Two new treatment-based ovarian cancer research projects awarded funding from the OCRF

how probing the proteins that drive ovarian cancer might halt its deadly spread.

Story by Michelle Fincke

Finding the chinks in ovarian cancer’s armour is complex: it’s deadly, difficult to diagnose and heartbreakingly resistant to existing treatment. Exposing its weaknesses to create effective new therapies depends on a deep understanding of what makes it tick, which means researchers need to ask a wide range of questions to find the answers they need.

The Ovarian Cancer Research Foundation (OCRF) has awarded significant new grants to two Melbourne-based research institutes that are pushing the boundaries to uncover what drives malignancy. What they learn will help target existing treatments as well as contribute to exciting new therapies to tackle ovarian cancer.

Taking different approaches, teams from the Hudson Institute of Medical Research and the Olivia Newton-John Cancer Research Institute (ONJCRI) will investigate two proteins that contribute to ovarian cancer’s growth and spread.

Professor Ron Firestein and his team from the Hudson Institute are deploying state-of-the-art genomic technology to develop a greater understanding of ovarian cancer biology, specifically the protein called PAX8. The OCRF has awarded Professor Firestein and his colleagues $238,527 over the next two years.

I've always been drawn to questions in research that can produce a clinical impact for patients, but at the same time, projects that advance our fundamental knowledge of biology and how cellular processes work,” Professor Firestein says. “There's a real urgency to identify and validate new drug targets, but at the same time, to understand the biology of ovarian cancer at a deeper level. And this project really deals with both of those questions.”

PAX8’s role as a key driver of ovarian cancer is well documented. Research has shown that it is essential for the development and sustenance of ovarian cancer cells. So, remove PAX8 and solve the heartbreak of ovarian cancer? If only it were so simple.

PAX8 and its activity are extremely difficult to target, so Professor Firestein and his team are heading upstream to learn more about the proteins that are needed to make PAX8 itself. By figuring out which proteins are needed for producing PAX8, they can begin to devise new drugs that will turn the tap off and stop this harmful protein from driving ovarian cancer growth.

“Knocking out” genes with next-gen technology

It’s complex research, but the advent of next-gen gene-editing technology called CRISPR screening – work that earned the Nobel Prize for Chemistry in 2020 – makes it feasible to attempt analysis that, just five years ago, couldn’t be done. The team will examine about 20,000 genes in a single experiment, ‘knocking out’ those they don’t need to identify which ones are important for the growth of ovarian cancer.

“Until CRISPR came along, it was very challenging to identify which are the drivers and which are the passengers,” says Professor Firestein. “And in terms of cancer therapy, obviously, we want to target the genes that are really driving the cancer growth invasion, the metastases.”

Identifying the gene or pathway that enables the growth and spread of cancer can potentially expose the Achilles heel of the disease. Even if there is no current drug therapy available or even possible, Professor Firestein says that establishing this fundamental knowledge is a big step in making it happen soon.

“It presents an opportunity to develop the next generation precision oncology drug targets, and realistically, that's a process that takes five or 10 years. The fact that the Ovarian Cancer Research Foundation is willing to fund this kind of work speaks to their long-term vision,” he says.

ONJCRI targets the environment in which deadly cancer grows

Professor Matthias Ernst, director of the ONJCRI, and his team are hoping their research, into yet another protein that contributes to malignancy will help create more effective targeted therapies to fight ovarian cancer. Of every five women diagnosed, three will die from the disease, as their cancer either responds poorly to existing drugs, or not at all. “We want to translate our discoveries from the laboratory bench into the clinic and have patient impact,” says Professor Ernst.

The ONJCRI team has been awarded $299,286 over two years to continue its already significant work in unravelling the way cancer development and growth appears to have a connection to a protein called Hematopoietic Cell Kinase, or HCK.

HCK is found within immune cells called macrophages. While these immune cells have a positive role to play within the body as “garbage collectors” gobbling up potentially harmful pathogens, Professor Ernst’s team has been exploring their role in the growth and spread of bowel, stomach and the particularly deadly pancreatic cancer.

Their research has shown that macrophages with increased HCK protein create a more effective environment for the development of potentially deadly tumours. But when Professor Ernst’s team took aim at HCK with a targeted drug that halts its activity, macrophages lost their ability to promote the growth and spread of several different cancers. The team’s early-stage modelling indicates that current chemotherapy could work better when used in combination with anti-HCK drugs for a range of cancers.

“With this as a background, of course we thought about ovarian cancer, and in particular high grade serous ovarian cancer – a sub-type with a high mortality rate – because that is obviously a disease that has been difficult to tackle and has a particularly grim outlook for patients,” says Professor Ernst.

The OCRF grant will enable his team to gather more data and to explore the potential for new therapies, including immunotherapy. One of the most exciting developments in cancer therapy, immunotherapy has been a gamechanger in the treatment of melanoma, but so far has failed to make an impact on ovarian cancer.

“We hope, of course, that drugs that can inhibit HCK will eventually reach into the clinic and have impact,” says Professor Ernst. 

“With this grant, we hope to generate sufficient data to really make a strong case that future development efforts should include its potential application for patients with high grade serous ovarian cancer.

“The project is focused on ovarian cancer patients and I would be delighted if the results can benefit them, but it has an added bonus in that the knowledge we gain may help patients with other rare cancers as well. Ultimately I want to help as many cancer patients as possible.”