Overview
Lipids are the building blocks of cells and the lipids in prostate cancer cells are known to be different to those in normal prostate cells. The activity of some lipid enzymes are also increased in prostate cancer cells when compared to normal cells. We are leading a global research programs to better understand the role that lipids play in controlling prostate cancer behaviour. We have shown that lipids from the diet and body fat can profoundly influence prostate cancer cell behaviour, including disease aggressiveness and resistance to drugs. We are using this knowledge to i) develop sensitive probes for lipid biomarkers to predict disease behaviour and the likely response of men to different prostate cancer drugs to better guide treatment and improve health outcomes ii) evaluate lipid enzyme inhibitors as a novel drug approach for treating prostate cancer, and iii) better inform lifestyle-related prevention strategies to reduce the risk of aggressive disease.
We acknowledge the following organisations for their funding:
Movember, Prostate Cancer Foundation of Australia, Cancer Council SA, Cancer Australia (Cure Cancer Australia), Cancer Australia (Tour de Cure), US Department of Defense, The University of Adelaide, The Hospital Research Foundation, the Masonic Charities Trust.
Project 1: The Circulating Lipidome as a Prognostic Marker
Using data generated over the last three years using a cohort of more than 300 Adelaide and 300 Sydney men with localised prostate cancer at diagnosis, we have identified particular patterns of lipid species in blood (referred to as the lipidome signature) which are associated with better and worse prognosis of prostate cancer. Furthermore, preliminary evidence suggests that alterations in the lipid metabolism within these cancers is reflected in these blood profiles.
The preliminary results from the 300 cases requires validation in larger cohort of men including those with more advanced disease. We are analysing the lipidome signature of men treated at the Mayo Clinic (Rochester, USA) for disease at multiple stages and men from NSW with hormone sensitive metastatic disease and castration resistant metastatic disease to investigate associations with outcomes.
Contact: Professor Lisa Butler
Key reference: Butler LM et al. Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention . Adv Drug Deliv Rev . 2020 Jul 23;S0169-409X(20)30097-1. doi: 10.1016/j.addr.2020.07.013.
Project 2: Prostate cancer and lipid metabolism based therapies
With our state (Flinders University), interstate (Monash Uni) and international (Leuven, Belgium) collaborators, we will be testing in preclinical models, a suite of potential drugs that target aberrant lipid metabolism in prostate cancer tumours. These include ELOVL5, acetyl coA-carboxylase and other androgen-regulated lipogenic genes. The preclinical models include a range of cell line models across the natural course of disease, mouse xenograft models, human patient-derived explants, and organoids of patient-derived xenografts.
The goal of this research is to develop better prognostic blood tests for prostate cancer using lipidome signatures which would then be used to prescribe the most appropriate lipid modifying therapies on an individual basis– including the repurposing of current therapies and development of new therapies that target adverse lipid metabolism within prostate cancer to improve outcomes.
Contact: Professor Lisa Butler
Key reference: Nassar ZD et al. Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis. Elife . 2020 Jul 20;9:e54166. doi: 10.7554/eLife.54166.
Project 3: Statins and the lipidome in prostate cancer
In men with prostate cancer, we have identified particular patterns of lipid species in blood (referred to as the lipidome signature) which are associated with a better and worse prognosis. Preliminary evidence also suggests that alterations in the lipid metabolism within these cancers is reflected in these blood profiles.
As the poor prognostic lipid signature has features targeted by statin usage, we initiated a prospective clinical trial across 5 Centres in Australia where we are giving men with prostate cancer statins, a class of drug used to reduce blood cholesterol levels, to examine whether statins reverse a poor prognosis lipidome signature. If successful, this will lead to future studies to investigate effects on patient outcomes.
The specific aim of the clinical study is to assess whether treatment with simvastatin (Statin) during treatment for metastatic castration-resistant prostate cancer can reverse a poor prognostic plasma lipid signature. Participants are being treated with simvastatin 40mg daily (oral tablet) for 12 weeks, at the same time as starting chemotherapy (docetaxel or cabazitaxel) or novel anti-androgen treatment (abiraterone or enzalutamide).
ANZ Clinical Trials Register Study ID: ACTRN12617000965303 (NSW Study)
Contact: Professor Lisa Butler