Prof Oliver Sieber, Lab Head | WEHI Researcher Profile

Q: Identification of clinically-relevant molecular subtypes of bowel, oral and brain cancers.

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.

Q: Study of the molecular mechanisms of bowel, oral and brain cancer progression

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.

Q: Improving the use of treatments for patients with bowel, oral and brain cancer

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.

Q: Discovery of new drug treatments for bowel, oral and brain cancer

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.

About

My research aims to identify new and more effective treatments for individuals affected by cancers of the bowel, oral cavity and brain.

After gaining my PhD at Cancer Research UK in 2004, I undertook 6 years postdoctoral training at Cancer Research UK, the University of Oxford and the Ludwig Institute of Cancer Research (LICR Melbourne) in the field of cancer biology.

I was Joint Laboratory Head at the LICR Melbourne from 2009-12, before joining WEHI as Laboratory Head. At WEHI, I set up the Stafford Fox Centre for Cancer Stem Cell Disease Modelling to facilitate the development of precision medicine approaches for cancer utilising patient-derived organoids. I serve as Deputy Chair of the Translational Research Committee of the Australasian Gastro-Intestinal Trials Group (AGITG).

My research team integrates laboratory and clinical studies, working with academic and hospital partners, to advance our understanding of tumour biology and improve outcomes for bowel, oral and brain cancer.

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Selected publications from Prof Oliver Sieber

Luk IY, Mooi JK, Mouradov D, Tan T, Scott CM, Chionh F, Jenkins LJ, Reehorst CM, Nightingale R, Savas P, Tse JW, Crake RL, Batlle E, Arango D, Dopeso H, Gibbs P, Tebbutt NC, Luwor RB, Scott AM, Basheer F, Dhillon AS, Clemons NJ, Williams DS, Firestein R, Sieber OM, Mariadason JM. Model systems and unique biological features of high and low-grade colorectal cancer (CRC) revealed by xenografting 84 human CRC cell lines. Communications Biology. 2025;8(1):10.1038/s42003-025-08251-0

Wang Z, Burigotto M, Ghetti S, Vaillant F, Tan T, Capaldo BD, Palmieri M, Hirokawa Y, Tai L, Simpson DS, Chang C, Huang AS, Lieschke E, Diepstraten ST, Kaloni D, Riffkin C, Huang DCS, Suen CSNLW, Garnham AL, Gibbs P, Visvader JE, Sieber OM, Herold MJ, Fava LL, Kelly GL, Strasser A. Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells. Cancer Discovery. 2024;14(2):10.1158/2159-8290.cd-23-0402

Tan T, Mouradov D, Lee M, Gard G, Hirokawa Y, Li S, Lin C, Li F, Luo H, Wu K, Palmieri M, Leong E, Clarke J, Sakthianandeswaren A, Brasier H, Tie J, Tebbutt NC, Jalali A, Wong R, Burgess AW, Gibbs P, Sieber OM. Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer. Cell Reports Medicine. 2023;4(12):10.1016/j.xcrm.2023.101335

Mouradov D, Greenfield P, Li S, In E-J, 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. Oncomicrobial Community Profiling Identifies Clinicomolecular and Prognostic Subtypes of Colorectal Cancer. Gastroenterology. 2023;165(1):10.1053/j.gastro.2023.03.205

Hirokawa Y, Clarke J, Palmieri M, Tan T, Mouradov D, Li S, Lin C, Li F, Luo H, Wu K, Faux M, Tan CW, Lee M, Gard G, Gibbs P, Burgess AW, Sieber OM. Low-viscosity matrix suspension culture enables scalable analysis of patient-derived organoids and tumoroids from the large intestine. Communications Biology. 2021;4(1):10.1038/s42003-021-02607-y

Williams DS, Mouradov D, Jorissen RN, Newman MR, Amini E, Nickless DK, Teague JA, Fang CG, Palmieri M, Parsons MJ, Sakthianandeswaren A, Li S, Ward RL, Hawkins NJ, Faragher I, Jones IT, Gibbs P, Sieber OM. Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes. Gut. 2019;68(3):10.1136/gutjnl-2017-315664

Domingo E, Camps C, Kaisaki PJ, Parsons MJ, Mouradov D, Pentony MM, Makino S, Palmieri M, Ward RL, Hawkins NJ, Gibbs P, Askautrud H, Oukrif D, Wang H, Wood J, Tomlinson E, Bark Y, Kaur K, Johnstone EC, Palles C, Church DN, Novelli M, Danielsen HE, Sherlock J, Kerr D, Kerr R, Sieber O, Taylor JC, Tomlinson I. Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series. The Lancet Gastroenterology & Hepatology. 2018;3(9):10.1016/s2468-1253(18)30117-1

Sakthianandeswaren A, Parsons MJ, Mouradov D, MacKinnon RN, Catimel B, Liu S, Palmieri M, Love C, Jorissen RN, Li S, Whitehead L, Putoczki TL, Preaudet A, Tsui C, Nowell CJ, Ward RL, Hawkins NJ, Desai J, Gibbs P, Ernst M, Street I, Buchert M, Sieber OM. MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors. Cancer Discovery. 2018;8(8):10.1158/2159-8290.cd-17-0909

Wang J, Mouradov D, Wang X, Jorissen RN, Chambers MC, Zimmerman LJ, Vasaikar S, Love CG, Li S, Lowes K, Leuchowius K-J, Jousset H, Weinstock J, Yau C, Mariadason J, Shi Z, Ban Y, Chen X, Coffey RJC, Slebos RJC, Burgess AW, Liebler DC, Zhang B, Sieber OM. Colorectal Cancer Cell Line Proteomes Are Representative of Primary Tumors and Predict Drug Sensitivity. Gastroenterology. 2017;153(4):10.1053/j.gastro.2017.06.008

Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RKS, Bisgaard M-L, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJW, Tomlinson IPM. Multiple Colorectal Adenomas, Classic Adenomatous Polyposis, and Germ-Line Mutations in MYH. New England Journal of Medicine. 2003;348(9):10.1056/nejmoa025283

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Lab research projects

Identification of clinically-relevant molecular subtypes of bowel, oral and brain cancers.

Study of the molecular mechanisms of bowel, oral and brain cancer progression

Improving the use of treatments for patients with bowel, oral and brain cancer

Discovery of new drug treatments for bowel, oral and brain cancer

Prof Oliver Sieber

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