# Targeting Serine and Glycine Metabolic Vulnerabilities in Melanoma Brain Metastasis

> **NIH NIH F31** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $46,752

## Abstract

Project Summary
 Brain metastases (BM) are a major contributor to mortality in melanoma. BM are found in 44% of Stage
IV melanoma patients resulting in a median survival of 4 months and a 5-year survival rate of less than 20%.
The poor prognosis of brain metastatic melanoma is due in part to the lack of therapies that provide an effective
and durable response. There are no therapies specifically designed to target brain metastases. The brain
microenvironment, relative to blood plasma, is unique because it has low concentrations of amino acids.
Amongst the most changed amino acids are serine and glycine. The plasma concentration of serine is 114 µM
and decreases to 24 µM in the cerebrospinal fluid (CSF), a proxy for amino acid concentrations in the brain.
Glycine levels also decrease from 232 µM in plasma to 5 µM in CSF. We have made media that mimics CSF
serine and glycine concentrations.
 My preliminary data shows that two human melanoma cell lines, A375 and SK-MEL-28, have increased
serine and glycine synthesis in CSF environments. This suggests that cells become dependent on synthesizing
serine and glycine and can be targeted to decrease the viability of melanoma cells. The first and rate-limiting
step of serine synthesis is catalyzed by phosphoglycerate dehydrogenase (PHGDH) and can be inhibited using
small molecule inhibitors, PH719 and PH755. Glycine is made from serine by serine hydroxy methyltransferase
1/2 (SHMT1/2) and can be targeted by the small molecule inhibitors SHIN1 and AGF347. My initial experiments
demonstrate that melanoma cells are sensitized to these serine and glycine synthesis inhibitors in CSF
conditions. These data suggest that mice with melanoma BM treated with either PHGDH or SHMT1/2 inhibitors
may have decreased brain tumor burden and that this could provide a novel target for patients with BM who
otherwise have limited therapeutic options. To determine if our in vitro data are applicable in vivo, we will
establish melanoma brain metastases by intracardiac injection of GFP-luciferase-labeled melanoma cell lines
into the hearts of NCr-Foxn1nu (Nude) mice. The growth of these cells in mice will be monitored using
bioluminescence imaging (IVIS). We will use doxycycline inducible deletion of PHGDH and SHMT1/2 to
determine if upon deletion of these enzymes there a reduction in brain lesions.
 The findings from this study will provide knowledge about the implications of the serine and glycine
synthesis pathway in amino acid depleted environments like the brain and provide novel therapeutic targets for
BM to improve patient outcomes.

## Key facts

- **NIH application ID:** 10439744
- **Project number:** 5F31CA250364-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Victoria Margarita Osorio Vasquez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439744

## Citation

> US National Institutes of Health, RePORTER application 10439744, Targeting Serine and Glycine Metabolic Vulnerabilities in Melanoma Brain Metastasis (5F31CA250364-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439744. Licensed CC0.

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