Tothill Laboratory: Rare Disease Oncogenomics (RADIO)

Tothill Laboratory: Rare Disease Oncogenomics (RADIO)

The Rare Disease Oncogenomics (RADIO) Laboratory in the University of Melbourne Centre for Cancer Research (UMCCR) is dedicated to translational research of rare and orphan cancers.

Our research encompasses neuroendocrine cancers, including tumours of the sympathetic tissues (phaeochromocytoma and parganglioma) and rare skin cancer types, such as Merkel cell carcinoma, as well as cancers of unknown primary (CUP). We use state-of-the-art genomic methods (massively parallel sequencing) to survey the genetic landscape of cancers cells to elucidate their underlying biology and to develop better prognostic and predictive biomarkers of disease response to therapy. Another major focus encompasses the use of gene-expression profiling of tissues and single-cells combined with immune profiling technologies to understand the interplay between tumour genetics and immune response in cancer.

Projects

  1. A5 SDHB Genomics Study: Phaeochromocytoma (latin: dusky coloured tumour) and paraganglioma (PPGL) are two related tumour types originating from the sympathetic and parasympathetic tissues of the adrenal medulla and extra-adrenal paraganglia. Approximately 10-20% develop metastatic disease and these patients are highly enriched in individuals carrying an SDHB mutation. We are employing integrated genomic methods to understand why only some SDHB PPGL patients will develop metastatic disease, to identify clinical biomarkers of metastatic risk and new therapeutic targets.

    Key Collaborations

    Peter MacCallum Cancer Centre, Melbourne (Prof Rod Hicks)

    Kolling Institute and Royal North Shore Hospital, Sydney (Prof Rory Clifton-Bligh, Prof Anthony Gill)

    National Institute of Health, Bethesda, USA (Prof Karel Pacak)

    American Australian Asian Adrenal Alliance (A5) (USA, Australia, New Zealand, Canada, Singapore)

    Key Sponsors

    National Health and Medical Research Council (NHMRC)

    Pheo-Para Alliance, USA

    Paradifference, Sweden

  2. Understanding the biology of Merkel cell carcinoma (MCC): MCC is a highly aggressive and often fatal neuroendocrine skin cancer linked to viral infection and excessive sun exposure. With a view to developing better treatments for MCC, we seek to better understand the biology of this disease, especially the viral-negative subtype, which is more common in Australia compared to USA and Europe. While immunotherapy has shown great promise in early clinical trials for the treatment of MCC, it is not effective for many patients. We want to understand why only some tumours induce a strong immune response or will respond to immunotherapy and to develop new surveillance biomarkers (e.g circulating tumour DNA) for monitoring patient response to treatment.

    Key Collaborations

    Peter MacCallum Cancer Centre, (Prof Rod Hicks, Dr Shahneen Sandhu, A/Prof Paul Neeson, Skin and Melanoma Unit)

    University Hospital Essen/West German Cancer Centre/ German Cancer Consortium (DKTK) (Prof J├╝rgen Becker)

    Melanoma Institute Australia, Sydney (Prof Richard Scolyer)

    Royal North Shore Hospital, Sydney (Prof Anthony Gill)

    Peter Doherty Institute (Prof Dale Godfrey)

    ANZMTG (Australasian Merkel Interest Group, AMIGOs)(Sydney, Brisbane Adelaide, Melbourne)

  3. Developing clinical genomic methods for cancer of known primary (CUP): CUP is a metastatic cancer arising in the absence of a diagnosed primary tumour. It represents a heterogeneous collection of tumours that share a propensity for rapid metastatic spread despite the primary tumour remaining small and undetected. CUP is a devastating disease with a notoriously poor prognosis and an orphan disease as it significantly challenges the current paradigm for patient care, given that identifying a Tissue Of Origin (TOO) remains the universal starting point for cancer treatment. We are developing faster and more precise methods that can assist a TOO diagnosis and are involved with a clinical study (Solving Unknown Primary CacnER, SUPER) evaluating clinical genomic methods to identify TOO and therapeutic vulnerabilities of CUP tumours.

Key Collaborations

Peter MacCallum Cancer Centre (Dr Linda Mileshkin, Prof David Bowtell, Dr Penny Schofield)

Australian SUPER study group (Victoria, NSW, NT, SA)

Key Sponsors

National Health and Medical Research Council (NHMRC)

Victorian Cancer Agency

Cancer Australia

Publications

See complete list of Richard Tothill’s publications.

  1. Dwight, T., Flynn, A., Amarasinghe, K., Benn, D.E. Lupat, R., Li, J.,…Tothill, R.W (2017). TERT Structural rearrangements in metastatic pheochromocytomas. Endocrine-Related Cancer. Accepted 3rd Oct.
  2. Lefebure M*, Tothill RW*,…, Johnstone RW (2017). Genomic characterisation of Eµ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene. Nature Communications. Mar;8:14581 * contributed equally.

  3. Flynn,A, Dwight, T, Benn, D, Deb, S, Colebatch, AJ, Fox, S… Tothill, R.W (2017) Cousins not twins: intra and inter-tumoral heterogeneity in syndromic neuroendocrine tumours. Journal of Pathology. 242(3):273-283

  4. Flynn A, Dwight T, Harris J, Benn D, Zhou L, Hogg A, Catchpoole, D, … Tothill, RW (2016) Pheo-type: a diagnostic gene-expression assay for the classification of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 101(3): 1034-43

  5. Moran S,…Tothill, R….et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 17, 1386-1395 (2016).
  6. Wong SQ, Waldeck K, Vergara IA, Schroder J, Madore J, Wilmott JS, …Tothill, RW (2015). UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas. Cancer Research 75(24):5228-34

  7. Flynn, A., Benn, D., Clifton-Bligh, R., Robinson, B., Trainer, A. H., James, P., … Tothill, R. W (2015). The genomic landscape of phaeochromocytoma. Journal of Pathology. 236(1): 78–89

  8. Tothill, RW, Shi, F, Paiman, L, Bedo, J, Kowalczyk, A, Mileshkin, L, et al (2015) Development and Validation of a Gene Expression Tumour Classifier for Cancer of Unknown Primary. Pathology 47(1): 7-12
  9. Tothill, R.W., Li, J., Mileshkin, L., Doig, K., Siganakis, T., Cowin, P., et al (2013) Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary. Journal of Pathology. 231(4): 413-23.

  10. Tothill R, Estall V, Rischin D. Merkel cell carcinoma: emerging biology, current approaches, and future directions. (2015) Am Soc Clin Oncol Educ Book; 35:e519–26.
  11. Meldrum, C., Doyle,M.A. and Tothill, R.W. (2011) Next-Generation Sequencing for Cancer Diagnostics: a Practical Perspective. Clinical Biochemist Reviews 32: 177-95