Studies supported by the APGI BioResource
Fostering Worldwide Collaboration for Precision Research
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.
Targeting the Lysyl Oxidases in Pancreatic Ductal Adenocarcinoma
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.
Identifying precision therapeutics for pancreatic cancer based on a novel genomic signature
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.
Seeing is believing
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.
Targeting the SRC/JAK/STAT3 signalling pathway: A novel and promising therapeutic strategy for pancreatic cancer
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.
Tissue biomarker in pancreatic cancer: Translation research sub-study from the GAP clinical trial
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.
Pathway to a novel treatment for pancreatic cancer- targeting the microenvironment (stroma)
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.
Unravelling mucinous tumours of the ovary and intestinal tract: diagnosis, classification and molecular profiling
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.
Starvation of pancreatic tumours by metabolically reprogramming both tumour and stromal cells
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.
Role of exosomes in immune response in pancreatic cancer
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 mesenchyman transition 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