Previous studies from the Rogers lab identified the molecular mechanisms of action of bisphosphonate drugs, a "blockbuster" class of agents used to inhibit bone destruction in patients with common bone diseaes such as post-menopausal osteoporosis and cancer-associated bone loss. We showed that these drugs inhibit FPP synthase, an enzyme of the mevalonate (cholesterol biosynthesis) pathway, in bone-destroying osteoclasts. Blocking this enzyme prevents the lipid modification (prenylation) of small GTPase signalling proteins that are essential for osteoclast function.
Inhibition of FPP synthase also leads indirectly to activation of gamma,delta-T cells and is the cause of the acute phase reaction to bisphosphonate therapy. Our current research seeks to identify the mechanisms underlying other side effects and "pleiotropic" (off-target) actions of bisphosphonates, including apparent anti-tumour activity and beneficial effects on mortality. Our recent findings, using state-of-the-art intravital imaging approaches, indicate that these drugs may have anti-cancer activity by acting on tumour-associated macrophages rather than directly on tumour cells.
Our expertise in studying the mevalonate pathway and protein prenylation led to a new research focus on mevalonate kinase deficiency, a rare autoinflammatory disease caused by mutations in an enzyme in this pathway. We recently demonstrated that protein prenylation is defective in circulating blood cells in patients with this disorder, leading to enhanced assembly of the NLRP3 inflammasome. Our current studies aim to further clarify the cause of inflammation in this disease and to develop new therapeutic approaches that restore normal protein prenylation.
We have strong collaborative links with members of the Immunology Division and Cancer Division. Our work is funded by grants from NHMRC, Cancer Council NSW, Allergy & Immunology Foundation Australasia, Marian & EH Flack Trust, and a revolutionary team award (program grant) from Prostate Cancer Foundation Australia/Movember.