Rare Disease Oncogenomics (RADIO) Lab | Associate Professor Richard Tothill

Cancer of unknown primary (CUP) is defined by the inability to diagnose the site of origin of a metastatic cancer after conventional clinical investigations. CUP patients have one of the worst survival outcomes of all cancers. Genomics can be helpful to resolve the site of origin of these cancers by identifying genomic features that are indicative of a specific cancer type, such as breast, lung or biliary tree. Genomics can also inform precision treatments such as small molecule inhibitors or immunotherapy which may improve survival outcomes for these patients who would otherwise receive non-directed chemotherapy.

SUPER-NEXT is a prospective national study incorporating real-time clinical whole-genome sequencing into the diagnostic work-up of patients with CUP. SUPER-NEXT utilises state-of-the-art genomic approaches to help resolve tissue of origin of CUP and identify potential targeted treatment approaches. The study is run in collaboration with Professor Linda Mileshkin at the Peter MacCallum Cancer Centre.

SUPER-NEXT is investigating the impact of clinical genomics for CUP patients measured by a) improvement in the certainty of a pathological diagnosis for site of origin, b) changes in treatment decisions by oncologists c) improvement in patient survival, d) patient reported outcome measures  and e) health economics (Prof Louisa Collins, Viertel Cancer Research Centre at Cancer Council, QLD). SUPER-NEXT is also building a biobank of patient samples with comprehensive clinical annotation for future research.

SUPER-NEXT is also informing the use of clinical genomics in another CUP study called CUPID, led by Prof Chris Karapetis at Flinders Centre for Innovation in Cancer in Adelaide, South Australia.

FAPI-CUP is an MRFF-funded clinical trial led by Prof Linda Mileshkin at the Peter Mac testing the role of a new PET radiopharmaceutical agent called FAPI to help resolve CUP primary cancer diagnosis compared to conventional FDG-PET. FAPI also has therapeutic potential to deliver targeted radiation therapy to a tumour by attaching a particle emitting radioactive element to the FAPI compound.

The RADIO lab is investigating the additive value of clinical whole-genome and transcriptome sequencing of CUP patients with results from FAPI and FDG-PET scans. This will also identify potential genomic biomarkers of FAPI radiopharmaceutical treatment response.

Phaeochromocytoma (PC) and paraganglioma (PG) are rare neuroendocrine tumours that develop from the adrenal glands and autonomic nerve junctions, respectively, are heritable – have the potential to run in families – in 40%. PCPG have the potential to synthesise and release catecholamines (e.g. adrenaline, noradrenaline, dopamine) into blood circulation, which can cause severe high blood pressure and life-threatening heart damage. Although many PCPG have an indolent disease course, some can be clinically aggressive and once they have spread (metastasised) to a distant site in the body they are incurable and hard to treat. There are currently insufficient clinical biomarkers to predict whether a patient’s PCPG cancer is likely to metastasise.

Diagnosis of PCPG relies on clinical suspicion and accurate diagnostic methods. In patients suspected to have PCPG standard testing has high false positive rates and lacks negative predictive value resulting in protracted diagnostic journeys. Indeed, the mainstay of PPGL diagnosis is detection of elevated catecholamines yet this is uninformative in the 15% of patients with non-secretory tumours. The RADIO Lab, in collaboration with the Peter Mac NET Unit, an ENETS Centre of Excellence, is undertaking analysis of circulating tumour DNA (ctDNA) in blood plasma to assess feasibility of liquid biopsy in patients with PCPG for diagnosis and precision treatment decision-making. Levels of ctDNA are also being compared to PET imaging to benchmark liquid biopsy results to contemporary cancer imaging.

Merkel cell carcinoma (MCC) is an aggressive form of skin cancer, caused by either viral infection or UV-sunlight, with a five-year survival of only 50 percent. Australia has the highest incidence of MCC worldwide attributed to high sun-exposure.

Pancreatic Neuroendocrine Tumours (PNETs) are rare neuroendocrine tumours arising from the pancreas. PNETs have the potential to synthesis and release hormones that can cause debilitating low blood sugars, diarrhoea and malnutrition. Because PNETs exhibit a spectrum of clinical behaviours their diagnosis can be challenging, while factors that influence treatment response is poorly understood.

Standard biopsies are often unfeasible in NET patients due to tumour inaccessibility and the risk of dangerous hormone release. As part of a multi-site liquid biopsy study called SANGUIS led by Prof Michael Michael at the Peter Mac, the RADIO Lab is testing non-invasive liquid biopsy methods to detect circulating tumour DNA and NET related proteins in patient blood, benchmarking against conventional blood and imaging biomarkers. The aim is to develop non-invasive methods to enable better NET diagnosis, surveillance, personalised treatment allocation and detection of the emergence of treatment resistance.

The RADIO Lab is using advanced methods such as next-generation sequencing, single cell genomics and immune profiling of MCC to understand the genomic pathology of these cancers and the interaction between MCC cancer cells and the immune system. The lab has a particular interest in non-conventional T cells found in the tumour microenvironment called gamma delta T cells. The lab is collaborating with researchers at the Peter Doherty Institute to understand why some MCC tumours attract these non-conventional T cells and whether they can be harnessed for more effective treatment.

RADIO Lab is leading translational studies for two MRFF clinical trials – iMAT and GoTHAM administered by Melanoma and Skin Cancer Trials Ltd (MASC). iMAT (PI: Wen Xu, University of Queensland) involves the application of adjuvant immunotherapy in patients with Stage I-III disease while GoTHAM (PI: Shahneen Sandhu) is testing the combination of immunotherapy with radiation in late stage (stage IV) disease. Translational studies for these trials are using genomics and immune profiling to understand immunotherapy treatment response. Both trials also involve application of liquid biopsy as a prognostic and surveillance biomarker.