How Activation Of The Protein p53 Boosts The Immune Response Against Tumours (Medicine)

Researchers at Karolinska Institutet publish new findings in the journal Cancer Discovery showing how pharmacological activation of the protein p53 boosts the immune response against tumours. The results can be of significance to the development of new combination therapies that will give more cancer patients access to immunotherapy.

Given its ability to react to damage to cellular DNA and the key part it is thought to play in preventing tumour growth, the protein p53 has been dubbed the “guardian of the genome”. Half of all tumours have mutations in the gene that codes for the protein, and in many other tumours, p53 is  disabled by another protein, MDM2.

It has long been known that p53 is able to silence certain sequences in our genome called endogenous retroviruses (i.e. DNA elements evolutionarily inherited from viruses), thus preventing genome instability. The researchers now show that the protein can also activate these sequences in cancer cells, leading to anti-tumour immune response.

Astonishing discovery

Galina Selivanova. Photo: John Sennett

“This was an astonishing discovery. When we blocked the suppressor MDM2, p53 activated endogenous retroviruses which induced antiviral response and boosted the production of immune-activating interferons,” says lead investigator Galina Selivanova, Professor at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.

The results were obtained when the researchers blocked MDM2 in mouse models using a substance coded as ALRN-6924 from the US company Aileron Therapeutics. The increase of interferon response was also seen in tumour samples from two patients taking part in the company’s clinical trials of ALRN-6924.

There are synergies

“This shows that there are synergies that should be exploited between substances that block MDM2 and modern immunotherapies,” Professor Selivanova continues. “A combination of these can be particularly important for patients who don’t respond to immunotherapy.”

Immunotherapy, or immuno-oncology, is described as a revolution in modern cancer treatment in the way it triggers the body’s immune system to fight cancer cells. However, it does not work with all patients, and the presence of interferons could be a biomarker for whether or not immunotherapy will prove efficacious.

“If we can increase the level of interferons, we can therefore increase the chances that the immunotherapy will succeed.”

Re-activating p53

Professor Selivanova is a pioneer in research on how mutated p53 can be re-activated using special molecules, one of which, APR-246, is undergoing clinical studies under the name Eprenetapopt at Aprea Therapeutics, a company that she co-founded.

“We now want to examine if Eprenetapopt produces the same interferon boost and can have the same potential to increase access to immunotherapy for patients with severe forms of cancer,” she says. 

The study was conducted at Karolinska Institutet and financed by the Swedish Cancer Society, the Swedish Research Council and Karolinska Institutet. Co-authors Vincent Guerlavais, Luis A. Carvajal, Manuel Aivado and D. Allen Annis are all employed by Aileron Therapeutics.

Featured image credit: Getty images

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Publication

“Pharmacological activation of p53 triggers viral mimicry response thereby abolishing tumor immune evasion and promoting anti-tumor immunity”. Xiaolei Zhou, Madhurendra Singh, Gema Sanz Santos, Vincent Guerlavais, Luis A. Carvajal, Manuel Aivado, Yue Zhan, Mariana M.S. Oliveira, Lisa S. Westerberg, D. Allen Annis, John Inge Johnsen and Galina Selivanova. Cancer Discovery, online 6 July 2021, doi: 10.1158/2159-8290.CD-20-1741.

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Provided by Karolinska Institute

Researchers Develop Virus-based Treatment Platform to Fight Pancreatic Cancer (Medicine)

Researchers from Queen Mary University of London and Zhengzhou University have developed a powerful therapeutic platform that uses a modified virus for the treatment of pancreatic cancer.

Researchers from Queen Mary University of London and Zhengzhou University have developed a powerful therapeutic platform that uses a modified virus for the treatment of pancreatic cancer. By using the virus in combination with other drugs, the treatment significantly extended survival in preclinical models of pancreatic cancer.

Viruses that can selectively infect and destroy cancer cells, known as oncolytic viruses, are a promising new class of therapeutics for cancer. Through various mechanisms, oncolytic viruses kill cancer cells and elicit strong anti-tumour immune responses. However, current oncolytic virotherapy is unable to produce a long-term cure in patients, and the treatment has to be delivered directly into the tumour – a route that is not feasible for deeply embedded tumours, or tumours that have spread around the body.

The study, published today in the Journal for ImmunoTherapy of Cancer, describes a novel platform for the treatment of pancreatic cancer using an oncolytic Vaccinia virus that was modified to improve its safety, ability to spread within and between tumours and capacity to activate potent anti-tumour immune responses.

The research was supported by the Medical Research Council (MRC), Pancreatic Cancer Research Fund, Pancreatic Cancer UK, Nature Sciences Foundation of China and National Key R&D Program of China.

A re-engineered virus system

The study built upon previous work by the team (Ferguson et al, 2019; Ahmed et al, 2020), which developed a modified Vaccinia virus through the deletion of two viral genes. By combining treatment with the modified virus and a clinically available drug (PI3Kδ inhibitor) that prevented the destruction of the virus particles by the body’s immune cells, the team created an effective treatment platform that was systemic (i.e. could travel through the body), specifically targeted pancreatic tumours and activated the immune system against the tumours in preclinical models.

In this new study, to improve the efficacy of the treatment platform, the team re-engineered the virus by modifying its genetic code to contain an additional, altered copy of a protein that is crucial to the ability of the virus to spread within and between tumours. The team also armed the virus with a protein called IL-21, which improved the virus’ ability to trigger an immune response against the cancer.

Professor Yaohe Wang, from Barts Cancer Institute, Queen Mary University of London, who led the study, said: “This platform provides a powerful therapeutic to target multiple aspects of pancreatic cancer simultaneously through a convenient administration approach (intravenous injection), significantly improving the prospects of disease eradication and prevention of recurrence in pancreatic cancer patients. This platform is also suitable for treatment of other human tumour types.”

Following administration of the novel oncolytic Vaccinia virus (named VVL-21) in preclinical models of pancreatic cancer, the virus successfully remodelled the suppressive tumour microenvironment to trigger potent anti-tumour immune responses. Importantly, treatment with VVL-21 also sensitised tumours to treatment with a type of immunotherapy known as an immune checkpoint inhibitor.

The combination of the three therapeutics – VVL-21, PI3Kδ inhibitor and the immune checkpoint inhibitor – created a powerful systemic therapeutic platform that significantly extended survival in a number of different, complex preclinical models of pancreatic cancer.

The deadliest of the common cancers

Pancreatic cancer is the 11th most common cancer in the UK; however, it has the lowest survival rate of all the common cancers, with less than 7% of patients surviving their cancer for five years or more. Pancreatic cancer is often diagnosed in the late stages of its development when the cancer is advanced or has spread to other parts of the body, making treatment difficult.

Chemotherapy and radiotherapy alone are relatively unsuccessful in treating pancreatic cancer and while surgery to remove the tumour offers the best chance of survival, more than 80% of patients ultimately die of the disease due to local recurrence and/or distant metastasis.

While immunotherapeutics such as immune checkpoint inhibition (ICI) have emerged as a promising new therapeutic approach, pancreatic cancer in particular is unresponsive to ICI monotherapy. The new virus developed in this study demonstrated a promising synergistic anti-tumour effect in combination with ICI immunotherapy.

Following additional funding from the MRC, the team are now hoping to conduct the necessary steps required to take the viral treatment system forward into phase I clinical trials to determine its potential within the clinic.

Dr Louisa Chard Dunmall, senior postdoctoral researcher at Barts Cancer Institute, Queen Mary University of London and joint first author of the study, said: “The current prognosis for patients with pancreatic cancer has not improved for many decades and so we urgently require new treatments that can improve long-term survival. Our platform provides an exciting new mechanism of attacking the tumour in these patients and we are grateful that we have received further funding from the MRC to support this project through pre-clinical toxicity testing and virus manufacture in the hope that we can take this platform forward into phase I clinical trials within the next 3 years.”

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Reference: Giulia Marelli, Louisa S Chard Dunmall, Ming Yuan, Carmela Di Gioia, Jinxin Miao, Zhenguo Cheng, Zhongxian Zhang, Peng Liu, Jahangir Ahmed, Rathi Gangeswaran, Nicholas Lemoine, Yaohe Wang, ” A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer”, Journal for ImmunoTherapy of Cancer, 9(1), 2021. https://jitc.bmj.com/content/9/1/e001624 http://dx.doi.org/10.1136/jitc-2020-001624

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Provided by Queensmary University of London

New Combination of Immunotherapies Shows Great Promise for Treating Lung Cancer (Medicine)

McMaster researchers have established in lab settings that a novel combination of two forms of immunotherapy can be highly effective for treating lung cancer, which causes more deaths than any other form of cancer.

McMaster researchers Sophie Poznanski and Ali Ashkar have established that a novel combination of two forms of immunotherapy can be highly effective for treating lung cancer. (Photo by Georgia Kirkos/McMaster University)

The new treatment, yet to be tested on patients, uses one form of therapy to kill a significant number of lung tumour cells, while triggering changes to the tumour that enable the second therapy to finish the job.

The first therapy employs suppressed “natural killer” immune cells by extracting them from patients’ tumours or blood and supercharging them for three weeks.

The researchers condition the cells by expanding and activating them using tumour-like feeder cells to improve their effectiveness before sending them back into battle against notoriously challenging lung tumours.

The supercharged cells are very effective on their own, but in combination with another form of treatment called checkpoint blockade therapy, create a potentially revolutionary treatment.

“We’ve found that re-arming lung cancer patients’ natural killer immune cells acts as a triple threat against lung cancer,” explains Sophie Poznanski, the McMaster PhD student and CIHR Vanier Scholar who is lead author of a paper to be published Friday, Jan 22 in the Journal for ImmunoTherapy of Cancer.

McMaster researcher Ali Ashkar, whose team has developed a new form of treatment for lung cancer, using a combination of immunotherapies. © Georgia Kirkos, McMaster University

“First, these highly activated cells are able to kill tumour cells efficiently. Second, in doing so, they also reactivate tumour killing by exhausted immune cells within the patients’ tumours. And third, they release factors that sensitize patients’ tumours to another immunotherapy called immune checkpoint blockade therapy.

“As a result, we’ve found that the combination of these two therapies induces robust tumour destruction against patient tumours that are initially non-responsive to therapy.”

Previous breakthroughs in checkpoint blockade therapy had earned Japanese researcher Tasuku Honjo and American immunologist James Allison the 2018 Nobel Prize for Medicine or Physiology.

Checkpoint blockade therapy works by unlocking cancer’s defence against the body’s natural immune response. The therapy can be highly effective in resolving even advanced cases of lung cancer – but it only works in about 10 per cent of patients who receive it.

The research team, featuring 10 authors in total, has shown that the supercharged immune cells, when deployed, release an agent that breaks down tumours’ resistance to checkpoint blockade therapy, allowing it to work on the vast majority of lung-cancer patients whose tumours would otherwise resist the treatment.

Once activated, the natural killer cells are able to secrete inflammatory factors that help enhance the target of the blockchain that the other immunotherapy treats.

McMaster University researcher Sophie Poznanski is the lead author of a paper presenting a new form of lung cancer treatment using a novel combination of immunotherapies. © Georgia Kirkos, McMaster University

“We needed to find a one-two punch to dismantle the hostile lung tumor environment,” says Ali Ashkar, a professor of Pathology and Molecular Medicine and a Canada Research Chair who is Poznanski’s research supervisor and the corresponding author on the paper.

“Not only is this providing a new treatment for hard-to-treat lung cancer tumors with the natural killer cells, but that treatment also converts the patients who are not responsive to PD1-blockade therapy into highly responsive candidates for this effective treatment”.

Such progress is possible because of the close collaboration among clinical practitioners and lab-based researchers at McMaster and its partner institutions, Ashkar says.

He said the team’s clinical practitioners, who work with cancer patients every day, provided critical wisdom and collected vital samples from patients at St. Joseph’s Healthcare Hamilton. Ashkar says those clinicians’ insights and the samples were integral to the research.

Co-author Yaron Shargall, chief of the division of thoracic surgery at McMaster’s Michael G. DeGroote School of Medicine and a thoracic surgeon at St. Joseph’s Healthcare Hamilton, says the promising outcome is the result of close links between basic science and clinical medicine.

“It was successful mostly due to the facts that the two groups have spent long hours together, discussing potential ways of combining forces and defining a linkagebetween a highly specific basic science technology and a very practical clinical, day-to-day dilemmas,” he said.

“This led to a flawless collaboration which resulted in a very elegant, potentially practice-changing, study.”

The researchers are now working to organize a human clinical trial of the combined therapies, a process that could be under way within months, since both immunotherapies have already been approved for individual use.

Provided by McMaster University

Novel RNA Factors May Help Cancer Cells Thrive (Medicine)

Like Peter Pan, some cells never grow up. In cancer, undifferentiated stem cells may help tumors such as glioblastoma become more aggressive than other forms of the disease. Certain groups of genes are supposed to help cells along the path to maturity, leaving their youthful “stemness” behind. This requires sweeping changes in the microRNAome — the world of small non-coding material, known as microRNAs, that control where and when genes are turned on and off. Many microRNAs are tumor-suppressive; in cancer, the microRNAome is distorted and disrupted. Recent work by researchers at Brigham and Women’s Hospital pinpoints critical changes in an enzyme known as DICER, which create a cascade of effects on this microRNAome. The team identified primary actors circ2082, a circular RNA, and RBM3, an RNA-binding protein, which form a complex with DICER to trap it in the nucleus of glioblastoma cells, therefore disrupting the cytoplasmic microRNAome. Findings are published in Science Advances.

“We are always trying to find the magic bullet to fight cancer. The problem with the magic bullet is that it’s only going to hit a few tumor cells, since the other tumor cells don’t have that target. We are looking for the common vulnerability — what is the common thing that we can target?” said Antonio Chiocca, MD, PhD, chair of the Brigham’s Department of Neurosurgery. “With this discovery, we can target something way upstream: a very common target at the epigenetic level.”

Prior research showed the number of microRNAs expressed in cancer cells to be low when compared to non-cancerous cells. In addressing this observation, primary researchers Jakub Godlewski, PhD, and Agnieszka Bronisz, PhD, both formerly at the Brigham and now based at the Mossakowski Medical Research Centre of Polish Academy of Sciences, Warsaw, Poland, led a team that determined the absence of DICER enzyme is likely the cause of this cytoplasmic microRNA depletion. The team discovered DICER was being trapped in the nucleus by repressive interactions with RBM3 and circ2082.

In order to characterize these new actors, researchers used patient-derived glioblastoma cells, which allowed them to study outcomes genetically and phenotypically similar to real patient outcomes. The cells were studied both in vitro and in vivo through implantation into the brains of lab mice. The level of microRNA expression in these mice changed their survival rates. If circ2082 was knocked down, the nuclear DICER complex of circ2082, DICER, and RBM3 was disrupted, more microRNAs were present in the cytoplasm, and the survival outcome was far greater. In these mice whose tumors had circ2082 knocked down, death by tumorigenesis never occurred, while their non-knockdown counterparts all experienced death by tumorigenesis.

The downstream effect of this circ2082 expression also heavily influenced morbidity in human patients whose tissues were retrospectively analyzed. Patients with circ2082-dependent signature less widely expressed had overall longer lifespans after cancer diagnosis.

“Targeting these upstream tumor proliferators has the potential to dramatically change the cancer treatment landscape,” said Chiocca. “We look forward to clinical translation of this research as we search for the right inhibitors.”

This research was funded by the National Cancer Institute 1R01 CA176203-01A1 (to J.G.), K08NS101091, and R01NS11614 (to P.P.); and the National Science Center Poland (2018/29/B/NZ1/01016) (to A.B.). 

Reference: Bronisz, Agnieszka, et al. The nuclear DICER–circular RNA complex drives the deregulation of the glioblastoma cell microRNAome Science Advances DOI: 10.1126/sciadv.abc0221 https://advances.sciencemag.org/content/6/51/eabc0221

Provided by Brigham and Women’s Hospital

Scientists Create ON-OFF Switches to Control CAR T Cell Activity (Medicine)

Scientists at Dana-Farber Cancer Institute and Mass General Cancer Center have created molecular ON-OFF switches to regulate the activity of CAR T cells, a potent form of cell-based immunotherapy that has had dramatic success in treating some advanced cancers, but which pose a significant risk of toxic side effects.

CAR T cells are immune cells genetically modified to recognize and attack tumors cells. Once given, these “living drugs” proliferate and kill tumor cells over weeks to months, in some cases causing life-threatening inflammatory reactions that are difficult to control. In this way, CAR T cells are unlike more established forms of cancer therapy – chemotherapy or radiotherapy for instance – whose dose can be precisely tuned up or down over time.

The scientists reported in Science Translational Medicine the development of switchable CAR T cells that can be turned on or off by giving a commonly used cancer drug, lenalidomide. In the laboratory, the researchers designed OFF-switch CAR T cells that could be quickly, reversibly turned off by administering the drug, after which the CAR T cells recovered their anti-tumor activity. Separately, the researchers also reported ON-switch CAR T cells that only killed tumor cells during lenalidomide treatment.

In the future, switchable cell therapies might allow patients with their physicians to take a pill – or not – to tune the amount of CAR T cell activity from day to day, hopefully reducing toxic side effects.

“From the start, our goal was to build cancer therapies that are less hard on people. Having built these switches using human genetic sequences and an FDA-approved drug, we are excited for the potential to translate this research to clinical use,” said Max Jan, MD, PhD, first author of the report. He is affiliated with the laboratories of Benjamin Ebert, MD, PhD, and Marcela Maus, MD, PhD, the report’s senior authors. Other authors include researchers from the Broad Institute of MIT and Harvard, and Harvard Medical School.

CAR T cells are created by harvesting immune T cells from the patient and reprogramming them in the laboratory to produce a finely-tuned receptor molecule, termed a CAR (for chimeric antigen receptor), that recognizes a distinctive protein on the surface of the patient’s cancer cells. The CAR T cells, after being engineered in the lab and returned to the patient, circulate through the body and home in on the cancer cells by binding to the distinctive surface protein they have been engineered to recognize. This binding event stimulates an immune attack, destruction of the cancer cells, and proliferation of the CAR T cells.

A drawback, however, is that uncontrolled proliferation of the CAR T cells sometimes triggers cytokine release syndrome (CRS), the release of inflammation-causing signals throughout the body that can cause toxicities ranging from mild fever to life-threatening organ failure. Current management of these toxic reactions relies on intensive care unit support and drugs including immunosuppressive corticosteroids, while many researchers are trying to develop methods of controlling the activity of CAR T cells in order to prevent these toxic side effects.

“CAR T cells can be fantastically effective therapies, but they can also have serious toxicities and can cause significant morbidity and mortality,” said Ebert who is Chair of Medical Oncology at Dana-Farber. “They are currently difficult to control once administered to the patient.”

CAR T cell therapy has had most success in blood cancers. Three CAR T agents have been approved: Kymriah for children and young adults with B-cell precursor acute lymphoblastic leukemia (ALL), both Kymriah and Yescarta for treatment of adults with diffuse large B-cell lymphoma and Tecartus for adults with mantle cell lymphoma. Scientists are investigating an array of different approaches with the aim of extending the reach of CAR T therapies to other blood cancers and to solid tumors, if a number of hurdles can be overcome, including the problem of treatment toxicity.

To create the ON and OFF switch systems for CAR T cells, the scientists used a relatively new technique known as targeted protein degradation. It exploits a mechanism that cells use to dispose of unwanted or abnormal proteins; the proteins are marked for destruction by a structure within cells that acts like a garbage disposal. A small number of drugs, including lenalidomide, act by targeting specific proteins for degradation using this pathway.

The researchers used this technique to engineer small protein tags that are sent to the cellular garbage disposal by lenalidomide. When this degradation tag was affixed to the CAR, it allowed the tagged CAR to be degraded during drug treatment, thereby stopping T cells from recognizing cancer cells. Because CAR proteins are continually manufactured by these engineered T cells, after drug treatment new CAR proteins accumulate and restore the cell’s anti-tumor function. The researchers propose that the switch system might in the future allow patients to have their CAR T cell treatment temporarily paused to prevent short-term toxicity and still have long-term therapeutic effects against their cancer.

The scientists also built an ON-switch CAR by further engineering the proteins that physically interact with lenalidomide. This system has the potential to be especially safe, because the T cells only recognize and attack tumor cells during drug treatment. If used to treat cancers such as multiple myeloma that are sensitive to lenalidomide, ON-switch CAR T cells could allow for a coordinated attack by the immune cells and the drug that controls them.

“The long-term goal is to have multiple different drugs that control different on and off switches” so that scientists can develop “ever-more complex cellular therapies,” explained Ebert.

This work was supported by the National Institutes of Health grants (R01HL082945, P01CA108631, and P50CA206963), the Howard Hughes Medical Institute, the Edward P. EvansFoundation, and the Leukemia and Lymphoma Society.

Provided by Dana-Farber Cancer Institute

About Dana-Farber Cancer Institute

Dana-Farber Cancer Institute is one of the world’s leading centers of cancer research and treatment. Dana-Farber’s mission is to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. We provide the latest treatments in cancer for adults through Dana-Farber/Brigham and Women’s Cancer Center and for children through Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Dana-Farber is the only hospital nationwide with a top 10 U.S. News & World Report Best Cancer Hospital ranking in both adult and pediatric care.

As a global leader in oncology, Dana-Farber is dedicated to a unique and equal balance between cancer research and care, translating the results of discovery into new treatments for patients locally and around the world, offering more than 1,100 clinical trials.

New Clues to Prostate Cancer (Medicine)

Why aggressive subtype can resist treatment?

Australian research has identified a new mechanism in which prostate cancer cells can ‘switch’ character and become resistant to therapy.

These findings, just published in Cell Reports, are an important development in unravelling how an aggressive subtype of prostate cancer, neuroendocrine prostate cancer (NEPC), develops after hormonal therapies.

Flinders University Associate Professor Luke Selth, from the Flinders Health and Medical Research Institute. © The Hospital Research Foundation

It is well established that some tumours show increased cellular ‘plasticity’ in response to new or stressful conditions, such as cancer therapy, says lead researcher Associate Professor Luke Selth, from the Flinders Health and Medical Research Institute.

This plasticity allows the cancer cells to adapt and continue to grow by evolving into different cell types that no longer respond to the therapy.

“Increased cellular plasticity is increasingly recognised as a key feature by which prostate cancers become resistant to therapy and progress to a lethal stage,” he says.

“Our new study reveals that a particular molecule, the microRNA ‘miR-194’, can enhance this plasticity in prostate cancer, leading to the emergence of NEPC.

“By targeting miR-194, we were able to slow down and inhibit the growth of prostate cancer models with neuroendocrine features.”

Associate Professor Selth says while this study is a long way from clinical application, it “nevertheless provides us with important new insights into how prostate cancers ‘evolve’ in response to therapy”.

There are currently no effective treatments for NEPC, with estimates up to 15% of men may develop this aggressive subtype of prostate cancer after hormonal treatment – a major problem because these men face “very poor outcomes”.

“By revealing another regulator of prostate cancer cell plasticity that can promote evolution of tumours, our study highlights why prostate cancer is so difficult to cure.

“While this reality is sobering, we hope that our study and lots of other research going on around the world will eventually lead to smarter, more targeted ways to treat NEPC or even prevent its emergence,” Associate Professor Selth says.

Reference: RC Fernandes, J Toubia, S Townley, AR Hanson, BK Dredge, KA Pillman, AG Bert, JM Winter, R Iggo, R Das, D Obinata, MURAL investigators, S Sandhu, GP Risbridger, RA Taylor, MG Lawrence, LM Butler, A Zoubeidi, PA Gregory, WD Tilley, TE Hickey, GJ Goodall and LA Selth, ‘Post-transcriptional gene regulation by microRNA-194 promotes neuroendocrine transdifferentiation in prostate cancer’, Cell Reports (Elsevier), 2020. DOI: 10.1016/j.celrep.2020.108585

Provided by Flinders University

Study Identifies Distinct Sub-types of Aggressive Tumours to Allow For Targeted Treatment (Medicine)

Study led by Singapore clinician-scientists has found a way to classify angiosarcomas into three subtypes, allowing for more targeted treatment, better outcomes for patients and the development of new therapies.

• Angiosarcomas are clinically aggressive tumours that are more prevalent in Asian populations.
• Study led by Singapore clinician-scientists has found a way to classify angiosarcomas into three subtypes, allowing for more targeted treatment, better outcomes for patients and the development of new therapies.
• Findings were published in The Journal of Clinical Investigation in October this year.

A new study led by clinician-scientists from the National Cancer Centre Singapore (NCCS), with collaborators from research institutions worldwide, has found that angiosarcomas have unique genomic and immune profiles which allow them to be classified into three different subtypes. With this new and improved classification system, patients can be treated using a personalised-medicine approach and it will encourage the development of novel treatments.

© Jason Chan et al.

Angiosarcomas, a type of cancer that forms in the lining of the blood and lymph vessels, are more commonly found in Asia making up 7% of all sarcoma diagnoses. Angiosarcomas are aggressive and can spread to various regions of the body and most often occur on the scalp and face.

For angiosarcomas that have not spread, a combined approach using surgery, radiotherapy and/or chemotherapy is often the course of action for treatment. Once the cancer has metastasised, various chemotherapy treatments are typically administered, which often have poor clinical efficacy and little benefit. As a result, angiosarcomas present a challenge for clinicians and patients because treatment options are limited and prognosis is bleak.

“At NCCS, we treat around 100 patients with sarcomas a year. With a deeper understanding of the tumours, we can better treat these group of patients,” said Clinical Assistant Professor Jason Chan, first author of the study and Consultant Medical Oncologist, Division of Medical Oncology, NCCS.

For the study, 68 patients diagnosed with angiosarcoma at NCCS and Singapore General Hospital between 2000 to 2015 were identified. The research team analysed the tumour samples using multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence.

Multiomic sequencing, which is used to find associations or pinpoint biomarkers in biological entities, like an angiosarcoma, found that 50% of the head and neck angiosarcomas exhibited higher tumour mutation burden (TMB) and UV mutational signatures. This indicated that half of the head and neck angiosarcomas may have developed as a result of UV exposure, and are likely to respond to a type of cancer treatment known as immune checkpoint inhibitors.

NanoString profiling, a technology that profiles gene expression in tumours, revealed that patients with angiosarcomas were grouped into three clusters. Patients in the third cluster had specific enrichment of immune cells and genes involved in immune-related signalling. Tumour inflammation signature (TIS) scores were also highest in this third cluster. Cluster one, like cluster three, was found to be predominantly head and neck angiosarcomas although with a lower inflammation footprint. Cluster two exhibited higher expression of genes that typically promote tumour growth and spread. They were also mainly secondary sarcomas, meaning they had previous exposure to certain environmental or genetic risk factors.

Recent clinical studies have shown that treating tumours with high TMB and TIS scores with immune checkpoint inhibitors showed promising results. By stratifying these 68 angiosarcoma patients, the study results suggest that checkpoint immunotherapy can be used for clusters one and three, while the tumour-promoting genes that are highly expressed in cluster two could be explored as potential treatment targets using targeted therapies.

“Our results are very promising, as they show that we can potentially use existing modes of therapy, like immunotherapy to treat a subset of angiosarcoma patients,” said Clin Asst Prof Chan. “The next step will be to perform further molecular and immunological dissection of angiosarcomas to get more insight into how we can best use precision medicine to target these cancers.”

The findings, published in The Journal of Clinical Investigation in October of this year, is testament that research can directly improve patient care.

“Understanding angiosarcomas will allow oncologists to treat their patients in a more targeted way and it is also a confirmation that NCCS is continuously conducting cutting edge, translational research that has an impact on patients,” said Professor Soo Khee Chee, senior author of the study and Founding Director, NCCS.

The research team plans to further the study by investigating the molecular and genomic profiles of other sarcoma subtypes. This study is part of a plan to investigate rare cancers and establish NCCS as a leading global cancer centre.

Reference: Jason Yongsheng Chan, … , Bin Tean Teh, Khee Chee Soo, “Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma”, J Clin Invest. 2020;130(11):5833-5846. https://doi.org/10.1172/JCI139080. https://www.jci.org/articles/view/139080

Provided by Singhealth

About the National Cancer Centre Singapore

National Cancer Centre Singapore (NCCS) provides a holistic and multi-disciplinary approach to cancer treatment and patient care. We see close to 65 per cent of the public sector oncology cases, and they are benefiting from the sub-specialisation of our clinical oncologists.

To deliver among the best in cancer treatment and care, our clinicians work closely with our scientists who conduct robust cutting-edge clinical and translational research programmes which are internationally recognised. NCCS strives to be a global leading cancer centre, and shares its expertise and knowledge by offering training to local and overseas medical professionals.

http://www.nccs.com.sg

Bioactive Glass As a New Approach In The Treatment of Bone Cancer (Oncology / Medicine)

FAU develops bioactive glass for bone cancer research.

A team of researchers at FAU led by Prof. Dr. Aldo R. Boccaccini, Chair of Materials Science (Biomaterials) is producing bioactive glass that is being tested for suitability in the treatment of giant-cell tumours of the bone at Heidelberg University Hospital as part of a cooperation project. The cancer research foundation Deutsche Krebshilfe is funding the project with approximately 212,000 euros.

Prof. Dr. Aldo R. Boccaccini (Chair of Materials Science – Biomaterials) (Image: FAU)

The tiny particles of glass that contain biologically active ions such as zinc, magnesium or boron are being examined to determine if they form carbonated hydroxyapatite (CHA) upon contact with bodily fluids. The formation of such a layer of CHA enables the particles of glass to interact with the bone tissue. The team led by Prof. Dr. Aldo R. Boccaccini is one of the world’s leading groups researching into the development, production and characterisation of bioactive glass.

In the treatment of broken bones, patients are already benefiting from the effects of bioactive glass, which stimulate bone growth. However, these types of glass can also have a destructive effect on cells and this is exactly what the researchers at Heidelberg University Hospital hope to make use of. Cancer cells from giant-cell tumours of the bone seem to react more sensitively than healthy bone cells. The aim is to selectively kill off cancer cells thus preventing local relapses or recurring tumours. Relapses occur relatively frequently in giant-cell tumours and can lead to a serious form of the disease. The researchers hope to improve treatments for cancer patients with the glass.

Provided by Friedrich-Alexander-Universität Erlangen-Nürnberg

Scientists Discover the Immunomodulatory Activity of a Drug That Would Improve the Efficacy of Immunotherapy Against Breast Cancer (Medicine)

The team of Eva González-Suarez, from the CNIO and IDIBELL, and the team of Christos Sotiriou, from the Jules Bordet Institute, demonstrate that a drug already used to treat osteoporosis promotes the infiltration of immune cells in breast tumours. These findings propose a new target to increase the antitumor immune response and make breast cancer more sensitive to immunotherapy.

From left to right, Clara Gómez-Aleza, Guillermo Yoldi and Eva González-Suárez. /Idibell

Despite the success of immunotherapy in the treatment of cancers such as lung or melanoma, it is still not effective in breast cancers for being ‘cold’, with low infiltration of immune cells. Tumours use strategies to evade immune surveillance by reducing the infiltration of cells that could attack them or by attracting immunosuppressive cells. These strategies can contribute to the poor prognosis observed in breast cancer of young women and make them unresponsive to immunotherapy. For this reason, the identification of a therapy that could convert immunologically ‘cold’ tumours -in which immunotherapy is not effective- into ‘warm’ tumours would represent an important step to increase the efficiency of immunological therapies for breast cancer, since these are based on the reactivation of immune cells to attack tumour cells.

In an article published today in the journal Nature Communications, the Transformation and Metastasis Group led by Eva Gonzalez-Suarez, first from the Bellvitge Institute for Biomedical Research (IDIBELL) and currently at the Spanish National Cancer Research Center (CNIO), proposes RANK signalling pathway as a key candidate to modulate the immune response in breast tumours. Furthermore, in collaboration with Christos Sotiriou, from the Jules Bordet Institute in Belgium, RANK pathway’s immunomodulatory activity has been confirmed in a clinical trial with premenopausal patients with luminal breast cancer, one of the most resistant types to immunotherapy.

The study reports that the inhibition of RANK protein promotes the recruitment of immune cells within the tumor in mouse models and in patients with breast cancer. In addition, tumors appear to be more sensitive to immunotherapy after inhibiting RANK pathway in tumor cells. These results suggest that this protein is playing an essential role in the communication between tumor and immune cells. Furthermore, they point to RANK pathway as a possible escape route of cancer cells against immunotherapy.

The clinical trial led by Christos Sotiriou with cancer patients with premenopausal breast early stage showed that patients tolerate the administration of a monoclonal antibody that inhibits RANK, achieved good results enhancing infiltration of immune cells in tumours and identified biomarkers that could help select patients who would benefit from therapy.

The strength of this work lies in the fact that two independent studies, a clinical trial and preclinical research, conclude that inhibition of RANK signalling enhances antitumor immune response.

González-Suárez indicates that “the monoclonal antibody being tested in this study is used routinely for the treatment of bone diseases such as osteoporosis and bone metastases, but not for cancer treatment. Our results support the use of this antibody in combination with immunotherapy against breast cancer,” and adds: “This strategy could turn immunologically cold breast cancers into tumours sensitive to the immune system activity.”

Tumour immune surveillance

The immune system, which recognizes foreign microorganisms, viruses and bacteria, and provides a response to destroy these disease-causing agents, plays a similar role in protecting the body against malignancies. Cancer cells express abnormal proteins that can be recognized by immune cells because they act as tags that allow the immune system to find and destroy those cells.

The presence of immune cells within the tumour, the so-called immune infiltration, is associated with a good prognosis. However, tumours have mechanisms that allow them to escape the immune responses that often prevent the development of malignant tumours, which means that immunotherapy is not yet fully effective in the treatment of various types of cancer. Studies like the one now published by IDIBELL and CNIO contribute to improving this promising strategy for cancer treatments.

The study has been funded by the Ministry of Science and Innovation, the National Institute of Health Carlos III, the European Research Agency, the European Regional Development Fund, the La Marató de TV3 Foundation, the National Fund for Scientific Research of Belgium, Televie, the US National Institutes of Health, and Amgen.

Reference: Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells. Clara Gómez-Aleza et al (Nature Communications, 2020). DOI: 10.1038/s41467-020-20138-8

Provided by CNIO