We have a major focus on bowel cancer genomics, the application of high-throughput molecular profiling technologies to identify principal cancer genes and biomarkers of cancer risk and prognosis. We are conducting next-generation sequencing and microarray studies involving Australian and international patient cohorts to define molecular signatures associated with tumour characteristics and outcome.
Patient-focused investigations are being complemented with functional studies on cancer cell lines to distinguish driver from passenger mutations and to gain insights into molecular pathways of carcinogenesis. Molecularly-annotated cancer cell lines are further being used to explore the efficacy of novel drug therapies, both as single-agents and in combination with standard therapies.
We are developing organoids as ‘avatars’ of patient tumours to direct the use of therapies and to discover new treatment opportunities.
United Kingdom, University College London, BSc(Hons)
United Kingdom, University College London, PhD
Honorary Associate Professor, Sydney Medical School, The University of Sydney
Adjunct Associate Professor, School of Biomedical Sciences, Monash University
Honorary Associate Professor, Department of Surgery (RMH), The University of Melbourne
2018, NHMRC Senior Research Fellowship, SRFA
2014, NHMRC Research Excellence Award: Top Ranked Application – Career Development Fellowship Level 2 Biomedical 2013
2013, NHMRC RD Wright Biomedical Career Development Fellowship, Level 2
2022- Co-Chair, Translational Research Committee, Australasian Gastro-Intestinal Trials Group
2022- Member, Research Operations Committee, Australasian Gastro-Intestinal Trials Group
1. Palmieri M, Catimel B, Mouradov D, Sakthianandeswaren A, Kapp E, Ang CS, Williamson NA, Nowell CJ, Christie M, Desai J, Gibbs P, Burgess AW, Sieber OM. PI3K-alpha translocation mediates nuclear PtdIns(3,4,5)P3 effector signaling in colorectal cancer. Molecular & Cellular Proteomics. 2023 Apr;22(4):100529. PMID: 36931626
2. Wang Z, Hu H, Heitink L, Rogers K, You Y, Tan T, Suen CLW, Garnham A, Chen H, Lieschke E, Diepstraten ST, Chang C, Chen T, Moujalled D, Sutherland K, Lessene G, Sieber OM, Visvader J, Kelly GL, Strasser A. The anti-cancer agent APR-246 can activate several programmed cell death processes to kill malignant cells. Cell Death & Differentiation. 2023 Apr;30(4):1033-1046. PMID: 36739334
3. Mouradov D, Greenfield P, Li S, In EJ, Storey C, Sakthianandeswaren A, Georgeson P, Buchanan DD, Ward RL, Hawkins NJ, Skinner I, Jones IT, Gibbs P, Ma C, Liew YJ, Fung KYC, Sieber OM. Onco-microbial community profiling identifies clinico-molecular and prognostic subtypes of colorectal cancer. Gastroenterology. 2023 Mar 16:S0016-5085(23)00493-6. doi: 10.1053/j.gastro.2023.03.205. Online ahead of print. PMID: 36933623
4. Walker R, Georgeson P, Mahmood K, Joo JE, Makalic E, Clendenning M, Como J, Preston S, Joseland S, Pope BJ, Hutchinson RA, Kasem K, Walsh MD, Macrae FA, Win AK, Hopper JL, Mouradov D, Gibbs P, Sieber OM, O’Sullivan DE, Brenner DR, Gallinger S, Jenkins MA, Rosty C, Winship IM, Buchanan DD. Evaluating Multiple Next-Generation Sequencing-Derived Tumor Features to Accurately Predict DNA Mismatch Repair Status. Journal of Molecular Diagnostics. 2023 Feb;25(2):94-109. PMID: 36396080
5. Jenkins LJ, Luk IY, Fairlie WD, Lee EF, Palmieri M, Schoffer KL, Tan T, Ng I, Vukelic N, Tran S, Tse JWT, Nightingale R, Alam Z, Chionh F, Iatropoulos G, Ernst M, Afshar-Sterle S, Desai J, Gibbs P, Sieber OM, Dhillon AS, Tebbutt NC, Mariadason JM. Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death. Molecular Cancer Therapeutics. 2023 Jan 3;22(1):52-62. PMID: 36343387
6. Luk IY, Jenkins LJ, Schoffer KL, Ng I, Tse JWT, Mouradov D, Kaczmarczyk S, Nightingale R, Burrows AD, Anderson RL, Arango D, Dopeso H, Croft L, Richardson MF, Sieber OM, Liao Y, Mooi JK, Vukelic N, Reehorst CM, Afshar-Sterle S, Whitehall VLJ, Fennell L, Abud HE, Tebbutt NC, Phillips WA, Williams DS, Shi W, Mielke LA, Ernst M, Dhillon AS, Clemons NJ, Mariadason JM. Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression. Cell Death & Differentiation. 2022 Nov;29(11):2288-2302. PMID: 35606410
7. Gately L, Drummond K, Rosenthal M, Harrup R, Dowling A, Gogos A, Lwin Z, Collins I, Campbell D, Ahern E, Phillips C, Gan HK, Bennett I, Sieber OM, Gibbs P. Beyond standard data collection – the promise and potential of BRAIN (Brain tumour Registry Australia INnovation and translation registry). BMC Cancer. 2022 Jun 2;22(1):604. PMID: 35655179
8. Tan T, Hirokawa Y, Clarke J, Sakthianandeswaren A, Sieber OM. Low-viscosity Matrix Suspension Culture for Human Colorectal Epithelial Organoids and Tumoroids. Bio Protocol. 2022 Apr 20;12(8):e4394. PMID: 35800090
9. Georgeson P, Pope BJ, Rosty C, Clendenning M, Mahmood K, Jihoon E. Joo JE, Walker R, Ryan Hutchinson R, Preston S, Como J, Joseland S, Win AK, Finlay A. Macrae FA, Hopper JL, Mouradov D, Gibbs P, Sieber OM, O’Sullivan D, Mealey N, Brenner D, Gallinger S, Jenkins MA, Winship IM, Daniel D. Buchanan DD. Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers. Gut. 2021 Nov;70(11):2138-2149. PMID: 33414168
10. P Mittal, MR Condina, M Klingler-Hoffmann, G Kaur, MK Oehler, OM Sieber, M Palmieri, S Kommoss, S Brucker, MD McDonnell, P Hoffmann. Cancer Tissue Classification Using Supervised Machine Learning Applied to MALDI Mass Spectrometry Imaging. Cancers. 2021 Oct 27;13 (21), 5388. PMID: 34771551
Understanding the molecular pathology of cancer is essential for predicting tumour clinical behaviour, for guiding treatment and for the development of new targeted therapies. Next-generation sequencing and microarray technologies provide the opportunity to comprehensively profile the genetic and epigenetic alterations of cancer genomes. We are applying these technologies in community and clinical trial patient cohorts to identify clinically-relevant tumour molecular subtypes, genomic signatures of outcome and principal driver genes. Clinical diagnostics development is being pursued in collaboration with industry partners. New therapeutic opportunities tailored to tumour molecular make-up are being investigated using advanced cell line and organoid model systems.
Genomics studies are uncovering an increasing number of novel candidate cancer genes for cancer. Some of these candidates will be clinically important driver genes contributing to tumourigenesis and malignant progression, whilst others will be neutral passengers. To systematically identify key driver genes, we are conducting high-throughput candidate knock-down screens for cell viability and migration using a panel of cancer cell lines representing the molecular subtypes of the disease. Lead candidates supported by high-throughput screening results are being taken forward in expanded tailored functional studies in vitro and in vivo to demonstrate their pathogenicity.
A key barrier to improving cancer outcomes is that clinicians have inadequate means to predict which drug option is going to be best for each patient. Consequently, many patients receive ineffective, costly drugs and suffer unnecessary toxicities. Organoid technology, the ability to grow patient tumour tissue in the laboratory, offers an opportunity for informing clinical care as a ‘living pathology’ assay. Our team is pioneering drug testing platforms to pre-screen patient drug options on organoids – complementing clinical assessment and molecular analyses – for personalisation of treatment. Our technology is currently being evaluated in clinical trails in collaboration with our hospital partners.
Treatment outcomes for patients with bowel, oral and brain cancer remain poor. A key problem is that cancers are genetically diverse, with some cells inevitably resistant to any given treatment. Combining drugs targeting distinct essential cellular functions is the principal strategy to overcome this problem, but developing such combinations in the clinic is challenging given the number of agents. We are utilising robotics to test drugs representing the human pharmacopeia in pairwise combinations on human cancer cell lines and organoid models capturing the genetic diversity of the disease. Lead drug combinations are being progressed for clinical development.