New collaboration focuses on cancer prevention, diagnosis and therapy

A new collaborative research program developed by the Research Centre for Molecular Cancer Prevention at La Trobe, in partnership with the Cancer Biology Research Center (CBRC) at Tel Aviv University and ONJCRI, as the La Trobe School of Cancer Medicine; has seen the development of three new cancer research projects, funded through a new international collaboration. The projects focus on cancer prevention, diagnosis and therapy.

The collaboration between the three institutions developed from a workshop in which scientists from the institutions identified areas where complementary research could drive significant breakthroughs in cancer prevention, diagnosis and therapy.

The innovative research projects address issues that impact the lives of cancer patients in Australia, Israel and the rest of the world. The projects are:

Investigating the role of p53 in metastatic organotropism of breast cancer using optical barcoding

This project will investigate new molecular markers for breast cancer to help predict the risk of brain metastasis and provide new avenues for breast cancer therapy

  • Dr Delphine Merino, Olivia Newton-John Cancer Research Institute Adjunct, School of Cancer Medicine at La Trobe University
  • Dr Uri Ben-David, Sackler Faculty of Medicine Tel-Aviv University. 

A new strategy of targeting c-MYC for treating familial adenomatous polyposis (FAP)

This project will test a combination of two clinically-approved drugs as a new cancer prevention strategy for families with higher genetic risk of colon cancer.

Reprogramming the tumour microenvironment of glioblastoma to improve response to chemotherapy

This project will develop a new combination therapy for glioblastoma that uses a novel drug that alters immune function in the tissue surrounding the tumour to make it more responsive to chemotherapy.

 

La Trobe Deputy Vice-Chancellor (Research and Industry Engagement) Prof Susan Dodds said the research will resonate with the health sector as well as those who are facing cancer.

“La Trobe researchers are focused on improving lives and health outcomes of people around the world. This collaboration enables our experts to work with other researchers to advance their understanding and develop treatments and therapies for cancer. The three projects which have been chosen will have a positive impact on the many individuals and families who are affected by cancer.”

Prof Dan Peer, Vice President for Research and Development at Tel Aviv University is pleased at the new partnership.

“Tel Aviv University has a long-standing commitment for identifying novel biomarkers, improve cancer diagnostics and generate novel therapeutic modalities to treat cancer. It is a pleasure to strengthen our relationship with La Trobe University and the Olivia Newton-John Cancer Research Institute in Melbourne.”

Prof Matthias Ernst, ONJCRI Director agreed.

“Funding initiatives like this one provide a fantastic opportunities for our brightest scientists across two continents to bring together their talents to address issues which ultimately impact on how we can treat cancer patients better.”

Ron Gerstenfeld, Deputy Chief of Mission at the Embassy of Israel, Canberra, said, “The Embassy is delighted to take part in this significant initiative, bringing together exceptional scientists from both Australia and Israel and promoting new avenues for cancer research. Collaborations like this are only one example of the great potential of cooperation between our countries and the important contributions they have not only on a local, but also a global scale.”


MRFF funding awarded to researchers

La Trobe University and ONJCRI researchers (as the La Trobe School of Cancer Medicine) will advance knowledge of transplant cure rates for Hodgkin Lymphoma, therapy for thyroid cancer, and other fields, thanks to $5.97 million awarded to La Trobe in the latest round of the Medical Research Future Fund (MRFF). The MRFF funding scheme aims to transform health and medical research and innovation to improve lives, build the economy and contribute to health system sustainability.

La Trobe University Deputy Vice-Chancellor (Research and Industry Engagement) Prof Susan Dodds is thrilled with La Trobe’s success.

“La Trobe researchers are focused on improving lives and health outcomes of people around the world. This funding enables our researchers together with clinical partners to advance their understanding and develop treatments and therapies for diseases like cancer, which affect so many individuals and families,” Prof Dodds said.

“I am particularly pleased that three of the successful projects are from the Olivia Newton-John Cancer Research Institute which is La Trobe University's School of Cancer Medicine. This School is located in the Olivia Newton-John Cancer Centre, a comprehensive cancer centre at Austin Health. This important partnership between institutions is focused on discovering and developing breakthrough cancer therapies to provide the best health outcomes for patients. It is great that their important work has been recognised with this funding.”

Prof Matthias Ernst, Head of the La Trobe University School of Cancer Medicine, agreed.

“The three ONJCRI MRFF funded projects will enable us to perform the cutting edge translational research that will make a real difference to treatment outcomes for cancer patients and allow our laboratory scientist to understand the underlying molecular mechanisms on which we can build our next discoveries,” Prof Ernst said.

About the research projects

I-124 PET Directed Redifferentiation Therapy for Radioiodine Refractory Thyroid Cancer - the I-FIRST Study

Led by: Prof Andrew Scott AM

For patients with advanced thyroid cancer, tumours that no longer trap radioiodine have an extremely poor prognosis and more effective treatments are urgently required. This study will examine whether redifferentiation therapy is able to resensitize tumours to radioiodine treatment and improve patient survival and quality of life.

 

Employing rational novel agent combination therapy to improve transplant cure rates for relapsed/refractory Hodgkin Lymphoma

Led by: A/Prof Eliza Hawkes

Hodgkin Lymphoma (HL) is a rare malignancy, with 500 new cases annually in young Australians. While 70 per cent of patients are cured with front line treatment, 30 per cent of patients require second line therapy which often fails resulting in death. Immunotherapy and targeted therapies have dramatically improved survival in haematological malignancies. This study will combine two agents currently approved in recurrent HL to maximise survival of these young Australians.

 

Repurposing valproate for the treatment of colorectal cancer

Led by: Prof Niall Tebbutt

Colorectal cancer is a major cause of cancer related deaths for which there is an urgent need to develop new treatments. The drug valproate has been used to treat epilepsy and mood disorders for over 50 years. We have found that valproate can profoundly increase the anti-tumour activity of a class of drugs known as EGFR inhibitors in laboratory models of colon cancer. We will now test the activity of this drug combination in a phase II clinical trial in patients with advanced colon cancer.

 

Congratulations also to Prof Della Forster, from the La Trobe University School of Nursing and Midwiferywhose project will focus on the ‘Impact of midwife-led group antenatal care and education on caesarean section’.


Bioinformatics in cancer research and therapy symposium - 10 June 2021

Registrations and abstract submissions are now open for our one day symposium focusing on the development and application of bioinformatics methods in cancer research.

About this event

The Bioinformatics in Cancer Research and Therapy Symposium is a virtual, one day research event that will be hosted by our Bioinformatics and Cancer Genomics Laboratory on 10 June 2021. The main focus of the symposium is on the development and application of bioinformatics methods in various areas of cancer research.

Invited speakers

Call for abstracts now open 

Presenters are invited to submit abstracts for their oral and e-poster presentations in any of the following themes:

Symposium themes

  1. Bioinformatics and cancer genomics - Bioinformatics methodology development for analysing cancer genomics data or biological discoveries made from the analysis of such data.
  2. Bioinformatics in cancer therapy - Successful application of bioinformatics, such as genome-wide expression and mutation profiling, in the development of novel cancer therapies such as immunotherapy.
  3. Single-cell genomics - Bioinformatics methodology development for analysing single-cell genomics data and the application of single-cell genomics in cancer studies.
  4. Machine learning and AI in cancer - The use of machine learning and artificial intelligence algorithms in cancer diagnosis and treatment.

Submission guidelines

  • All abstracts should be submitted via email to bioinf@onjcri.org.au
  • A word limit of 250 words applies for all abstracts
  • Abstracts/interest to present should be submitted by 10 April 2021
  • Authors should indicate if their abstract should be considered for either oral presentation, e-poster presentation or both
  • Indicate if the presenting author is a student

Key dates

  • Abstract submissions: 10 March 2021
  • Abstract submissions close: 10 April 2021
  • Notification of abstract acceptance: TBA
  • Symposium attendance registrations open: 10 March 2021 - book now
  • Symposium attendance registrations close: 9 June 2021
  • Symposium: 10 June 2021

Launch of The Lancet Oncology Commission on Medical Imaging and Nuclear Medicine

ONJCRI's Prof Andrew Scott, AM, Head of our Tumour Targeting Program and Director of the Austin Health Department of Molecular Imaging and Therapy, is part of a global team working to better understand the inequitable access to imaging and nuclear medicine resources across the world. The following article highlights the announcement of this work.

Vienna, Austria: The Lancet Oncology Commission on Medical Imaging and Nuclear Medicine, launched on 4 March 2021 during the European Congress of Radiology 2021, presents results from the first-ever comprehensive effort to quantify imaging and nuclear medicine resources worldwide, highlighting dramatic inequalities in access to these resources. It also shows for the first time that scaling up access to imaging and nuclear medicine for cancer patients in low-income and middle-income countries (LMICs) would yield substantial health and economic benefits, and it calls for an overarching global strategy to address this need.

By 2030, worldwide, annual numbers of new cancer cases and cancer deaths are expected to reach roughly 22 million and 13 million, respectively. Even more concerning, approximately 80% of the disability-adjusted life years lost to cancer are in LMICs, where only about 5% of the global funding for cancer control and care is applied. Imaging is essential to provide timely diagnosis, appropriate treatment selection and planning, and optimal outcomes for patients with cancer.

“The aim of the Commission was to provide data and guidance to catalyze sustainable improvement of medical imaging and nuclear medicine services for cancer management, particularly in LMICs,” explains lead Commissioner Dr. Hedvig Hricak from Memorial Sloan Kettering Cancer Center, New York/USA.

Under the Commission, the International Atomic Energy Agency (IAEA) led a global effort to collect and collate data on equipment and workforce, with a focus on LMICs through the IAEA Medical Imaging and Nuclear Medicine Global Resources Database (IMAGINE). The effort revealed substantial differences in the numbers of imaging units per million population between high-income and low- and middle-income countries, as well as variations within income groups. It also revealed that availability of a well-trained workforce for imaging and nuclear medicine is a major issue affecting access to and quality of these services. “To date, comprehensive information on appropriate levels of imaging and nuclear medicine facilities and workforce required for cancer care have been limited. The data obtained allows estimates of projected equipment and workforce scale-up requirements for diagnostic imaging in cancer care,” says Dr. May Abdel-Wahab, co-first author of the Commission and Director of the IAEA Division of Human Health.

A microsimulation model developed by researchers at Harvard University estimated that the scale-up of imaging would avert 3.2% (2.47 million) of all 76 million deaths caused by cancer worldwide between 2020 and 2030, saving 54.92 million life-years. Model estimates indicate that a comprehensive scale-up of imaging, treatment, and care quality would avert 9.55 million (12·5%) of all cancer deaths worldwide, saving 232.30 million life-years. Combining the scale-up of imaging, treatment, and quality of care would provide a net benefit of $2.66 trillion and a net return of $12.43 per $1 invested.

“For the first time, we have evidence demonstrating the substantial health and economic benefits of scaling up imaging and nuclear medicine access for health outcomes of cancer patients globally and we have a compelling economic case for further investment in global scale-up of imaging and nuclear medicine,” says Dr. Rifat Atun, co-first author of the Commission and Professor of Global health Systems at Harvard University.

“Now we need to get governments and funding bodies on board to work together on scaling up imaging infrastructure in LMICs,” adds Dr. Hricak.

The Commission proposes an ambitious call to action to realize the health and economic benefits of scaling up imaging to reduce cancer burden globally. This goal is aligned with the aims of the 2017 WHO Cancer Resolution and with UN health targets in the 2030 agenda for sustainable development, particularly for reducing the burden of non-communicable diseases and implementing universal health coverage.

“The IAEA can support countries in upscaling their diagnostic imaging capabilities through fact-finding missions, technology transfer, capacity building, clinical research, education and training initiatives, quality management programs, and guidelines,” says Dr. May Abdel-Wahab.

"The Commission provides a clear path forward, and we look forward to collaborating with all stakeholders on implementing the call to action with the aim of improving cancer care for patients globally," says senior author of the Commission Prof Andrew Scott from Austin Health and the Olivia Newton-John Cancer Research Institute, Melbourne, Australia.

The Commission concludes that science and technology are not the barriers to a worldwide equitable scale-up of effective cancer imaging diagnostics; rather, achieving equitable scale-up is a matter of vision and political will. Successful scale-up will result from effective political leadership, active participation from all major stakeholders, and the alignment of country-level and global efforts to expand access to medical imaging and nuclear medicine for cancer care. Efforts must take into account local and regional conditions (e.g., the prevalence of particular cancers and the availability of specific kinds of treatments, among other factors), and must be coordinated with the scale-up of other cancer care resources and universal health coverage. Prof David Collingridge, Editor-in-Chief, The Lancet Oncology: “Cancer imaging is vital for accurate diagnosis and treatment, but huge global inequities exist and many of the world’s poorest countries suffer from a shortage or complete lack of the necessary technology and resources. We need to move the debate so that cancer imaging is placed alongside curative interventions as an essential component of comprehensive cancer care, and in turn, universal health coverage.”

 

The Lancet Oncology Commission on Medical Imaging and Nuclear Medicine was established in 2018, with the charge of examining global access to imaging and nuclear medicine for cancer care. The Commission brings together 17 leading global experts and the final report is peer reviewed and published in The Lancet Oncology. The report follows two previous Lancet Oncology Commissions in 2015 that assessed the gaps in access to cancer surgery and radiotherapy, and proposed actions to address the growing burden of cancer in LMICs. Find out more here: https://www.thelancet.com/lanonc/commissions 

The Lancet Oncology Commission on Medical Imaging and Nuclear Medicine is supported by the following 27 organizations: the African Association of Nuclear Medicine, the American College of Radiology, the Association of Latin American Societies of Biology and Nuclear Medicine, the Australian and New Zealand Society of Nuclear Medicine, the Asia Oceania Federation of Nuclear Medicine and Biology, the African Organisation for Research & Training in Cancer, the American Society of Clinical Oncology, the Arab Society of Nuclear Medicine, the African Society of Radiology, the American Society for Radiation Oncology, the Breast Cancer Research Foundation, the European Association of Nuclear Medicine, the European Society for Medical Oncology, the European Society of Radiology, the European Society for Radiotherapy and Oncology, the Hong Kong College of Radiologists, the International Atomic Energy Agency, the International Society for Strategic Studies in Radiology, the International Society of Radiology, the National Cancer Institute, the Pan-Arab Association of Radiological Societies, the Radiological Society of North America, the South African Society of Nuclear Medicine, the Society of Nuclear Medicine & Molecular Imaging, the Union for International Cancer Control, the World Federation of Nuclear Medicine and Biology, and the World Molecular Imaging Society.

Read the Commission at www.thelancet.com/commissions/medical-imaging-nuclear-medicine

 


Incredible efforts of Tour de Cure on their inaugural VIC Discovery Tour

On the weekend of 26-28 February 2021, 110 riders and support crew overcame COVID-19 restrictions to raise vital money for cancer research as part of the 2021 Tour de Cure Victorian Discovery Tour from Daylesford to Melbourne, via Ballarat and Ocean Grove.  They travelled through and supported rural Victorian towns, covering over 400km and 2000m elevation, and visited school children on the ride to present a strong message of ‘Be Fit, Be Healthy, Be Happy’.

Each cyclist has a personal connection to cancer, whether they be survivors, supporting loved ones with cancer, or paying tribute to loved ones that have succumbed to it, or as researchers or staff from ONJCRI. This tour raised over $480,000 (with a goal to hit
$500k by the end of March!) to support five research projects.

Geoff Coombes, Tour de Cure co-founder, says that they were proud to be partner with ONJCRI.

“Our inaugural Victorian Discovery Tour will bring four world class research projects to life at the ONJCRI, tackling stomach, colorectal, ovarian and rare cancers”, said Geoff.

The impact of COVID-19 has been felt across the entire cancer research community, with a dramatic reduction and slowing of available funds. Thanks to the tireless fundraising efforts of every rider and support crew member, and the generous support of corporate partners, we were able to exceed the original target to fund four projects. The money raised will allow our team to further expand their cancer knowledge and work to find new cancer treatments.


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"