Targeting the Serine/Glycine Synthesis Pathway in MYC-Driven Medulloblastoma

Background

Medulloblastoma is one of the most common malignant brain tumors in children, accounting for a significant proportion of childhood cancer deaths. Based on molecular characteristics, medulloblastoma is classified into four major subgroups: WNT, SHH, Group 3 (MBGrp3), and Group 4 (MBGrp4). Among these, Group 3 medulloblastoma (MBGrp3) is strongly associated with the amplification of the c-MYC (MYC) gene and is associated with poor patient prognosis. Although high MYC expression is a significant molecular feature of MBGrp3, direct targeting of MYC remains challenging. Therefore, identifying alternative therapeutic strategies has become a key focus of current research.

MYC-driven tumor cells often exhibit metabolic reprogramming, particularly the upregulation of the serine/glycine synthesis pathway (SGP). This pathway plays a critical role in tumor cell proliferation and survival. However, the metabolic characteristics of MYC-driven MBGrp3 have not been fully explored, providing an opportunity to identify new therapeutic targets.

Source of the Paper

This paper was co-authored by Magretta Adiamah, Bethany Poole, Janet C. Lindsey, and others, with the research team hailing from the Wolfson Childhood Cancer Research Centre at Newcastle University, the Institute of Cancer Research (ICR) in London, and other institutions. The paper was published online on October 8, 2024, in Neuro-Oncology, titled “MYC-dependent upregulation of the de novo serine and glycine synthesis pathway is a targetable metabolic vulnerability in group 3 medulloblastoma.”

Research Process and Results

1. Study Design and Model Construction

The research team first constructed three MYC-dependent MBGrp3 cell models: D425Med, HDMB03, and D283Med. These cell lines represent MYC-amplified and MYC-gained MBGrp3 subtypes. Using a tetracycline-inducible shRNA system, the researchers achieved MYC knockdown (KD) in these cells to study the impact of MYC on cellular metabolism.

2. Metabolic Profiling

To investigate the effects of MYC knockdown on cellular metabolism, the team employed high-resolution magic-angle spinning nuclear magnetic resonance (1H HRMAS) and stable isotope-resolved metabolomics (SIRM). These techniques allowed the researchers to detect changes in intracellular metabolites, particularly those related to one-carbon metabolism, such as glycine.

The results showed that MYC knockdown led to a significant increase in glycine levels, while de novo synthesis of serine and glycine decreased. Further analysis revealed that MYC knockdown reduced the expression and activity of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the serine/glycine synthesis pathway.

3. Pharmacological Inhibition of PHGDH

The research team further tested the effects of the PHGDH inhibitor NCT-503 in MYC-driven MBGrp3 cells. The results demonstrated that MYC-high cells were more sensitive to NCT-503, while MYC-knockdown cells showed reduced sensitivity to PHGDH inhibition. This suggests that MYC-driven MBGrp3 cells rely on PHGDH-mediated serine/glycine synthesis to sustain their proliferative capacity.

4. In Vivo Validation

To validate the effects of PHGDH inhibition in vivo, the team used two mouse models: a subcutaneous xenograft model and a genetically engineered mouse model (GEMM). In the xenograft model, NCT-503 significantly prolonged the survival of mice bearing MYC-amplified MBGrp3 tumors. In the GEMM model, NCT-503 also significantly reduced tumor burden and extended mouse survival.

5. Clinical Relevance Analysis

The research team analyzed PHGDH expression in primary medulloblastoma patient samples. The results showed that high PHGDH expression was significantly associated with MYC amplification and poor clinical outcomes. This indicates that PHGDH is not only a potential therapeutic target for MYC-driven MBGrp3 but may also serve as a prognostic marker.

Conclusions and Significance

This study reveals the dependency of MYC-driven MBGrp3 cells on the serine/glycine synthesis pathway and demonstrates the therapeutic potential of PHGDH inhibition in this subtype. The findings suggest that PHGDH inhibitors such as NCT-503 can significantly slow the growth of MYC-driven MBGrp3 tumors and extend survival in mice. Furthermore, high PHGDH expression is associated with MYC amplification and poor clinical outcomes, further supporting the clinical value of PHGDH as a therapeutic target.

Research Highlights

1. Novel Therapeutic Target: The study is the first to reveal the dependency of MYC-driven MBGrp3 cells on the serine/glycine synthesis pathway and proposes PHGDH as a potential therapeutic target.
2. Multilayer Experimental Validation: The research combines in vitro cell experiments, metabolomic analysis, and in vivo mouse models to comprehensively validate the therapeutic effects of PHGDH inhibition.
3. Clinical Relevance: By analyzing patient samples, the study demonstrates the correlation between high PHGDH expression, MYC amplification, and poor prognosis, providing a theoretical basis for future clinical trials.

Future Prospects

This study provides new therapeutic strategies for MYC-driven MBGrp3, particularly the development and application of PHGDH inhibitors. Future research could further explore the combination of PHGDH inhibitors with other chemotherapeutic agents to enhance treatment efficacy. Additionally, the research team recommends validating the efficacy of PHGDH inhibitors in larger-scale clinical trials to advance their clinical application.