Monepantel preclinical investigations to continue with PharmAust

PharmAust (ASX:PAA), a clinical-stage oncology company, has announced an extension of work for ONJCRI researchers to continue to investigate the mechanism of action of monepantel (MPL) upon cancer cells.

Researchers in our Cell Death and Survival Laboratory led by A/Prof Doug Fairlie and Dr Erinna Lee conducted a comprehensive RNA-Seq (RNA sequencing) screen investigating how the entire genome of cancer cells responds when treated with MPL. A select subset of genes was found to be either switched on or off by MPL in cancer cells, but not in non-cancer cells. The tested non-cancer cells’ mRNA profiles were relatively unaffected by MPL treatment.

Using state-of-the-art techniques, the team will now examine these genes in greater detail and match changes in their activity with changes in associated protein signalling pathways. These experiments are aimed at determining what happens within the cancer cell once MPL interacts with its primary molecular targets, and then exerts its downstream and definitive anti-cancer activity. Establishing MPL’s mechanism of action in this detail will enable differentiation of MPL’s effects upon cancer cells compared to other anti-cancer drugs, thus assisting with regulatory submissions and marketing moving through Phase III and IV trials.

Doug says “This is an exciting opportunity for us to move this study into its next phase and help us better understand the anticancer activity of MPL".

"This is important for the progression of the drug through the approval process so that it may eventually have real benefit for cancer patients.”

The work will be funded by PharmAust. PharmAust’s Chief Scientific Officer Dr Richard Mollard stated, “PharmAust is pleased to continue this productive relationship with ONJCRI. PharmAust is looking forward to seeing at the molecular level how MPL works in cells to combat disease, especially in terms of how MPL’s mechanism of action differs to other mTOR inhibitors presently in the clinic.”

 

About PharmAust (PAA):
PAA is a clinical-stage company developing therapeutics for both humans and animals. The company specialises in repurposing marketed drugs lowering the risks and costs of development. These efforts are supported by PAA’s subsidiary, Epichem, a highly successful contract medicinal chemistry company which generated $3.5 million in revenue in FY 2020.

PAA’s lead drug candidate is monepantel (MPL), a novel, potent and safe inhibitor of the mTOR pathway – a pathway having key influences in cancer growth and neurodegenerative diseases. MPL has been evaluated in Phase 1 clinical trials in humans and Phase 2 clinical trials in dogs. MPL treatment was well-tolerated in humans, demonstrating preliminary evidence of anticancer activity. MPL demonstrated objective anticancer activity in dogs. PAA is uniquely positioned to commercialise MPL for treatment of human and veterinary cancers as well as neurodegenerative disease as it advances a reformulated version of this drug through Phase 1 and 2 clinical trials.

 


NHMRC funding strengthens biliary cancer research focus

Biliary cancer is one of the most lethal human cancers and claims the lives of over 700 Australians each year. The prevalence of this disease is highest in parts of Asia, particularly North East Thailand, due to high rates of liver fluke infections.

Currently there are very few treatment options for these patients, which is why a team of researchers from key East Asian sites are investigating novel precision-based treatments for this disease. The team is led by Prof John Mariadason (pictured), Dr Andreas Behren and Dr Oliver Klein at the ONJCRI as the La Trobe University School of Cancer Medicine, and research colleagues Prof Temduang Limpaiboon from Khon Kaen University in Thailand and Prof Yoshimasa Saito from Keio University in Japan. These researchers have shared resources and expertise for many years including publishing a significant paper in 2019 and they have now secured funding through the NHMRC e-ASIA Joint Research Program Scheme.

The team has recently made the exciting discovery that some patients with biliary cancer respond to immunotherapy. They have also found that the biology of biliary tumours can be broken down into two main groups – the first is when the cancer cells still somewhat resemble the normal cells, and the second is when cells have transformed into an almost stem type cell. This new three-year funding will now enable the team to understand why only some patients respond to immunotherapy. The team will also conduct hypothesis-driven drug screening to precisely target the two types of biliary cancers they have identified. These studies will be strongly enhanced by the Japanese and Thai research teams who have access to a large number of patient samples and model systems called ‘organoids’, that they have been able to assemble through their location in hospitals which specialise in the care of patients with biliary cancer.

The project has three key priorities:

  1. Build local and international resources. Because biliary cancer is rare, the team will combine tumour samples from Australia, Japan and Thailand to discover trends that can inform cancer behaviour and response to treatment.
  2. Extend the use of existing cell line models and organoids. The team have already started to characterise cell lines and organoid models of this disease, which will be used to screen for new drugs to treat these cancers.
  3. Leverage findings from a successful world-first clinical trial of rare cancers to refine the use of immunotherapy to treat biliary cancer. The team will use findings from the clinical trial led by ONJCRI’s Dr Oliver Klein, Prof Jonathan Cebon and Dr Andreas Behren to see if there is a common thread that can be used to identify patients likely to benefit from immunotherapy that transcends race and ethnicity.

The NHMRC funding will also allow the collaboration and exchange of personnel and technologies across the three sites once COVID-19 restrictions are lifted.


Highly Cited Researcher recognition for Wei

Prof Wei Shi, Head of our Bioinformatics and Genomics Laboratory and representing the La Trobe University School of Cancer Medicine has been included on the global Web of Science Highly Cited Researchers List for 2020.

This list recognises the most influential researchers globally. It includes the top 0.1% of the most cited researchers in the world, across 22 fields. Wei was also awarded a place on this list in 2018.

Wei said, ‘I am humbled to receive this award and recognition, but this is not just about me - this is about team work. Together, we have published impactful research and we are glad to know that this is being used to help further progress science and discoveries.

Congratulations Wei, on this outstanding achievement.


INSIDER - Reflections during Breast Cancer Awareness Month

INSIDER is a new series that aims to highlight exciting developments from the world of cancer research and clinical trials. These posts are written by our research laboratory heads and the opinions expressed in these posts are those of the contributing author.

By Prof Robin Anderson, Head of the Translational Breast Cancer Program and Metastasis Research Laboratory

October is Breast Cancer Awareness month.  As we reflect on the unexpected events of 2020 that have forced us to make drastic, but hopefully temporary changes in lifestyle, it is a good time to reflect on the remarkable progress made over the past 30 years in the treatment of breast cancer, thanks to medical research.

The current five-year survival rate in Australia, based on data from 2012 to 2016, is 91% for women and 85% for men.

These five-year survival rates have increased from the 1987-1991 period when they were 75% for women and 76% for men. The increase in survival has been more dramatic for women, assisted by the increasing public awareness of symptoms, free mammography since 1994 and, importantly, medical research.  Breast cancer is a rare disease in men and is likely to be diagnosed at a more advanced stage.

These dramatic increases in survival rates are the result of many years of research in cancer institutes around the world, gaining new knowledge about the basic biology of breast cancer and seeking more effective therapies.  Breast cancer treatment varies depending on the type of cancer that develops.  The most common type of breast cancer typically responds well to endocrine therapy as the cancer needs the hormone estrogen to keep growing.  If deprived of estrogen, the cancer dies.  Endocrine therapy has been the mainstay of this type of breast cancer for the past three decades and results in close to 100% survival after 5 years. However, a few of these cancers can recur after many years and are more challenging to treat.  Medical researchers have now discovered new cell cycle inhibitors (specifically inhibiting CDKs 4 and 6) that dramatically prolong progression free survival when used in combination with endocrine agents.

Another type of breast cancer is called HER2 amplified breast cancer, so called because it is driven by a gene called Her2.  In the early 1990’s, patients with this type of cancer had a life expectancy of only 3-5 years.  The discovery of an antibody that specifically blocks Her2 function by medical researcher and medical oncologist Dennis Slamon revolutionised the treatment and now nearly all Her2 positive patients survive beyond 5 years.

The third major subtype, the so called triple negative breast cancer, is the most challenging type to treat and is the focus of researchers at the ONJCRI.  These patients are treated with standard chemotherapy to which most respond well, but it is not uncommon for the cancer to return.  There is very active research at ONJCRI and at many other cancer research institutes around the world seeking better therapies for this type of breast cancer.  Many new experimental treatments are emerging, but will need to be tested in clinical trials to see if they really can improve the outcome of triple negative breast cancer patients.


INSIDER – Using CRISPR to inactivate genes in tumour cells

INSIDER is a new series that aims to highlight exciting developments from the world of cancer research and clinical trials. These posts are written by our research laboratory heads and the opinions expressed in these posts are those of the contributing author.

By Prof Matthias Ernst, ONJCRI Director and Head of the Cancer and Inflammation Laboratory

Immunotherapy has without a doubt provided a quantum leap to the treatment of cancer not seen since the introduction of chemotherapy in the 1960’s. Our understanding on how we can re-engage a patient’s immune system to kill cancer cells is continuously being refined, since the ground-breaking work by the 2018 Nobel laureates Tasuku Honjo and James Allison and the many seminal contributions of immunologists, molecular biologists and oncologists before and after them. However, we still need to go a long way before we can deploy the exquisite power and specificity of the immune system to control a majority of cancer.

A recent study published in Nature by a team at the University of Toronto suggests that there is a potentially dazzling number of genes in cancer cells that enable them to evade being killed by the soldiers of the immune system, so called cytotoxic T lymphocytes (CTL). The team around Jason Moffat used a Nobel Prize awarded genome editing technique called CRISPR to inactivate each gene in tumour cells derived from genetically diverse models of breast, colon, kidney, and skin cancer to ask which gene prevents the killing of cancer cells when put together in a culture dish with CTLs.

When looking across all tumour models, the researchers identified nearly 200 genes, whose deletion altered the sensitivity or the resistance of cancer cells to CTL-mediated killing.

The team was able to validate their experimental approach because they identified genes already known to be mutated in patients who stopped responding to immunotherapy, confirming that their experimental approach worked. However, most surprisingly many of the genes they found were never before linked to evasion of cancer cell detection and killing by CTL such as cancer cell autophagy, a conserved pathway activated by distressed cells. Indeed, induction of autophagy in cancer cells made them resistant to cell CTL killing induced by the cytokines IFNγ and TNF.

The findings of this paper powerfully illustrate how the combination of large-scale screening efforts, together with already existing extensive cancer genome information, allows us to identify a plethora of potential new targets to further improve immunotherapy. The challenge will be to filter through the many candidates targets to strategically invest in those that are ultimately providing the broadest benefit to cancer patients.

Source:  NATURE, Vol 586, pages120–126 (2020); KA Lawson et al Functional genomic landscape of cancer-intrinsic evasion of killing by T cells"


Discovering new bait for the immune system may lead to additional treatments for melanoma

A collaborative study, led by ONJCRI and the Monash Biomedicine Discovery Institute (BDI) at Monash University, has uncovered new markers (HLA-associated peptides) that are uniquely present on melanoma tumours and could pave the way for therapeutic vaccines to be developed in the fight against melanoma.

Despite all improvements in melanoma treatment, every five hours one Australian dies because of the lack of effective treatment. A promising new approach harnesses the body’s own immune system to detect and kill tumour cells, through recognition of small tumour specific protein fragments (peptides) that decorate the surface of the tumour cells. The study, published in Cancer Immunology Research, a journal of the American Association for Cancer Research, has successfully identified thousands of peptides uniquely present on melanoma tumours that can be recognised by the immune system.

These observations have had an immediate clinical application, with the first clinical study on vaccination of melanoma patients using spliced peptides underway with collaborators at the Parker Institute for Cancer Immunotherapy, USA.

The study was co-led by ONJCRI's Dr Katherine Woods and Dr Andreas Behren (pictured) and BDI's Dr Pouya Faridi, Professor Anthony Purcell and Associate Professor Ralf Schittenhelm.

“We considered how a melanoma tumour might ‘look’ to the human immune system, under different growth conditions. The sheer scope of melanoma peptides that we identified in this study, many of which have never been reported before, was both surprising and inspiring,” said Dr Woods.

Findings have shown that some of these melanoma peptide markers are generated from a process called splicing. In splicing, a protein is first cut into small pieces (peptides) and then two of these pieces are pasted together to make a "spliced peptide". By identifying the exact spliced peptides, they can be synthesised outside of the body, then administered to patients to trigger the immune system into recognising and targeting tumours.

“The general goal of our study was to find new targets for melanoma treatment. We were unaware of the existence, prevalence and importance of these unique spliced peptides or if they could be recognised by the immune system. Now that we know they can, these peptides can be used as bait for the immune system to take action,” Dr Faridi said.

Dr Andreas Behren, Head of ONJCRI's Tumour Immunology Laboratory said: “Our finding, that we can successfully identify spliced melanoma peptides that are immunogenic across different patients, is very exciting.”

Professor Purcell notes: “Based on these studies, spliced peptide antigens have moved from an immunological curiosity to a whole new class of actionable targets not just in melanoma but other cancers as well. Using Dr Faridi’s new workflow we have been able to shine a spotlight on this previously ignored class of peptides opening up a previously untapped resource for immunotherapy and cancer vaccination. Indeed, the ubiquitous nature of this splicing process point towards this class of antigens playing roles in infectious disease, autoimmunity and allergy.

Read the paper in Cancer Immunology Research, a journal of the American Association for Cancer Research (DOI: 10.1158/2326-6066.CIR-19-0894)

Find out more about the Monash Biomedicine Discovery Institute

 


An easier way to analyse genes uncovered

Understanding the genetic make-up of cells, through a process known as RNA-sequencing, is an incredibly important process that allows researchers to better understand how cells work, grow and react with other cells. When analysing cancer cells, this research can help to identify where cancer starts, understand which treatments may be most effective for particular cells, or determining potential for cancer reoccurrence.

Currently, a process known as ‘Read Trimming’ is undertaken when analysing and mapping gene data through RNA-sequencing. In effect, this trimming removes adapter sequences and low-sequencing-quality bases (or in layman’s terms, some of the outliers of a data set) so that the analysis is focused on a more concentrated collection of gene data. While effective, this trimming does add significant data analysis time to each study and it is also unknown if the removal of the trimmed data impacts on the overall analysis or subsequent results of the remaining data set.

A study led by Prof Wei Shi, Head of our Bioinformatics and Cancer Genomics Laboratory, and Bioinformatician Dr Yang Liao, recently published in NAR Genomics and Bioinformatics Oxford Academic, has found that the read trimming process is not required for effective genome analysis. In fact, Wei and Yang found that by not undertaking read trimming (or only undertaking a ‘soft-clipping’), researchers can effectively analyse complete data sets faster, perform detailed analysis using less computational technology, while importantly providing equivalent or better data accuracy.

Wei said, “We found that adapter sequences can be effectively removed by a read aligner we developed via ’soft-clipping’ and that many low-sequencing-quality bases, which would be removed by read trimming tools, were rescued by the aligner”.

“Being able to conduct this analysis faster means that we also have access to results faster which is incredibly important when looking at scenarios for personalised medicine. Because doctors and their patients need to be able to access results as quickly as possible”, said Wei.

So, what does this mean for the future of RNA-sequencing?

“By sharing these findings, we hope that this will generate significant change to the way RNA-sequencing is performed by us and other researchers”, said Wei.

“We also hope that this will improve our ability to understand the properties and behaviours of different cells which can lead to more in-depth research and analysis of many cells, including cancer cells”.

 

Acknowledgments

This study has been possible thanks to the support of: Australian National Health and Medical Research Council, Walter and Eliza Hall Institute Centenary Fellowship sponsored by CSL, Victorian State Government Operational Infrastructure Support.

Wei and Yang also sincerely thank Prof Gordon K Smyth for suggesting this study.

 

Publication details

NAR Genomics and Bioinformatics - Oxford Academic: https://doi.org/10.1093/nargab/lqaa068

 

Image credit: Flavio Takemoto from FreeImages


Rare cancers clinical trial findings to have global benefit for patients

A phase II clinical trial led by the Olivia Newton-John Cancer Research Institute (ONJCRI), is showing exciting results for patients with rareupper gastrointestinal, neuroendocrine and gynaecological cancers.

The results of the rare upper gastrointestinal cancer cohort, that predominately enrolled patients who have biliary tract cancers like Anna pictured (and story below), have been published in JAMA Oncology. While results for trial participants with advanced neuroendocrine tumours were recently published in Clinical Cancer Research and the results for trial participants withadvanced gynaecological tumours were presented at the American Society of Clinical Oncology Annual Meeting - ASCO20 Virtual Scientific Program in May 2020.

The findings from this trial, which was generously supported by a grant from Bristol-Myers Squibb Ltd and Australian Government Medical Research Futures Fund, and championed by project partners Rare Cancers Australia, will have significant global implications for the treatment of patients with rare upper gastrointestinal, neuroendocrine and gynaecological cancers.

The current data demonstrates that trial participants who were treated with a combination of immune-stimulating anti-cancer drugs (Ipilimumab and Nivolumab)showed significant clinical benefit and life changing results.

Dr Oliver Klein, clinical trial co-lead, ONJCRI Clinician Fellow and Oncologist at Austin Health said, “These are promising results, in particular given that patients with rare cancers have limited treatment options compared to more common cancers”.

“Responses to immunotherapy were, as already seen in other malignancies, durable which contrasts with the generally short-lived responses obtained with chemotherapy”.

In this trial, ONJCRI, as the La Trobe University School of Cancer Medicine, investigated the use of the drugs Ipilimumab and Nivolumab as a combination immunotherapy which has so far not been trialled in patients with rare cancers. This combination treatment has already been shown to be an effective treatment for patients with metastatic melanoma, renal cell carcinoma, microsatellite unstable colorectal cancer and non-small cell lung cancer.

Globally, 20% of all cancer diagnoses, are for rare cancers. These patients currently have very limited access to treatment options and, as a result, have significantly reduced overall survival rate compared to patients with more common cancers.

Prof Jonathan Cebon, trial co-lead, Head, ONJCRI Cancer Immunobiology Cancer Program and Oncologist at Austin Health said, “This is an exciting day for people with rareupper gastrointestinal, neuroendocrine and gynaecological cancers”.

“As key players in the Australian cancer research community, we are very proud to be able to make this contribution in providing hope to patients with otherwise untreatable cancers.”

“This important trial is supported by our trial partners and generous Australians who donate to our research at ONJCRI,” said Prof Cebon.

The trial enrolment closed early in 2020 with trial participants currently in follow up. Ongoing translational research on tumour tissue and blood samples is aimed at identifying biomarkers to predict treatment response.

ONJCRI and the trial partners are also actively seeking additional opportunities and funding to expand the trial to more patients with rare cancers in rural and regional Australia.

 

ANNA’S STORY

Anna Anderson is grateful to be alive. When she was diagnosed with stage four gallbladder cancer her surgeon told her she had just months to live.

That was in October 2017.

The cancer was rare and aggressive and had metastasised to her liver.  With the outlook bleak, the mother-of-three was encouraged to get her affairs in order.

In January 2018 she joined the immunotherapy trial led by the Olivia Newton-John Cancer Research Institute, almost immediately things started to improve. Following less than a year on the trial, scans revealed Anna’s tumours had reduced to five per cent of their original size.

“The doctors are calling it a miracle,” she said. “I wouldn’t be here if not for the clinical trial”.

“I am incredibly grateful to the ONJCRI Team for the life changing work that they do. I hope that trial’s such as this will make it possible for others to benefit from the most up to date treatments modern medicine has to offer.”

 

Publication details

JAMA Oncology: https://jamanetwork.com/journals/jamaoncology/article-abstract/2768631

Clinical Cancer Research: https://clincancerres.aacrjournals.org/content/early/2020/06/12/1078-0432.CCR-20-0621

American Society of Clinical Oncology Annual Meeting - ASCO20 Virtual Scientific Program: https://meetinglibrary.asco.org/record/187511/abstract


Philanthropic funding to boost research into targeted therapies for colon cancer

Head of the Olivia Newton John Cancer Research Institute’s (ONJCRI) Cancer Therapeutics Development Group, Dr Ashwini Chand, along with ONJCRI Director and Head of the Cancer and Inflammation Program, Prof Matthias Ernst, have been awarded a coveted philanthropic grant to investigate new targeted therapies for colon cancer.

As successful applicants of the competitive Perpetual 2020 IMPACT grant program, Ashwini and Prof Ernst are set to further their translational research from the bench to the bedside.

Formed in 2018, the Cancer Therapeutics Development Group’s focus has been to discover pre-clinical drugs that are developed into new cancer treatments. By understanding how inflammatory cytokines contribute to the progression of colon cancers, we can find new ways of approaching the development of pre-clinical drugs that inhibit cancer growth and make the body’s immune cells more effective in killing cancer cells.

Through the generous support of the WALTER & NANCY LASCELLES MEMORIAL TRUST, The J and R McGauran Trust Fund, and the Perpetual Foundation - Eddy Dunn Endowment, the Cancer Therapeutics Development Group will be able to establish new cell-based technologies to further drug discovery efforts at ONJCRI. The funds will also enable the purchase of equipment that supports assay development and laboratory workflows. This will greatly enhance its capacity to progress our drug development programs.

“As a scientist, the ONJCRI provides a dynamic environment where I am able to translate my research discoveries into outcomes that will ultimately influence the health of patients,” says Ashwini.

“Bowel cancer is the second-most common cancer in men and women in Australia. With this generous funding, our research teams will be able to engage in further important colon cancer research specifically to develop targeted therapies for patients.”

Says Ashwini, “With the generous support of the Perpetual IMPACT scheme we will obtain a specific piece of equipment that allows us to making discoveries that will contribute to more efficient emergence of breakthrough cancer treatments. This generous funding will help us go much further.”

ONJCRI Director, Prof Ernst, says, “ONJCRI has enjoyed the generous and repeated support through the Perpetual IMPACT scheme, which is critical to the Institute’s mission to translate our discoveries at the laboratory bench into treatment that makes a difference to cancer patients.

“This support therefore not only provides us with opportunities to purchase new equipment and conduct critical experiments that we otherwise could not do, but it also gives the Institute and my colleagues a way to communicate with donors and those in philanthropy precisely what ONJCRI is continuing to do to help outsmart cancer.”

ONJCRI would like to thank the WALTER & NANCY LASCELLES MEMORIAL TRUST, The J and R McGauran Trust Fund, and the Perpetual Foundation - Eddy Dunn Endowment for their incredible support.