Using old drugs in new ways to make ovarian cancer cells visible to the immune system 

A major barrier to treating ovarian cancer is the immune system’s limited ability to recognise and attack the tumour cells. While conventional immunotherapies work well in cancers that already have immune cells inside them ('hot' tumours), they don’t work as well in cancers that lack immune cells ('cold' tumours), or in tumours that are able to hide from the immune system in other ways. To improve outcomes, new treatments are needed that can reshape the tumour’s immune environment and make it more responsive to immunotherapy.

This project is advancing exploration into a new treatment combination developed through a long-standing collaboration between Dr Gwo Yaw Ho at Monash University and Monash Health in Melbourne, and Professor Brian Gabrielli of Mater Research Institute, The University of Queensland, who is also an OCRF-funded researcher on a related project .

This new grant represents a critical step in moving the teams’ discoveries closer to clinical trials. The researchers are testing this treatment combination in high-grade serous ovarian cancer (HGSOC), the most common and aggressive form of gynaecological cancer due to its high rates of recurrence. They also hope to extend this work to other subtypes, such as clear cell ovarian cancer, in the future.

The new drug combination being tested includes a DNA-damaging drug called a CHK1 inhibitor (CHK1i), together with a low-dose chemotherapy drug, hydroxyurea (LDHU), which are both taken in tablet form. In laboratory studies, this combination has been shown to kill a wide range of ovarian cancer cells, including those resistant to standard treatments, and is more effective than either treatment alone. Importantly, early laboratory studies suggest this combination avoided harmful cell stress, which may mean that side effects like hair loss that occur with higher doses may be reduced or prevented.

In preclinical models, the treatment activated cancer-fighting immune cells called CD8+ T cells, and also reduced the number of cells that can suppress the body’s immune response – like Tregs and MDSCs – which often protect the tumour. It also increased levels of a protein called PD-L1 in the tumour. This could open the door to using immune checkpoint therapies (like PD-L1 inhibitors) which are used in other cancer types but usually don’t work well in ovarian cancer.

In this project, the researchers will test the CHK1i drug in combination with LDHU. They will also test anti-PD-L1 (an immunotherapy) with or without the checkpoint inhibitor drug.

The team will explore how this combination treatment reshapes the immune environment and whether it can be further improved by adding drugs that block PD-L1. They’ll also investigate how the treatment works at the cellular level, looking at inflammation and a type of cancer cell death called pyroptosis.