Breakthrough research results give hope to pancreatic cancer patients
Olivia Newton-John Cancer Research Institute paves the way for improving treatment of pancreatic cancer
Researchers from the Olivia Newton-John Cancer Research Institute (ONJ Cancer Research Institute) / the La Trobe University School of Cancer Medicine, have discovered a novel drug target to potentially improve the treatment of pancreatic cancer.
Pancreatic cancer is one of the most aggressive and deadliest cancers with very low survival rates – only 11 per cent of patients remaining alive five years after their initial diagnosis (AIHW).
Immunotherapy is one of the most powerful treatments for cancer. It involves boosting the ability of immune cells to recognize and remove cancer cells. However, currently pancreatic cancer is almost completely unresponsive.
The results of this new study, published in the prestigious journal, Cell Reports, was led by researchers at the ONJ Cancer Research Institute/ La Trobe University. The lead author of the study, Postdoctoral Research Fellow, Dr Ashleigh Poh, explained the importance of these new findings.
“We have identified a novel drug target that can improve the response of pancreatic tumors to immunotherapy. This is important because most pancreatic cancer patients do not respond to existing anti-cancer drugs, and the survival rate of pancreatic cancer has not improved over the past few decades. We hope to eventually translate these findings into the clinic and improve survival outcomes for pancreatic cancer patients.”
The study was led by Professor Matthias Ernst, Director of the ONJ Cancer Research Institute and Head of La Trobe University School of Cancer Medicine; and included international collaborators from the University of San Francisco. It shows that inhibition of hematopoietic cell kinase (HCK), a protein found in a type of immune cell, improves the response of pancreatic cancer to immunotherapy in preclinical models. It also reduced the spread of cancer cells to other areas of the body – a processes known as metastasis.
Professor Matthias Ernst warned that it is likely to take several years before the current discovery could reach clinical applications, but that the ONJ Cancer Research Institute is uniquely placed to accelerate these findings towards future clinical trials.
“Because we work in the same building as our oncologist colleagues at Austin Health, our discoveries in the laboratory can be quickly translated into patient trials. What this also means is that observations from the clinic can be investigated by our research team – a continual cycle of learning and improvement between scientific research and patient care.”
This research study made possible with thanks to the generous funding from the National Health and Medical Research Council (NHMRC), PanKind, Pancare Foundation and Tour de Cure.
Oncogenic Transcription Laboratory
Oncogenic Transcription Laboratory
Discovery of predictive biomarkers of response of colorectal cancers to EGFR/HDAC inhibition.
Supervisors:
Prof. John M. Mariadason, Prof Niall C. Tebbutt, Dr. Fiona Chionh
We have recently discovered that combined treatment of colorectal cancer cells with an EGFR inhibitor and a histone deacetylase (HDAC) inhibitor induces robust anti-tumour activity (apoptosis, differentiation) in pre-clinical models of colorectal cancer. Based on these findings, we are about to commence a phase II clinical trial (VADER) in which patients with KRAS wild type colorectal cancer will be randomized to receive either an EGFR inhibitor (cetuximab) alone, or in combination with a histone deacetylase inhibitor (valproate).
Currently, the specific mechanism of action of this treatment remains to be fully elucidated. Furthermore, whether some patients will preferentially respond to this treatment and the mechanisms which underpin response or resistance remain to be determined. The aims of this PhD thesis therefore are the following:
Specific aims:
Aim 1: To determine the molecular mechanisms by which combined EGFR/HDAC inhibition induces differentiation and apoptosis of colorectal cancer cells.
Aim 2: To identify predictive biomarkers of response to EGFR/HDAC inhibition by analysis of tumour samples from patients enrolled in the VADER trial.
The project will provide critical insight into the mechanism of action of a potential new treatment for colorectal cancer and enable the refinement of its use by identifying biomarkers which can predict treatment benefit.
The project will provide the candidate with extensive knowledge of cancer biology, and the transcriptional and signaling pathways which drive the disease and response to drug treatment. The candidate will also gain expertise into the analysis of clinical trial samples using cutting-edge molecular profiling tools.
Tumour Progression and Heterogeneity Laboratory
Tumour Progression and Heterogeneity Laboratory
Dr Delphine Merino
Studying the interactions between malignant breast cancer cells and normal cells from the tumour microenvironment
Breast cancer is one of the most common cancers in women. While many drugs have been developed over the past decades for the treatment of the disease, once breast cancer cells have spread to distant organs, it is difficult to treat. The objective of this PhD project is to understand how normal and malignant cells interact in different organs, and how these interactions can be targeted to stop the growth of metastatic lesions.
Our previous work, and work from others, have shown that breast cancer clones have different levels of ‘fitness’ depending on the tumour microenvironment. Using innovative technologies such as imaging, single cell sequencing and cellular barcoding, our laboratory is studying the survival and proliferation of malignant cells in different tissues, to propose new effective strategies to prevent or stop the progression of the disease.
Human cancer clones will be labelled with cellular barcodes by lentiviral infection and the behaviour of the clones will be studied in different tissues and conditions. These models will be used to identify the transcriptomic profile of malignant cells that are likely to cause metastatic recurrence and identify gene pathways that are influenced by normal cells from the tumour environment. In particular, we will focus on ‘druggable’ pathways, that could be exploited in cancer therapy. These findings will be further validated using drug assays.
Rare Cancer Trial Extended Nationwide
After the success of a previous clinical trial that used immunotherapy to target rare cancers, the team at the ONJCRI are conducting a second phase II trial to offer more patients a rare treatment option and try to find a biomarker to predict which patients respond to this treatment.
A cancer is considered rare if it affects fewer than six people per year per 100,000 of the population. This may seem like a small number, but collectively, these cancers account for around 20 per cent of all cancers diagnosed in Australia and worldwide. Despite this, individuals diagnosed with rare cancers often have limited treatment options and worse outcomes than those diagnosed with more common cancer types.
“There are very few clinical trials for rare cancers. Generally, you need a large number of patients to really see the benefit of treatments,” says Associate Professor Andreas Behren, Head of the Tumour Immunology Laboratory at the ONJCRI.
The two-year trial launched in 2021, will primarily target neuroendocrine cancers, biliary tract cancers, gynaecological cancers, and MSI-H cancers. Andreas explains that this Phase II clinical trial has come after the success of a previous trial led by Principal Investigator Professor Jonathan Cebon and Clinician-Scientist Dr Oliver Klein, who challenged the difficulty of running a rare cancer trial by using immunotherapy to target a variety of cancer types.
“Jonathan and Oliver basically grouped many rare cancers together for treatment. So, it didn’t matter if someone had cancer of the genital tract or of the GI tract, if it was a rare cancer than they were included in the study,” says Andreas.
“The trial was a huge success; response rates were higher than 30 per cent, which is unheard of in many of these types of cancers. But even better than the response rate was the fact that so many of the different cancer types responded.”
The current trial aims to confirm the efficacy of nivolumab combined with ipilimumab when tested on a larger number of patients with rare cancers while adding a new unique feature - genomic testing. Under the direction of Professor David Thomas at the Garvan Institute, this testing will give patients and their clinicians valuable information about why the treatment is working in some patients and not in others and may guide future and more targeted treatment strategies.
“One of the key things we are now trying to do is find a biomarker which will allow us to predict if someone will respond to treatment in a more targeted way. In a perfect world, we would be able to use a biomarker to identify patients who will respond well to treatment via a blood test or other mechanism,” says Andreas.
Clinical Trials Manager Dr Jodie Palmer is excited by the possibilities and sees firsthand how these trials can change someone’s outcome.
“This trial will treat 240 participants from nearly every state in Australia, with a strong focus on regional sites. We are hopeful that the response rates will be higher than the first trial due to selecting more of the cancer types that responded previously, so for many of the patients this trial could be lifesaving, or at the least life extending.” She said.
Dr Oliver Klein, an immunologist and lead clinician for the trial, reiterates the impact that this trial may have for the future of rare cancers.
“It’s exciting that the MoST-CIRCUIT trial is part of a larger network that enables tumours to be sequenced so we can investigate if these tumours harbour any mutated genes. This might also allow us to use targeted agents to treat that particular mutation.” Says Oliver.
“So, you have immunotherapy that is working via the patient’s immune system, but also, if your tumour includes a mutated gene, there may be an option for dual targeting, so it is quite unique and has the potential to be game changing for patents.”
This trial is funded by the Minderoo Foundation, with tumour testing and financial support from OMICO via the MoST genomic cancer medicine program, and trial drugs provided as in-kind support by Bristol Myers Squibb.
Dame Olivia Newton-John
We are deeply saddened to learn of Dame Olivia Newton-John’s sad passing.
As our Founding Champion, Olivia was a tireless supporter of people living with cancer, and a source of great inspiration to all of us at the Olivia Newton-John Cancer Research Institute.
Her energy, kindness and commitment to improving the lives of people living with cancer provided an extraordinary and meaningful source of light, encouragement and hope to many.
“Olivia’s determination to find new and better ways to beat cancer will continue to inspire the researchers at the Institute,” said Richard Balderstone, Chair of Olivia Newton-John Cancer Research Institute.
Her advocacy for compassionate and whole-of-person cancer care, her curiosity and her unfailing commitment to supporting new discoveries in cancer treatment and patient care continues to inspire our work at the Institute.
Olivia will be remembered for her warm-hearted spirit and the enormous impact she has had on so many lives. She will remain a source of great inspiration to the entire team at the Institute in their continued commitment to conduct world-leading innovative research into new and more effective ways to treat cancer.
“Everybody at the Institute is in shock at hearing the news that Olivia Newton-John has passed today. We send our profound condolences to Olivia’s family. Olivia was focused on finding kinder and more effective treatments for cancer and we remain steadfast in continuing this important work in the memory of Olivia and everyone who has been affected by cancer,” said Professor Matthias Ernst, Director of the Olivia Newton-John Cancer Research Institute.
We are forever grateful for Olivia’s association with the Institute.
Our thoughts are with Olivia’s family and friends at this difficult time.
For media enquiries, please contact: media@onjcri.org.au.
Learning from low response rates
While we hope for all clinical trials to be successful, unfortunately this is not always the case. In many instances, using the information from unsuccessful trials is just as important.
Immunotherapy is a relatively new type of cancer treatment that enables the body’s immune system to find and destroy cancer cells. While chemotherapy works to kill cancer cells, immunotherapy uses drugs called checkpoint inhibitors to harness the body's own immune system to fight cancer.
While some cancer types respond well to immunotherapies, many cancers, including most colorectal cancers, remain resistant to current immunotherapies.
“Immunotherapies have revolutionised the way some cancers are treated. However, there are also cancers where immunotherapy just doesn’t work as well,” says Dr Amr Allam, Postdoctoral Research Fellow at the ONJCRI.
“In 2021, colorectal cancer affected over 15,000 Australians. If detected early, many patients can have positive outcomes after undergoing surgery and chemotherapy treatment. However, in 50% of patients, the cancer will progress, and devastatingly the survival rate drops to approximately 12 months when the cancer is detected at late stages. Immunotherapies provide promising results in treating some types of colorectal cancers, but most patients currently remain unresponsive to immunotherapy,” he explains.
“The immune system can detect some cancer cells easier than others. For instance, if a tumour harbours many mutations, then the immune system can detect it easier. But there are many other factors that contribute to this and that we do not understand that well,” says Dr Allam.
Dr Allam, who currently works in the Cancer and Immunity Program at the ONJCRI is using data and samples from a previous clinical trial for colon cancer to work out why this might be the case, and how we can use this information to inform future research and improve current immunotherapy approaches for this disease.
“My current work is based on a previous clinical trial. The trial was run in 2018 and used a drug called Napabucasin that attempted to improve response to an immune checkpoint inhibitor, called Nivolumab, in patients with advanced colorectal cancer. The trial unfortunately revealed a low response rate, but it did allow us to collect a large number of samples from patients before, during and at the end of the trial. I am now comparing the various immune cell types in these samples to better understand why some patients responded and many did not. This will inform us how we should aim to alter the response of a patient’s immune system so that this person then responds to immunotherapy and how we would test this in a future clinical trial,” says Dr Allam.
“A better understanding of the interplay between cancer cells and the surrounding normal and immune cells will also help us to identify biomarkers, which will enable us to predicate in the future which patients are likely to respond. Also, this can provide better approach to stratify patients, ensuring the best therapy tailored for a specific patient at an individual level.”
“Asking questions like, does the microenvironment change after treatment? Or, do we see better activity in the immune cells? Or, do we see changes in tumour structures? all help us get a better understanding of what happens between normal cells and cancer cells that collectively make up the so called tumour microenvironment. We are also using statistical analysis to understand if patients would have benefited if they could be treated in the earlier stages of their disease,” says Dr Allam.
These questions have led to Dr Allam to investigate how combining drugs that targeting the tumour microenvironment with immunotherapy treatment could improve patient outcomes.
“Using a variety of preclinical models, we are now exploring how such combination therapies can stop the progression of tumours. Our research is at very exciting exploratory stages and already shows some positive results. We have learnt that targeting a key molecule called STAT3, either genetically or pharmacologically, lowers the metastatic burden in our preclinical models. STAT3 plays an integral role in promoting “features” of cancer, namely cancer cell survival, proliferation, migration to distant organs survival, and cancer cell evasion of the immune system. This is likely to be an important finding because thus far metastatic colorectal cancer is currently very difficult to treat.” explains Dr Allam.
“There is no ‘one-size-fits all’ with cancer treatment so being able to take observations in patients back to the lab like we have in this instance is crucial to ensure progress in this area of research and eventually translated our findings from the laboratory into the clinic to provide the best possible treatment for cancer patients.”
Rare cancer models: the key to improving biliary cancer outcomes
Dr Ian Luk, a Post-Doctoral Research Fellow in the ONJCRI’s Oncogenic Transcription Laboratory has been awarded a two-year fellowship to develop mouse models of biliary cancer for drug testing.
The biliary tract is a system of organs and ducts required for the transport of bile produced by the liver, forming an important part of our digestive system. Cancer of the biliary tract is rare but aggressive, and for the most part patients diagnosed with this type of cancer respond poorly to conventional treatments.
“Biliary cancer is most common in Southeast Asian countries however, the incidence for this disease has been steadily growing in Australia and westernised countries for reasons currently unknown,” says Dr Luk.
“Biliary cancer is a particularly challenging disease to study due to its relatively low incidence and because most patients who present with biliary cancer do so in its late stages with inoperable disease, therefore limiting access to patient samples. A further limitation is the lack of genetically defined animal models where researchers can test novel drugs and drug combinations, to assess efficacy and safety in order to inform clinical trials.”
Dr Luk is hoping to change this after recently being awarded the Smith-Barrett Fellowship from Pancare Foundation. The two-year fellowship will allow Dr Luk to develop a series of genetically defined mouse models of biliary cancer mimicking human disease.
“Developing robust animal models of the disease remains our best opportunity to identify and test new treatments for biliary tumours. From these models, we are able to generate tumour organoids which can be grown, expanded and re-implanted into mice to facilitate the discovery of novel therapies and therapeutic combinations that can be translated into clinical trials, which are urgently needed to improve outcomes for patients with biliary cancer,” explains Dr Luk.
The ONJCRI group has extensive expertise in establishing mouse models. After successfully establishing tumour organoids from a series of mouse colon tumour models, they now plan to use this expertise to develop mouse biliary tumour models that will then be used by the wider research community that they hope will make a difference to patient outcomes.
“Outcomes for patients with advanced biliary cancer has only seen minimal improvement in the past 2 decades, with median survival remaining unacceptably low at only 12 months. There is an urgent need to develop new treatments for these patients and we hope that developing these models is the first step in making a significant difference in this area.”