Studies supported by the APGI BioResource
Fostering Worldwide Collaboration for Precision Research
The Avner APGI BioResource is one of the largest resources of pancreatic cancer research biomaterials in the world and available to the scientific community. The list below identify recent projects we have supported.
Repurposing itraconazole to treat molecular subtypes of pancreatic cancer
This team has demonstrated that a therapeutic strategy involving itraconazole and current standard-of-care chemotherapy Gemcitabine/Abraxane is very effective in pancreatic tumours. This project will investigate what proportion of patients characterised by these markers may potentially benefit from this new combination treatment strategy.
Expression of novel PET targets in precursors of pancreatic cancer: Implications for early diagnosis
Even in those who undergo regular testing for pancreatic cancer, this terrible disease is usually incurable by the time it is discovered. PET imaging is an exciting and rapidly progressing area of medicine where small deposits of cancer may be detected early. This type of imaging relies on injecting a “tracer” into the blood stream which targets the cancer tissue. To use this technology to diagnose pancreatic cancer early, the tracers that target the disease in its earliest stages must be figured out. This project will use a large array of samples of pre-cancerous and cancerous pancreatic lesions to determine the targetability of two promising new PET tracers. This will guide extremely important research into how PET scans might be used to diagnose early pancreatic cancer, particularly in high-risk individuals undergoing regular testing.
Molecular profiling to detect early-steps of pancreatic carcinogenesis to improve prognosis and clinical outcome of IPMN patients
Pancreatic ductal adenocarcinoma is a lethal cancer disease, develops predominantly through distinct precursor lesions, pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). While progression of PanIN into invasive cancer has been well characterised, there is an urgent need to understand the biology of IPMNs. IPMNs present a unique clinical challenge, as they are very frequent and incidentally found in about 13% of subjects who undergo routine abdominal imaging studies. This study will identify and validate biomarkers responsible for degeneration of IPMN and the early metastatic dissemination of IPMN-derived pancreatic ductal adenocarcinoma in order to stratify IPMN patients to different therapeutic interventions.
Detection of circulating tumour cells in pancreatic cancer
Pancreatic cancer is a deadly disease. While early surgery is the only potentially curative treatment option, most pancreatic cancers will have already spread by the bloodstream because they can shed these cells called ‘circulating tumour cells’ (CTCs). This team will study patient blood to detect and analyse these CTCs using unique technology which could revolutionise pancreatic cancer management by identifying patient-specific therapies to prevent relapse.
Targeting epigenomic regulators in pancreatic cancer
Pancreatic adenocarcinoma remains a therapeutic challenge, making the identification of new targets and development of novel treatment strategies for this disease of paramount importance. This team’s long-term goal is to advance context-dependent models for the improved use of epigenomic inhibitors in this disease. This project studies the role of epigenomic regulators at the replication fork to tolerate the rapid division of cancer cells causing replication stress and the utility of their inhibition in tumors with high versus low levels of replication stress.
Development of novel tretment strategies to overcome chemo-resistance in pancreatic cancer
Pancreatic cancer has the lowest survival rate (~9.8%) of all major cancers. Poor response to chemotherapy is a major clinical problem for pancreatic cancer patients. Pancreatic cancer patients with chemotherapy-resistant tumours currently do not have other targeted therapies available to them. The project team has analysed pancreatic tumour tissue to identify key pathways which can be targeted to overcome chemotherapy-resistance in patients. This project aims to perform comprehensive pre-clinical evaluation to determine if inhibition of these pathways could overcome chemotherapy resistance in pancreatic cancer patients.
Targeting cell death pathways in pancreatic cancer
All cells possess the ability to kill themselves by a process called “apoptosis”. When this becomes defective, cancer can arise and make tumours highly resistant to treatment. Proteins of the “BCL-2” protein family are often produced at very high levels in cancer cells, leading to defective apoptosis. A new class of drugs has now been developed to specifically target these proteins, and one of these has shown promising results in the clinic. As pancreatic cancer cells are renowned for their resistance to treatment, cell lines will be tested against a suite of these drugs. This study will identify critical “survival factors” in pancreatic cancer and potentially new and more effective treatment options for pancreatic cancer patients.
Assessing the prognostic/predictive value of Tpm3.1 expression in Human Pancreatic Cancer Cells and Cancer-Associated Pancreatic Stellate Cells
The mechanical properties of tumours are a potential target for the development of new therapeutic strategies. This is particularly true in the case of pancreatic cancer. This group has identified a regulator of these mechanical properties that is found to be enriched in all cancer cells and have developed chemicals that target this regulator. The regulator will be evaluated to see if it is present in elevated levels in pancreatic tumours.
A novel theranostic for pancreatic cancer
The project lays the groundwork to develop new radio-labelled antibodies for improved imaging and treatment of pancreatic cancer. Using disease-relevant patient-derived cells grown as tumours in mice, and state-of-the-art imaging equipment, the project will evaluate the effectiveness of the radio-labelled antibodies for tumour staging, response to therapy, and treatment of pancreatic cancer.
Uncovering the broad clinical utility of Toll-like receptors in pancreatic cancer
This project aims to demonstrate that overactivation of key regulators of the body’s immune system, called Toll-like receptors (TLRs), play a critical role in promoting both the growth of pancreatic tumors, and the resistance of tumors to chemotherapy drugs. The identification of TLRs as novel biomarkers to predict patient survival outcomes and the response of patient tumors to chemotherapy drugs, as well as drug targets for future evaluation in clinical studies on pancreatic cancer patients, is primed to deliver high translational impact through its broad clinical utility.
Patient relapse is a common event in most stand-of-care chemotherapy for pancreatic cancer. Treatment resistance is partially driven by a tumour scarring response (fibrosis), which restricts chemotherapy from entering the tumour, and also enhances tumour growth and spread around the body (metastasis). To mitigate resistance, therapeutics that disrupt this tumour fibrosis should increase chemotherapy efficacy. Tumour fibrosis is primarily composed of collagen I, which fundamentally requires the Lysyl Oxidase (LOX) family of enzymes. A novel LOX inhibitor has been developed which has shown significant promise in improving chemotherapy and survival in the pre-clinical models.
Using single-cell genomics, a unique mutational pattern has been identified that is characterised by an abundance of short interstitial deletions. The working hypothesis is that those deletions are generated via a mechanism involving replicative stress. This unique mutational pattern may predispose cancers to DNA replication check point inhibitors.
This project focuses on the mapping and targeting the extracellular matrix (the surrounding areas of the tumour) in pancreatic cancer. A cancer cell’s surroundings significantly impact on disease progression. Our team has devised a new way to dissolve cells from tumours, leaving behind the delicate 3D-architecture of the matrix to allow us to study and tap into the vast and currently unexplored reservoir of anti-cancer matrix targets in this disease.
This group has shown that a therapeutic strategy involving both SRC and JAK inhibitors is very effective in pancreatic tumours characterised by high expression of phospho-STAT3 and mutations in P53. This project investigates further what proportion of patients characterised by these markers may potentially benefit from this new treatment strategy.
The Australasian Gastro-Intestinal Trials group conducted a phase II clinical trial, “Gemcitabine and Abraxane for resectable pancreatic cancer” (GAP), for patients with pancreatic cancer. Resected tumour and blood samples were collected along with clinical data. The overall aim of this trial was to determine if preoperative chemotherapy had the potential to improve surgical and long-term outcomes. 42 patients were enrolled through the GAP trial. We have assessed patients for the RNA expression of some specific markers of immune cells using the Nanostring platform. Immunohistochemistry (IHC) has also been performed and these markers need to be confirmed in a bigger cohort of patients available through the APGI.
This project proposes a novel drug combination for pancreatic cancer which will target not only cancer cells, but also specific cells in the tissue surrounding cancer cells, which help cancer growth. The proposed two-pronged strategy has high potential to significantly improve the outcome of patients with pancreatic cancer.
Mucinous ovarian cancer is a rare type of ovarian cancer. Making a diagnosis of mucinous ovarian cancer is especially challenging, particularly when the cancer has spread, with uncertainty about whether it started in the ovary or in the pancreas, colon, appendix or elsewhere. A large study to combine mucinous ovarian cancers with primary tumours from the pancreas and other sites is needed to understand the cellular and genetic characteristics of mucinous cancers. This project will examine their genetic profiles to better characterise these cancers with the ultimate goal of uncovering new treatment targets, and designing clinical trials that guide treatment options.
We have identified a protein that, when inhibited, can reduce pancreatic cancer cell and cancer-promoting pancreatic stellate cell survival and increase the effectiveness of existing cancer drugs. This project will assess whether this protein is also a potential prognostic/predictive factor for pancreatic cancer. The findings from this project can potentially be applied to personalise medicine for pancreatic cancer patients.
Immunotherapy has been found to be very effective in certain type of tumours; however, this is not the case for pancreatic cancer which is very resistant to it. The aim of this project is to understand why this happens and to find a way to increase the efficacy of immunotherapy in pancreatic cancer. To this purpose, we investigated the role of exosomes in pancreatic cancer. Exosomes are small bubbles released by cells, in particular tumour cells, containing messages that regulate the behaviour of surrounding cells. The most significant result that has been found is the presence of a lipid and a cytokine in large amounts in pancreatic cancer exosomes compared to normal ones. Both can affect anticancer immune response. Therefore, understanding the role of these molecules carried by exosomes could be crucial to improve immunotherapy successfulness in pancreatic cancer.
Epithelial-mesenchymal transition (EMT) is an important biological process in development, wound healing, formation of stem cells and cancer progression. Using high-throughput technologies, we have investigated the role of novel biomolecules that drive EMT in pancreatic cancer. This study revealed novel biomolecule vital for EMT and has the potential to provide significant insights into the tremendous plasticity of differentiated epithelial cells. Although this knowledge has the potential to redefine our understanding of cell state, function and polarity, the clinical relevance can only be established through systematic analysis of EMT candidates in patient cohorts. Tissue microarrays from APGI will be used to assess the expression of novel markers of EMT along with diagnostic and prognostic value.
Previously supported studies