# The Role of Glucose-6-Phosphatase in Hepatocellular Carcinoma

> **NIH NIH F30** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $38,795

## Abstract

PROJECT SUMMARY
Although hepatocellular carcinoma (HCC) is the most common form of liver cancer, there are few therapies that
are effective in treating this malignant disease. With less than 10% of patients who have HCC surviving beyond
5 years, it is important to identify additional therapeutic vulnerabilities. Metabolic alterations are a key feature of
HCC pathogenesis, and represent targets that may reveal liabilities in HCC. Glucose-6-Phosphatase (G6PC) is
recurrently downregulated in HCC and the magnitude of this downregulation correlates with patient outcome.
Sequencing studies of HCCs reveal that somatic mutations occur in a subset of these malignancies. Additional
evidence for G6PC involvement in HCC comes from Glycogen Storage Disease Type 1a (GSD1a), where
germline mutations in G6PC lead to benign and malignant forms of liver cancer without cirrhosis. The functional
relevance of recurrent mutations in G6PC or loss of G6PC expression to HCC pathogenesis in unclear. I
hypothesize that loss of G6PC stimulates anabolic metabolic pathways required for tumor cell growth and are
sufficient to drive hepatocyte proliferation and tumor initiation. The Specific Aims of this proposal aim to (1)
determine how loss of G6PC alters metabolism to support tumor growth, (2) test whether G6PC can increase
proliferation, and (3) explore ways in which G6PC loss influences liver tumors initiation and progression in mouse
HCC models. We will use G6PC deficient in vitro and in vivo models that faithfully recapitulate aspects of GSD1a
biology in patients, and stable isotope tracing to dissect how loss of G6PC rewires metabolic pathways.
Altogether, these Aims will elucidate how G6PC loss influences non-cirrhotic development of HCC, and will
provide insight into Glycogen Storage Disease Type 1a. We hope to identify metabolic liabilities in HCC
pathogenesis that may provide new therapeutic strategies for this deadly disease.

## Key facts

- **NIH application ID:** 10343735
- **Project number:** 5F30CA254150-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Sherwin Kelekar
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,795
- **Award type:** 5
- **Project period:** 2021-02-03 → 2025-02-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343735

## Citation

> US National Institutes of Health, RePORTER application 10343735, The Role of Glucose-6-Phosphatase in Hepatocellular Carcinoma (5F30CA254150-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10343735. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*