Metastatic castration-resistant prostate cancer (mCRPC) is the second leading cause of male cancer mortality, resulting in more than 375,000 deaths globally each year.
Prostate cancer is the most commonly diagnosed cancer in Australian men, with 1 in 6 men being diagnosed within their lifetime.
Through their work, Dr Jenni Gunter and her colleagues at the Australian Prostate Cancer Research Centre of Queensland (APCRC-Q) endeavour to find out why therapies for advanced prostate cancer and metastatic (cancer cells breaking away from the main tumour and spreading around the body) prostate cancer eventually stopped working, and how they might prevent it.
They first started looking into this problem around 10 years ago when a brand-new drug had entered the market.
“If prostate cancer is detected early, most men will be treated with surgery or radiation therapy. These methods typically have success rates in the 90s,” said Dr Gunter.
“However, this does not account for men who are either diagnosed late or who will go on to develop disease outside of the prostate. In such cases, we need to use a therapy that can get anywhere in the body.”
These treatments work by blocking the action of androgen (sex hormone) receptors which effectively treats the cancer. As described by Dr Gunter, while effective, in some patients we see the tumour return quickly.
“It didn't shut down the cancer completely. While we could suppress the functions that we knew could help the tumour grow, we did not understand what the tumour was using to grow despite the therapy.”
These gaps in knowledge galvanised Dr Gunter and her colleagues to study the multiple mechanisms that were contributing to this resistance to therapy. They sought to answer questions like: what do these men need to take now? Can they take something alongside or in sequence with these with these new inhibitors?
“We needed to identify what these predictable alternative routes that the tumours were using in order to prevent further growth and the aggressive spread around the body,” Dr Gunter adds.
“Collaboratively, at our centre, APCRC-Q, we extensively modelled the reaction of prostate cancer to standard of care therapy to ascertain metabolic changes that are occurring inside that cell and by extension, how these changes overcome therapeutic pressures to continue growing,” she explained.
“One of these change pathways we came across that was under appreciated was the branched chain amino acid degradation pathway.”
“These amino acids cannot be synthesized naturally by humans and must be supplied by dietary means. Such amino acids are used by adipocytes (fat cells) as fuel to make lipids (fat).”
“Little else is known about this process, especially in prostate cancer. However, when we put the cells under pressure of the of the standard of care therapy, we noticed they were starved of energy, particularly, they were starved mostly of lipids.”
“As part of the cell’s mechanism to overcome these shortages, enzyme pathways are turned up to accommodate changes in the energy cycle and to increase the production of lipids.”
Essentially, the key to cancer cell growth and division is a consistent supply of energy. Specifically, the ability to manipulate and harness energy pathways. Dr Gunter and her colleagues discovered that, targeting these alternative routes would starve the cancer cell of the fuel needed to thrive.
“When we limited access to this energy source and reduced the lipid content, we realised that the cells did not possess ancillary mechanisms of production,” she said.
In speaking to Dr Gunter about the prospects of the project following the publishing of the teams’ work, they would ideally hope to conduct preclinical trials in the near future and develop inhibitor drugs. However, Dr Gunter is wary that this area remains understudied.
“In our experiments, it's been enough to kill the cells. What we need to do now is make sure that that's still true as we move out of the dish and into the patient and continue the hunt for further drug development,” Dr Gunter said.
“So that’s our starting point in developing a new drug to target this enzyme while keeping our minds open to other contributary factors to these pathways. We will also aim to structure this in a way that allows testing in preclinical models.”
With research funding crucial to progress, Dr Gunter said the team is incredibly thankful for the support they’ve received so far.
“We're often asked when and if cancer will be cured. I would say that we've probably cured cancer 25 times, maybe even 2500 times, but cancers are highly adapted at bypassing treatment for the sake of survival.”
“PARF funding has been fundamental to keeping our team together and essential in affording us a new and fresh platform for clinical development but also allowing us to reevaluate current academic literature and our textbook knowledge.”
“We take every single donation and grant that we get incredibly seriously because it is a tough landscape out there now and we must make every dollar count.”
You can donate to vital prostate cancer research here.
