Cancer Genetics & Genomics

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Cancer Genetics & Genomics - Research at Peter Mac

Our laboratory focuses on the molecular characterisation of ovarian and gastric cancer, cancers of unknown primary, and on understanding the role of the Siah E3 ligases in cancer progression.

Research Focus

Genomic characterisation of human ovarian and gastric cancer. Coordination of the Australian Ovarian Cancer Study cohort. Development of a molecular diagnostic for cancers of unknown primary. Biochemical and functional characterisation of Siah E3 ligases in cancer models. Development of novel small molecules targeted to the Siah proteins.

Research Overview

Our focus is the molecular characterisation of key mutational events in ovarian cancer, particularly in selected clinical cohorts, such as women with primary or acquired chemotherapy resistance. This work is underpinned by an outstanding bioresource, the Australian Ovarian Cancer Study (AOCS), allowing us to create the largest gene expression dataset for ovarian cancer to date. For example, current studies have revealed novel molecular subtypes of serous ovarian cancer. This research has been supported by the awarding of a DoD Translational Research Partnership grant (US$750,000), 2009-11. We are pursuing similar goals in gastric cancer, one of the three most common causes of cancer death in the world. The gastric cancer program is led by Associate Professor Alex Boussioutas, a specialist gastroenterologist and clinician–researcher. Siah proteins function as ubiquitin E3 ligases and have been shown to bind to a wide range of potential substrates in in vitro assays. Research from our laboratory and collaborative studies have identified the mechanism of interaction of Siah with substrates, defined the 3D structure of the Siah substrate-binding domain, generated germline mutant mice and demonstrated a striking role for Siah proteins in regulating HIF1a-mediated responses in hypoxic cells via targeting of PHD proteins for degradation. Current studies focus on Siah’s role in tumour angiogenesis and inflammation. We are developing small molecule inhibitors in collaboration with the Centre for Cancer Therapeutics (Institute of Cancer Research, UK).