The idea
The team wanted to understand why people respond differently to a drug called trametinib so that treatment can be personalised. They also wanted to find some possible new treatments for LGSOC.
Project background
Low grade serous ovarian cancer is less common than the high-grade form and affects around 700 women each year in the UK.
While most cases of ovarian cancer occur in women of 60 years or more in age, low-grade serous ovarian cancer tends to affect younger women – in their 40s – and is often resistant to chemotherapy. Since it is less common, less research has been carried out on this type of ovarian cancer. This means that few treatment options exist and therefore there is an urgent need to develop new approaches.
This project built on the work of a landmark clinical trial in recurrent low grade serous ovarian cancer known as the LOGS trial, led by Professor Gourley and colleagues from the USA. Patients in this trial receiving a drug called trametinib (MEKINIST®) experienced a substantially improved response compared with standard chemotherapy treatment. It also reduced the chance of the cancer coming back again. It is hoped that the results from the LOGS trial could lead to trametinib becoming a new, targeted treatment for women with low-grade serous ovarian cancer.
The results from the LOGS trial represent a huge step forward for women with low grade serous ovarian cancer, but it was clear that some people on the trial responded well to trametinib, while others did not. A key aim of this research was to identify how the tumours differ in these two groups of women, and how this influences their response to treatment.
Project plan
This project had two distinct parts. In the first part, the team performed whole exome sequencing of around 250 recurrent LGSOCs cases enrolled in the GOG281/LOGS trial. This was a phase II/III trial of trametinib for relapsed LGSOC. The team compared these cases against 100 unselected LGSOC cases. The team used these data to identify patient subgroups likely to derive greatest benefit from trametinib, endocrine therapy and standard chemotherapy, and those most likely to experience relapse.
In the second part, using LGSOC cell lines recently developed in the laboratories, the team performed a drug screen of over 1,500 compounds to identify novel treatment options for recurrent LGSOC. This included FDA-approved agents that could potentially be fast-tracked into clinical trials.
Research results
The team found three subgroups of recurrent LGSOC based around changes to the MAPK signalling pathway. Patients with classical mutations have increased survival, possibly because their disease progresses slower, and they also have a better response to trametinib. Patients without mutations (so called wild-type) may be less responsive to trametinib and therefore need different treatment options. A third group have non-classical mutations of the MAPK-associated genes the team are investigating whether these patients also respond better to trametinib beyond the scope of this grant.
By comparing the findings in recurrent LGSOC with an unselected group, researchers found that patients with mutations may be less likely to experience recurrence.
The team found 16 potential new treatments for LGSOC. These drugs killed cells at extremely low concentrations. Some of the drugs killed cells that are resistant to trametinib suggesting those drugs may work for patients what do not benefit from trametinib. The team are now testing these treatments in 3D models of tumours and the most promising drugs will be taken forward into clinical trials.
Why is this research important to those affected by ovarian cancer?
To be able to develop new treatments, researchers and clinicians need to understand the biology for each different type of ovarian cancer. This research project has contributed valuable information about the biology in the MAPK pathway in women with LGSOC. This knowledge adds to the overall picture of the biology of this form of ovarian cancer, and can be built on to develop new treatments. The team have also identified possible new treatments that could be tested in clinical trials, and may eventually be licenced as new treatments for LGSOC.
Watch Dr Robb Hollis talk about the project.
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Fact file
Researcher: Professor Charlie Gourley and Dr Robb Hollis
Institution: University of Edinburgh
Project dates: April 2019 to October 2022
Funding awarded: £190,490
Project status: complete
Publications: Gershenson DM, Miller A, Brady WE, Paul J, Carty K, Rodgers W, et al, Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial, 2022, The Lancet, 399 (10324), 541-553, DOI: https://doi.org/10.1016/S0140-6736(21)02175-9
