Oliver Sieber-Projects

Oliver Sieber-Projects


Discovery of inherited variants affecting bowel cancer risk and progression

As a member of the international COGENT (COlorectal cancer GENeTics) consortium we are participating in genome-wide association (GWA) studies to identify inherited variants underlying bowel cancer susceptibility. Ongoing GWA analyses are focusing on improving statistical methodologies to identify causal variants, detecting interactions between risk alleles, subgroup analyses and incorporating non-genetic risk factors into risk models. Analogously, inherited variation might play a critical role in determining the natural course of the disease, perhaps by influencing tumour molecular evolution. We are working on linking GWA data to tumour molecular and clinical characteristics to test for the existence of inherited variants influencing bowel cancer progression.

Identification of clinically-relevant molecular subtypes of bowel cancer

Understanding the molecular pathology of bowel 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 developed using high-content compound screening approaches on patient-derived bowel cancer cell lines.

Study of the molecular mechanisms of bowel cancer progession

Genomics studies are uncovering an increasing number of novel candidate cancer genes for bowel 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 bowel 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.

High-throughput discovery of new drug combinations for metastatic bowel cancer

Treatment outcomes for patients with metastatic bowel cancer remain poor, with most tumours developing resistance within 24 months. 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 bowel cancer cell lines capturing the genetic diversity of the disease. Lead drug combinations are being progressed for clinical development.