Liver Cancer Project

Defeating Primary Liver Cancer

(Lay) Summary of Research Proposal

Liver cancer is one of the deadliest cancers, ranking 2nd in terms of absolute years of life lost, only behind lung cancer. Very little is known about the diverse biological causes. The current “one-size-fits-all” treatments only prolong a patient’s lifespan by 2-3 months. To fight this disease, the project team aims to collect blood and tumour samples and analyse them using a novel and sophisticated research pipeline to identify new tests for prediction/prevention and develop desperately needed new therapies.

Overview of Research Proposal

Hepatocellular carcinoma (HCC) is a disease of global significance with a very poor prognosis. Australia has had a consistent 4-5% increase in HCC incidence every year since 1982. There is no reliable biomarker available to predict HCC development or progression and patients are often diagnosed in later stages when treatment options are limited. Current therapies are associated with high toxicities, with only a minority of patients responding. A more detailed understanding of molecular HCC drivers is urgently required to personalise treatment and improve prognosis.

The multidisciplinary project team (including hepatologists, radiologists, pathologists, liver cancer researchers, genomic scientists, computational biologists, immunologists, data and software experts, and community members) has come together as the WA Liver Cancer Collaborative (WALCC) to defeat HCC. The WALCC will generate a comprehensive HCC data- and biobank, collected prospectively, comprising detailed clinical, imaging and pathological data together with OMICS and advanced single-cell profiling of HCC and normal tissue. In this flagship project, detailed “genomic molecular fingerprints” will be determined for ~500 HCC patients from samples of primary and recurrent and/or resistant disease. Our in-depth understanding of 4 key themes of HCC biology: tumour heterogeneity, tumour microenvironment, drug resistance and metastasis, will be transformed. The WALCC will also develop patient-derived organoid/xenograft platforms, enabling functional evaluation of newly identified biomarkers, novel therapeutic targets and innovative drug combinations, conferring powerful research advantages and driving fundamental progress in the field. Finally, the biobank and its platforms will enable development of tailored medicine approaches for patients, especially in advanced disease, positioning WA researchers at the leading edge of discoveries that can be translated into precision- HCC treatments for improved clinical outcomes.

Project Aims

To establish an innovative research pipeline, combining (a) coordinated and centralised tissue/serum biobanking, (b) integrated, cutting edge “multi-OMICS” technologies, (c) mid-to-high throughput patient-derived organoid (PDO) and (d) patient-derived xenograft (PDX) screening platforms, with the overarching goal to (e) generate the world’s first publicly accessible database linking molecular hepatocellular cancer patient profiles with drug screening data for accurate treatment outcome predictions.

Performance Measures & Milestones

WALCC performance will be reported annually. Metrics include number of:

patients/tumour samples
completed WGS/single cell RNA-seq
organoid lines generated/screens performed
database interrogations
publications, presentations using biobank/platforms
EMCRs/EMCHs involved
grants/fellowships leveraged/enabled, eg. MRFF, NHMRC, Future Health & Innovation Fund (FHIF, WA)
presentations at scientific/community meetings and
times the biobank has helped guide clinical management.

Management Milestones

June 2020 – Establish headquarters
Aug 2020 – WALCC Governance meeting
Sept 2020 – Start regular monthly stream/platform and quarterly WALCC meetings
June 2021 – MRFF/ACRF applications to expand into a national program
June each year – AGM & annual report to CRT

Data Generation Milestones

Dec 2020 – Ethics/consent forms completed, partner departments on-boarded
June 2021 – Database architecture finalised, methods validated
June 2021 – Data from first 20 patients available, incl. clinical/imaging/pathology data, WGS/single cell RNA-seq profiling
March 2021 – Database comprises 120 patients, ~8 with recurrent HCC, incl. WGS/single cell RNA-seq
Dec 2022 – Database 250 samples
Dec 2023 – Database 375 samples
Dec 2025 – Database 500 samples

Publication Milestones

Dec 2021 – Major paper describing bio-bank architecture/structure
June 2022 – Major paper identifies new drivers in recurrent HCC
Dec 2022 – Major paper using PDO screens identifies novel HCC therapy
Dec 2022 – 2nd flagship publication on mechanisms of resistance
June 2023 – 3rd flagship publication on tumour heterogeneity

Resource Sharing

The WALCC operates an inclusive model of collaboration/resource sharing. Equipment will be based on 2 campuses (Perkins/Curtin) to which all WALCC members have open access, prioritised by the Governing Board. The WALCC will enable individual researchers to conduct studies not possible as a single, or even program-leading, scientist.

Outcomes for Cancer

The West Australian Liver Cancer Collective (WALCC) will develop a world-class HCC biobank and database serving as an invaluable resource for defining the biology of advanced and recurrent disease and the identification of new biomarkers and therapeutics. Growth of the biobank will promote the essential role of tissue in the ‘work-up’ of HCC patients. Genomic studies will provide critical new data elucidating HCC biology from diagnosis to advanced disease and enable tumour type stratification. The project will define the cellular composition of HCC, identify new pathways/targets, leading to functional studies and development of new ways to abrogate the disease. Combining the genomic fingerprint with results of PDO/PDX screening studies will, for the first time, provide an opportunity to introduce precision medicine into the therapy selection for patients. This will be a fundamental milestone and it is envisaged this will lead to improved survival.

Longitudinal studies on patient-matched samples will be powerful as mechanisms of metastasis and key drivers of drug resistance are identified, inclusive of the role of the microenvironment, which has assumed great importance with the advent of immunotherapy in HCC.

In summary, the WALCC will establish a foundation of knowledge through its biobank and PDO/PDX platforms that will bring a new level of precision to our understanding of HCC biology, discover new ways to inhibit HCC growth, restore sensitivity to drugs such as sorafenib and target previously un-discovered pathways.

Summary of Program Progress to November 2021

(a) Key achievements

The Liver Cancer Collaborative CRT program made significant progress despite the challenges of COVID-19.The Liver Cancer Collaborative (LCC) was formalised with more than 45 collaborators across Perth including clinicians, research scientists, and students, and a multi-institution agreement bringing together the 8 key funding partners. Headquarters were established at the Harry Perkins Institute of Medical Research, ethics and governance for the biobank were achieved, collection of clinical samples commenced, appointments of several new program staff were made and project governance was developed. The LCC is now in a strong position to build capacity and tackle the important clinical challenges of improving poor outcomes for patients with liver cancer.

(b) Main challenges

The Cancer Research Trust awarded the grant “Defeating Primary Liver Cancer” in June 2020. At this time there was still significant uncertainty as to the trajectory and impact COVID-19 would have in Australia. Although Australia fared much better than most other countries there were several issues that directly affected this project including:

patients delayed presenting to the Hepatology Clinic at SGCH. This meant reduced opportunity to recruit patients and collect samples for the biobank.
worldwide supply chains were compromised including redirection of molecular based consumables to COVID testing, altered production focus to cope with the crisis and significant delays in transportation of products to Australia.
delays in bringing key overseas personnel into Australia due to travel bans as well as the uncertainty and lack of available flights.
significant obstacles and delays with employing staff within the universities and hospitals due predominantly to their institutional response to the pandemic.

The issues described above caused significant delays in establishing key components of the program and meeting prescribed milestones. The Cancer Research Trust granted a six-month extension to the completion of project milestones in October 2020.