# Molecular studies of the MR-detectable oncometabolite glycerophosphocholine

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $374,578

## Abstract

Choline phospholipid metabolism is profoundly altered in cancer. While a lot of research has been devoted
toward elucidating the molecular origins of elevated phosphocholine (PC) in cancer, little attention has been
paid to the oncometabolite glycerophosphocholine (GPC) and its underlying molecular biology. High-resolution
(HR) magnetic resonance spectroscopy (MRS) studies have shown that GPC is higher than PC in normal
breast epithelial cells, whereas PC is higher than GPC in breast cancer cells. This finding is known as “GPC to
PC switch” in the choline metabolite profile upon malignant transformation. To date, the genes and specific
enzymes responsible for the cancer-related alterations in GPC are unknown. The changes in cellular GPC
levels could occur through glycerophosphocholine-phosphodiesterase (GPC-PDE) or lysophospholipase (LPL).
By combining HR MRS with gene silencing strategies, we have observed that silencing of GDPD5 and
GDPD6, both of which are GPC-PDEs, significantly increased the GPC levels in breast cancer cells, while
reducing their proliferation, migration, and invasion. Chemotherapy treatment of breast cancer cells with
doxorubicin resulted in down-modulation of the choline cycle genes choline kinase alpha (Chkα),
phospholipase D1 (PLD1), and GDPD6, thereby resulting in a net increase of GPC and a decrease in PC
along with a significant inhibition of proliferation. These preliminary data clearly point towards an important role
of GDPD5 and GDPD6 in breast cancer cell aggressiveness and treatment response to chemotherapy. Our
new preliminary data with three different commonly used FDA-approved chemotherapeutic agents indicate that
there is value in exploring GPC as an additional biomarker of treatment response independent of PC, which, of
course, would be in addition to other valuable imaging biomarkers. We will also investigate the reciprocal
interactions between oncogenic signaling pathways and GPC-regulating enzymes that are critical for tumor
maintenance and progression. The proposed research will provide novel insight into the molecular regulation of
the oncometabolite GPC in breast cancer, and will help understand its role in cancer progression. Our findings
will provide the foundation for interpreting GPC levels detected by noninvasive 1H and 31P MRS as an
additional complementary biomarker of transformation, staging, and response to therapy. GPC or critical GPC-
regulating enzymes may also be useful biomarkers of transformation, staging, and response to therapy in
biopsied tissue samples ex vivo. The enzymes studied in this proposal, e.g. GDPD5 and GDPD6, may prove
useful as anticancer targets, either alone or in combination with chemotherapy treatment of breast cancer.

## Key facts

- **NIH application ID:** 10219979
- **Project number:** 5R01CA213428-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Kristine Glunde
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,578
- **Award type:** 5
- **Project period:** 2017-06-09 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219979

## Citation

> US National Institutes of Health, RePORTER application 10219979, Molecular studies of the MR-detectable oncometabolite glycerophosphocholine (5R01CA213428-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219979. Licensed CC0.

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