Towards a new era in ovarian granulosa cell tumour research: genomics, diagnostics and new therapies 

Granulosa cell tumours (GCTs) are a rare subtype of ovarian cancer. This subtype includes adult GCT and the even rarer juvenile GCT type. GCT tumours are hormone-driven and as a result can produce high levels of oestrogen in addition to other hormones. During the natural reproductive cycle, granulosa cells surround the egg during follicle development, where they change into another cell type known as luteal cells after ovulation.  However, in some cases, granulosa cells fail to undergo this transformation and instead grow abnormally to become cancerous granulosa tumour cells. 

Current treatment options for GCTs lack long-term efficacy, and recurrence remains a significant challenge, often occurring decades after initial treatment. 

Associate Professor Chu’s lab has been investigating this rare ovarian cancer for over two decades and is now globally recognised as one of the most advanced teams focused on GCT. Their work has advanced the understanding of the disease's molecular underpinnings and identified potential combination therapies. 

In this project the team are building on their previous work to confirm the origins of GCTs, because if they can confirm how the disease forms and what genes and pathways it relies on, then they can also devise an effective and targeted treatment strategy. The team are investigating several facets of the disease, from diagnostics to therapeutic approaches.   

In this project the team aim to: 

• Analyse patterns and gaps from patient-documented medical experiences: The team collaborates with the GCT Survivor Sisters, a global Facebook group, comprising of over 1000 GCT patients, an extensive and important resource considering the rarity of GCTs. The group’s founders developed an in-depth survey that patients complete upon joining the group. It details every aspect of their GCT experience including diagnosis, recurrence, treatments and the nature of surgeries. They made this valuable data accessible to Associate Professor Chu’s lab, who are additionally working with Professor Vicki White from Deakin University to analyse this data and deduce insights. Important insights may contribute to better standardised treatment or surgical approaches specific to GCT, which is currently difficult due to its rarity. 
• Identify and verify the DNA mutations that lead to adult and juvenile GCT: Adult GCT are defined by a mutation in a gene called FOXL2, however this, mutation is not implicated in juvenile GCT. Therefore, this project involves whole genome sequencing of both adult and juvenile GCT samples to compare their genomic landscape and identify key differences between the two types. The team aims to uncover key mutations and pathways underlying both subtypes. This lab has the largest collection of juvenile GCT patient samples in the world, making this project incredibly important for this rare subtype. 
• Investigate how adult GCTs develop: The FOXL2 C134W mutation is central to adult GCTs, but its precise role in cancer development remains unclear.  They will explore this using preclinical lab models so that they can devise a personalised therapy specifically targeting this mutation in adult GCT.   
• Develop and validate a diagnostic test to detect GCT ovarian cancer and to monitor for recurrence: The lab is enhancing diagnostic tools originally developed by researchers at Prince Henry’s Institute (now the Hudson Institute). These tools measure inhibin, a hormone produced by ovarian granulosa cells that plays a key role in regulating follicle-stimulating hormones. Inhibin has proven to be an excellent biomarker for the early detection for GCT. Additionally, when combined with measurements of CA-125, it enhances detection for other ovarian cancers. This project aims to refine the diagnostic test by incorporating advanced detection technology to improve early diagnosis and monitor recurrence more effectively. 
• Testing a new combination treatment for GCT: Based on previous findings that proteins called Inhibitor of Apoptosis Proteins (IAPs), particularly XIAP, are associated with GCT development, the team is exploring drugs that are designed to stop these proteins from working called Smac-mimetics, as a therapeutic approach.  The team are performing a high-throughput-screen of several thousand different compounds, in order to identify effective combinations when used with Smac-mimetics that are suitable for clinical use. 

To uncover the genetic basis of granulosa cell tumours (GCTs) and identify potential therapeutic targets, the team is employing a comprehensive approach that integrates advanced sequencing, functional studies, and patient-driven data analysis. 

Gene sequencing 

To analyse and identify all gene mutations within both adult and juvenile GCTs, the team are conducting whole genome sequencing. They are also using gene editing techniques (CRISPR) to studying specific genes in cell line models to determine how the C134W mutation in the FOXL2 gene leads to GCT development. With RNA sequencing completed in a previously funded OCRF project, the team will conduct ChIP sequencing which involves capturing and observing how a protein binds to DNA to activate a particular gene.  

Testing treatment combinations and measuring toxicity 

To develop effective combination therapies for adult GCT, the team are trialing combinations of Smac mimetic drugs with PPAR agonist drugs. PPARγ is a type of hormone receptor that is highly activated in GCT. Therefore, the team are using PPARγ agonist drugs to reverse this activation, and Smac mimetics to inhibit the XIAP proteins that drive GCT tumour development. This promising combination, initially tested in a previous OCRF-funded study, is being trialed in pre-clinical mouse models. The team aims to compare its efficacy and safety against other potential combinations to identify the most effective therapeutic strategy.  

Patient-driven data analysis 

Insights from the GCT Survivor Sisters group—a global community of over 1,000 GCT patients—are providing valuable real-world data. Analysis of this dataset has revealed critical findings, including a strong correlation between tumour recurrence and surgical practices. For instance, recurrence is more likely when tumours are fragmented during surgery rather than removed intact. Additionally, the data highlights the importance of accurate pre-surgical identification of GCTs, as misdiagnosing them as benign cysts can lead to suboptimal surgical approaches and increased recurrence risk. The analysis also underscores geographical differences in treatment practices; for example, chemotherapy is rarely used in Australia due to its limited efficacy for GCTs, while it remains more common in the United States despite evidence suggesting its ineffectiveness.  

Patients with granulosa cell tumours can often experience recurrence decades later and so a way to both effectively treat it and monitor for recurrent disease is crucial. This project has the potential to provide a new and more effective treatment, develop a diagnostic tool for either identifying disease in the first instance or effectively monitoring recurrence, and it has uncovered important insights into the most beneficial surgical practices.  

As one of the most advanced GCT-focused labs in the world, Associate Professor Chu’s team are making important strides towards understanding GCT and treating it.