Metabolic Imaging Distinguishes Ovarian Cancer Subtypes and Detects Their Early and Variable Responses to Treatment

Metabolic Imaging Distinguishes Ovarian Cancer Subtypes and Detects Their Early and Variable Responses to Treatment

Academic Background

Ovarian cancer is one of the leading causes of cancer-related deaths in women, with high-grade serous ovarian cancer (HGSOC) being the most common lethal subtype. In recent years, metabolic subtypes have been identified in various cancers, including HGSOC. These metabolic subtypes exhibit distinct therapeutic vulnerabilities and prognoses. HGSOC has two metabolic subtypes: a high oxidative phosphorylation (High OXPHOS) subtype and a low oxidative phosphorylation (Low OXPHOS) subtype. The High OXPHOS subtype shows increased expression of genes encoding electron transport chain (ETC) components, increased oxygen consumption, and increased chemosensitivity, while the Low OXPHOS subtype exhibits glycolytic metabolism and is more drug-resistant.

Although gene copy number signatures have been used to classify HGSOC and can predict relapse after chemotherapy and overall survival, clinical assessment of these signatures through biopsy is challenging, especially when multiple tumor deposits are present. Metabolic imaging techniques may provide a non-invasive method to distinguish these subtypes and assess tumor responses to treatment.

Source of the Paper

This study was conducted by researchers from the Cancer Research UK Cambridge Institute and the University of Cambridge, including Ming Li Chia, Flaviu Bulat, Adam Gaunt, and others. It was published in Oncogene in 2024. The primary goal of the study was to distinguish HGSOC metabolic subtypes using metabolic imaging techniques and to detect their early responses to treatment.

Research Process and Results

1. Establishment of Tumor Models

The study used patient-derived organoids (PDOs) extracted from the ascites of HGSOC patients, which were subcutaneously implanted into immunocompromised mice to form xenografts. These tumor models were able to recapitulate the gene copy number signatures observed in HGSOC patients and mimic the clinical response to carboplatin observed in the corresponding patients.

Through Gene Set Variation Analysis (GSVA), the researchers found that PDOs 1 and 5 belonged to the Low OXPHOS metabolic subtype, while PDOs 2 and 11 belonged to the High OXPHOS metabolic subtype. Tumors of the Low OXPHOS subtype exhibited higher lactate dehydrogenase (LDH) activity and monocarboxylate transporter 4 (MCT4) expression, while tumors of the High OXPHOS subtype showed higher ETC gene expression.

2. Metabolic Imaging

The study employed two metabolic imaging techniques: 13C magnetic resonance spectroscopic imaging (13C MRS) and positron emission tomography (PET). Using 13C MRS to measure the metabolism of hyperpolarized [1-13C]pyruvate, the researchers found that tumors of the Low OXPHOS subtype exhibited higher lactate labeling, while tumors of the High OXPHOS subtype showed lower lactate labeling. However, PET measurements of 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([18F]FDG) uptake showed no significant differences between the two subtypes.

3. Early Detection of Treatment Response

The researchers further evaluated the early responses of these tumor models to carboplatin treatment. The results showed that tumors of the High OXPHOS subtype were sensitive to carboplatin treatment, as evidenced by significant decreases in lactate labeling and [18F]FDG uptake, while tumors of the Low OXPHOS subtype were resistant to carboplatin, with no significant changes observed in metabolic imaging. These changes were detectable before any changes in tumor volume, indicating that metabolic imaging techniques can be used for early assessment of treatment response.

4. Mechanisms of Metabolic Response

The study also explored the mechanisms underlying the metabolic changes induced by carboplatin treatment. Carboplatin treatment caused DNA double-strand breaks, activating poly(ADP-ribose) polymerase 1 (PARP1), which depleted the NAD(H) pool, thereby reducing the label exchange between hyperpolarized [1-13C]pyruvate and endogenous lactate. In tumors of the High OXPHOS subtype, the concentrations of NAD+ and NADH significantly decreased, and LDH activity was also significantly reduced, while no such changes were observed in tumors of the Low OXPHOS subtype.

Conclusions and Significance

This study successfully distinguished the two metabolic subtypes of HGSOC using metabolic imaging techniques and detected their early responses to carboplatin treatment. Tumors of the High OXPHOS subtype were sensitive to carboplatin, while those of the Low OXPHOS subtype exhibited drug resistance. 13C MRS imaging has the potential to be used clinically to distinguish Low OXPHOS and High OXPHOS tumors in HGSOC patients and to detect their differential responses to treatment.

Highlights of the Study

  1. Distinguishing Metabolic Subtypes: The study is the first to successfully distinguish the two metabolic subtypes of HGSOC using metabolic imaging techniques, providing a new tool for personalized treatment.
  2. Early Detection of Treatment Response: Metabolic imaging techniques can detect treatment responses before changes in tumor volume, offering an early assessment tool for clinical treatment.
  3. Mechanistic Insights: The study revealed the molecular mechanisms underlying the metabolic changes induced by carboplatin treatment, providing new insights into tumor drug resistance.

Application Value of the Study

This study offers new insights into personalized treatment for HGSOC. Using metabolic imaging techniques, clinicians can assess tumor responses early in the treatment process, allowing for timely adjustments to the treatment plan. Additionally, the study provides a theoretical foundation for the development of targeted therapies for different metabolic subtypes.

Other Valuable Information

The study also found that the amplification and increased expression of the c-Myc gene in Low OXPHOS subtype tumors may be the primary driver of their metabolic characteristics, while High OXPHOS subtype tumors exhibited activation of the EGFR signaling pathway. These findings provide new directions for future targeted therapy research.

Through innovative metabolic imaging techniques, this study provides important scientific evidence for personalized treatment and early assessment of treatment responses in HGSOC.