line and patient derived EOC xenografts in SCID mice. We will assess
the impact of an intact immune system (including FRβ-expressing tumor-associated macrophages) using a FRα-
...

## Key facts

- **NIH application ID:** 9972742
- **Project number:** 5F31CA243215-02
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Adrianne Wallace-Povirk
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $42,826
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972742

## Citation

> US National Institutes of Health, RePORTER application 9972742, Targeting Mitochondrial One-Carbon Metabolism in Epithelial Ovarian Cancer (5F31CA243215-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9972742. Licensed CC0.

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