The Cancer Research Unit conducts trailblazing work on telomeres, which are important for all cancers.
Research in the Cancer Research Unit (CRU) aims to provide insights to molecular aspects of cancer biology that can be leveraged in the development of innovative diagnostic tools and improved cancer treatment strategies.
A central focus is the mechanisms that function to maintain the integrity of chromosome end structures called telomeres. Telomeres are lost in normal cells as they divide, which limits their ability to proliferate. In most cancers, telomere loss is overcome by activation of a telomere maintenance mechanism, involving an enzyme called telomerase or a process called Alternative Lengthening of Telomeres (ALT). The activation of a TMM provides cancer cells with unlimited ability to replicate (cellular immortality), and thus presents an important mechanism for therapeutic targeting. The CRU has a strong history of discoveries in telomere biology, including the discovery of the Alternative Lengthening of Telomere (ALT) mechanism in 1996 and the development of ALT detection methods that have been extensively applied by researchers across the world in studies of diverse cancer types. Current work in the CRU continues to investigate TMMs in cancer, with overarching aim to provide insights that can be applied in development of more effective cancer treatments.
In recent years, the CRU has integrated proteomic analyses as a powerful tool for discovery-based research and translation of telomere biology to clinical application. We apply proteomics, in conjunction with other ‘omic approaches to discover therapeutic targets, biomarkers and molecular vulnerabilities in cancer cells. Research in the CRU spans a broad spectrum of adult and paediatric cancers, with particular focus on ALT-driven cancers such as sarcomas and glioblastoma, as well as haematologic disorders.
Focused, translational-oriented research is needed to advance these discoveries to the next stages, where they can be useful to patients, and that’s where we are right now. However, we also need basic, curiosity-driven research to continue if we are to make the truly great discoveries. CMRI’s culture has long been supportive of both types of research.”
Director of CMRI, Co-Director of ProCan, and Head of the Cancer Research Unit
Project Manager, Cancer Research Unit
Therapies targeted at telomere lengthening mechanisms are expected to be a very effective and specific way of treating cancer. To provide a resource for exploiting telomere biology in cancer diagnosis and treatment, the CRU has characterised telomere maintenance mechanisms in approximately 1000 cancer-derived cell lines, representing more than 30 different types of cancers. This project, completed in collaboration with the Welcome-Sanger Institute (Cambridge UK), provides a dataset of telomere biology measures of unprecedented scale that uncovers under-appreciated complexity of telomere maintenance states in cancer. The CRU have used this dataset, in conjunction with proteomic data generated by ProCan® and other ‘omic data sets, to identify cancer cell vulnerabilities, therapeutics and biomarkers associated with telomere biology. The outcome of these studies will be applied in the development of therapeutic approaches for precision medicine cancer treatment.
Since the CRU discovered the ALT mechanism in 1996, it has proven far more difficult to understand than telomerase. ALT involves complex networks of genes required for DNA repair and chromosomal structure. Three key players for ALT have been identified (ATRX/DAX/His3.3), but investigations indicate that there is more to be discovered in this space. The CRU is using the C-circle assay (discovered in the CRU), proteomics and next generation genomic sequencing to further interrogate the ALT mechanism. These investigations utilise isogenic panels of cell lines the team has engineered over the past decade, while also leveraging the Group’s more recent 1000 cell line study, as well as emerging data from ongoing studies of cell lines and tumour tissue derived from ALT cancers such as osteosarcoma, Ewing sarcoma and brain cancers.
Despite the availability of new drugs and cell therapies, multiple myeloma remains an incurable disease, with treatment failure, disease evolution and high rates of relapse being the primary causes of fatality. To improve survival of patients with multiple myeloma, more sophisticated diagnostic methods are needed to precisely classify disease subsets, predict therapy response and identify the treatment most likely to cure the disease in individual patients. Toward this goal, the CRU is working to establish methodology and reference data sets for pioneering the application of state-of-the-art protein profiling (proteomics) technology in the diagnosis and classification of multiple myeloma.
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See the Full NCBI Bibliography.
Cancer Research Unit formed at CMRI. Goal: to understand cancer cell immortalisation in sufficient detail to find new cancer therapies.
Discovered Alternative Lengthening of Telomeres (ALT) mechanism of telomere maintenance in cancer, opening up a new field of research.
Found diagnostic marker for ALT, called APBs. Also showed that unknown factors in normal cells can repress ALT cancers.
Demonstrated that ALT involves DNA recombination.
First in world to identify the composition of active telomerase enzyme complex in human cells.
Developed C-circle assay for measuring ALT activity in cancer. Discovered telomere trimming mechanism that could one day be exploited to target and kill cancer cells.
C-circle assay licensed for research use as a test for ALT cancers. Also determined the number of ‘frayed’ telomere ends needed to signal senescence or cell aging.
Involved in international Starr Consortium study identifying key genetic change (loss of ATRX) in ALT.
Demonstrated that ALT has a normal counterpart in mouse cells, which also provides a new model system for studying the ALT mechanism.
Discovery and characterization of cancers that grow with ever shortening telomeres.
Development of an innovative approach to halting growth of ALT-driven cancers using cytolytic HSV.
Application of multi-omic approaches to analyse telomere maintenance mechanisms in cancer.
Develop cancer therapeutics that target vulnerabilities created by activation of telomere maintenance mechanisms.