Identifying new treatment options for rare and aggressive ovarian carcinosarcoma 

Dr Holly Barker’s team is investigating a treatment for a rare form of ovarian cancer called ovarian carcinosarcoma (OCS). It is the most aggressive gynaecological cancer, as it has two key types of cancerous cells that drive it: elongated sarcomatous cells and round carcinomatous cells. This makes it very hard to treat. 

There is currently no effective treatment when the standard-of-care, first-line treatment (the first treatment for a disease) stops working, which sadly occurs in most OCS cases. 

Dr Barker’s treatment project focuses on a chemotherapy called eribulin, combined with an immunotherapy called pembrolizumab, to determine if the combination offers a more effective treatment than those currently available.  

Eribulin is currently approved for use in treating aggressive breast cancer. Previous studies found that in some breast cancers, eribulin was working because it could reverse a process that makes round cells become elongated. Therefore, with eribulin treatment, elongated cancer cells could be changed into less aggressive round cancer cells. The team suspected that this action — triggered by eribulin—could be harnessed to treat OCS, converting the elongated cells into round cells, which will then respond to current standard treatments. Their preclinical studies showed that not only did OCS cells appear sensitive to eribulin, the drug also encouraged immune cells to gather around the cancerous cells. This suggested immunotherapy could help to activate these immune cells and help them to eliminate the cancer cells.  

With OCRF and Cancer Council Victoria funding, Dr Barker’s team aimed to: 

• Test the effectiveness of the chemotherapy drug, eribulin, in preclinical animal models to determine how well it could reduce the OCS growth alone, compared to platinum-therapy, the current standard of care treatment.  
• Test eribulin (chemotherapy) in combination with pembrolizumab (immunotherapy), in preclinical mouse models to determine if the combination is more effective than both the currently available OCS treatment and treatment with eribulin alone.  
• Conduct a large drug screen to identify other drugs or combinations that could potentially treat OCS effectively.  
• Develop complex preclinical organoid models, that closely mimic the human tumour microenvironment, so that the team can accurately test their newly identified treatments. 
• Determine which biomarkers best indicate that a tumour has responded to treatment. 
• Develop a high-throughput organoid screening pipeline to test patient samples in the future. This process would determine whether an individual’s OCS responds to various treatments. The goal is to implement this in real-time, to ensure that individuals diagnosed with OCS get the best treatments for their individual cancer. 

Determine whether the promising treatment combination of eribulin plus pembrolizumab works not only in the lab, but in the human body 

To further understand how eribulin effectively targets OCS, the team tested eribulin on human tumours grown in mice with human-like immune systems. This enabled them to observe that immune cells were recruited to tumours after eribulin treatment. Combining eribulin with an immunotherapy could activate these immune cells to kill even more tumour cells.   

Why is this treatment combination working? 

The team will not only study how well their treatment works alone and in combination with immunotherapy, but also investigate why.  

Immunotherapies have been considered less effective for ovarian cancers as ovarian cancer cells often don’t recruit immune cells in the first place. By treating with eribulin, immune cells can now be recruited. Tumour cells, however, can still stop the activity of these immune cells, allowing ovarian cancer cells to hide from the immune system. This is where immunotherapies can play a role. The immunotherapy pembrolizumab can remove the factors that allow tumour cells to hide, therefore immune cells can then find and attack the cancer cells. Long-term, the immune cells can recognise and remember these cancer cells, which could prevent the cancer from recurring.  

Discovering additional effective treatment combinations for OCS 

To identify additional treatment combinations, which could most effectively treat OCS, the team screened almost four thousand drugs to find promising combinations. This saw them arrive at testing some cisplatin (similar to current standard treatment for OCS) and eribulin (currently on trial for OCS) based combinations.  

What makes these other treatment combinations effective?  

In preliminary studies, Dr Barker observed that the DNA make-up of OCS was similar to the most common ovarian cancer, high-grade serous ovarian cancer. This is the reason OCS is treated with the same standard treatments as high-grade serous ovarian cancer, but these treatments don’t work well for OCS. This indicated that something else was occurring to drive the OCS subtype. So, rather than only looking at the DNA, they looked at the RNA to determine which genes were being switched on and off and identified that genes involved in the N-MYC/LIN28B pathway were being switched on. Therefore, some drugs in the large drug screen were selected because they could target the N-MYC pathway. 

Some drugs in the large drug screen were also selected because they could target the elongated sarcomatous cells (which aren’t present in high-grade serous ovarian cancer) and make them more like the round carcinomatous cells, which can be more effectively treated by standard therapies. Importantly, drugs that target N-MYC could also trigger elongated cells to become round cells, suggesting combinations involving these drugs with the standard treatments should be highly effective. 

A promising new treatment 

This project has provided at least one promising new combination treatment approach for OCS. 

During this project the team found that, in almost every laboratory model, eribulin more effectively reduced OCS tumour growth compared to currently used treatments. They also identified that HMGA2, a biological marker in the N-MYC/LIN28B pathway, could be used to predict how responsive a patient would be to this treatment, and to establish if treatment is working or not based on decreasing levels of HMGA2.  

A rare cancer clinical trial 

Data generated in this study was compelling enough to warrant a clinical trial. The EPOCH Phase II clinical trial is one of the few dedicated purely to a rare cancer. Dr Barker’s next step is to analyse the results of the trial to further understand how well this treatment combination of eribulin plus pembrolizumab worked in humans and whether it can progress towards becoming an approved OCS therapy.  

Screening for a treatment that targets a specific individual’s rare ovarian cancer 

In addition to the development of the clinical trial, Dr Barker’s team was able to carry out a large drug screen to identify additional effective combination therapies for OCS. During this study, the team has been establishing a way to screen drugs against a patient’s individual tumour sample. This involves screening the sample against many drugs in the lab and then, if an effective option is found, the patient could be treated accordingly, with the reassuring insight that they are likely to respond well. 

The team also tested eribulin on high-grade serous ovarian cancer and found that where samples had already been treated with other standard therapies and become resistant to them, eribulin worked. This indicates that this treatment combination may be able to be expanded for use to treat other ovarian cancer subtypes in the future.