Researchers at the Cancer Research UK Scotland Centre within the University of Edinburgh recently published a paper in Gynaecologic Oncology outlining the results of their drug screening study.
The study, led by Dr Robb Hollis and the laboratory of Professor Charlie Gourley, aimed to identify treatments that are already in use or currently being studied for other conditions to determine if they could be repurposed for treating low-grade serous ovarian cancer (LGSOC), either alone or in combination with trametinib.
The study employed a range of LGSOC cell lines representing the two main genetic subgroups: those with RAS/RAF mutations and those with RAS/RAF wild-type (un-mutated). Seven of these cell lines were created by Dr Mark Carey in Canada, with additional cell lines provided by Dr K.K. Wong at the University of Texas MD Anderson and Professor Gourley’s laboratory at the University of Edinburgh.
High throughput drug screening was performed with 1,610 drug compounds on their own. Of those, 37 agents showed more than a 50% reduction in cancer cell numbers compared to no treatment. From there, 16 agents were prioritised for further investigation; 11 treatments passed further tests in the lab. The four most promising of these (dasatinib, disulfiram, carfilzomib and romidepsin) were tested in combination with trametinib to identify if any of these combinations has synergistic effects, with dasatinib showing the best response.
The researchers were able to show that dasatinib was having an effect through its inhibition of SRC family kinase (SFK) by comparing it to a highly selective SFK inhibitor called NXP900 (developed at the University of Edinburgh), which showed similar results to dasatinib when combined with trametinib and applied to the LGSOC cell lines.
The study was successful in identifying several novel treatments which can be considered for inclusion in future clinical trials on their own and in combination with trametinib for low-grade serous ovarian cancer. A further expansion of the study, funded through the LGSOC Initiative, is currently underway – investigating whether any further potential trametinib combination treatments can be identified from the 1,610 drug library.
We acknowledge the generous support of Target Ovarian Cancer UK for this project. We also acknowledge the fundraising efforts of Nishtha Gupta, a young woman with low-grade serous ovarian cancer, which facilitated the ongoing expansion study through the Low-Grade Serous Ovarian Cancer Initiative.
The ovarian cancer team at the University of Edinburgh also receive funding from the Nicola Murray Foundation, a local ovarian cancer charity, and through the LGSOC Initiative which helps support their low-grade serous research.
About the medications identified in the study
- Trametinib is a mitogen-activated protein kinase (MEK) inhibitor that was found to be of benefit for recurrent LGSOC in a Phase III clinical trial
- Dasatinib is a tyrosine kinase inhibitor used in chronic myeloid leukaemia
- Disulfiram, an ALDH inhibitor used to treat alcohol dependency
- Carfilzomib is a proteasome inhibitor used in myeloma
- Romidepsin is an HDAC inhibitor used in cutaneous T Cell Lymphoma
- NXP900 is a novel drug discovered by researchers at the University of Edinburgh (that is currently undergoing safety tests in a Phase 1 clinical trial (by Nuvectis Pharma). It targets SFKs, which are enzymatic proteins that function abnormally in some cancers. They are involved in a range of cancer processes including cell growth, survival, invasion, adhesion and angiogenesis (creation of blood supply to feed the cancer).
Study publication:
Article reviewed by Dr Robb Hollis, study co-author.
Prior to August 2024, the Low Grade Serous Ovarian Cancer Initiative was known as Cure Our Ovarian Cancer.
