Tag Archives: #tumour

A CNIO Team Discovers How Telomere Involvement in Tumour Generation is Regulated (Biology)

The protein TRF1, which is part of the ‘protective shield’ at the ends of chromosomes, or telomeres, is regulated by the PI3K/AKT pathway, one of the most frequently affected pathways in numerous tumorigenic processes

When the researchers created human cancer lines that prevented AKT from modifying telomeres, they observed shorter telomeres and a reduced ability to generate tumours

The results show for the first time that telomeres respond to external signals that induce cell proliferation and that blocking these signals can interfere with immortality of cancer cells

The Telomeres and Telomerase Group led by Maria A. Blasco at the Spanish National Cancer Research Centre (CNIO) continues to make progress in unravelling the role that telomeres –the ends of chromosomes that are responsible for cellular ageing as they shorten– play in cancer. The CNIO team was among the first to propose that shelterins, proteins that wrap around telomeres and act as a protective shield, might be therapeutic targets for cancer treatment. Subsequently, they found that eliminating one of these shelterins, TRF1, blocks the initiation and progression of lung cancer and glioblastoma in mouse models and prevents glioblastoma stem cells from forming secondary tumours.  Now, in a study published in PLOS Genetics, they go one step further and describe for the first time how telomeres can be regulated by signals outside the cell that induce cell proliferation and have been implicated in cancer. The finding opens the door to new therapeutic possibilities targeting telomeres to help treat cancer.

The CNIO group was also the first to find a link between TRF1 and the PI3K/AKT signalling pathway. This metabolic pathway, which also encompasses mTOR, is one of the pathways most frequently affected in numerous tumorigenic processes. However, it was not known whether preventing TRF1 regulation by this pathway can have an impact on telomere length and its ability to form tumours. AKT acts as a transmitter of extracellular signals triggered by, among others, nutrients, growth factors and immune regulators, to the interior of cells. CNIO researchers Raúl Sánchez and Paula Martínez, directed by Maria A Blasco, set out to determine the involvement of telomeres in this signalling pathway.

To do this, the researchers modified the TRF1 protein in cells to make it unresponsive to AKT, using the gene-editing tool CRISPR/Cas9. This way, TRF1 and the telomeres became invisible to any extracellular signals transmitted by AKT.  Telomeres in these cells shortened and accumulated more damage; most importantly, the cells were no longer able to form tumours, indicating that telomeres are important targets of AKT and its role in cancer development.

“Most importantly, we found that when TRF1 can’t be phosphorylated by AKT, the latter has a lower potential to generate tumours,” explains Blasco.

The paper shows that telomeres are among the most important intracellular targets of the AKT pathway to form tumours, since, although neither the function of AKT nor of any of the thousands of proteins that are regulated by it was altered, only blocking AKT’s ability to modify telomeres was sufficient to slow tumour growth.  

The next step will be to generate genetically modified mice with telomeres that are invisible to AKT. The authors anticipate that these mice will be more resistant to cancer.

The study was funded by the Spanish Ministry of Science and Innovation, the Carlos III Health Institute, the Spanish State Research Agency, the European Research Council, the European Regional Development Fund, the Autonomous Community of Madrid, the Botín Foundation and Banco Santander through Santander Universities, and World Cancer Research.

Featured image: When TRF1 is phosphorylated by AKT, telomeres are normal (top); in the cell lines where AKT doesn’t modify TRF1, telomeres are shorter and have a lower potential to generate tumours (bottom). /PLOS Genetics


Reference article

AKT-dependent signaling of extracellular cues through telomeres impact on tumorigenesis. Raúl Sánchez-Vázquez, Paula Martínez, Maria A. Blasco (PLOS Genetics, 2021). DOI: doi.org/10.1371/journal.pgen.1009410


Provided by CNIO

The Role of T Cells in Fighting Cancer (Medicine)

New CU research shows a wider variety of T cells means a better immune system response.

New research from CU Cancer Center member Jing Hong Wang, MD, PhD, and recent University of Colorado Immunology program graduate Rachel Woolaver, PhD, may help researchers develop more effective personalized immunotherapy for cancer patients.

Working within Wang’s specialty of cancer immunology and head and neck squamous cell carcinomas (HNSCCs), the researchers worked to establish a mouse model that would help them understand why some hosts’ immune systems reject tumors easily, while others have a harder time doing so. Their research was published last week in the Journal for ImmunoTherapy of Cancer.

“It’s particularly interesting now because the field of cancer treatment has really been going in the direction of immunotherapy, where you give drugs that can reactivate the immune system and get it to kill the tumors on its own,” Woolaver says.

That’s in contrast to chemotherapy and radiation, which can kill other cells along with tumor cells. “We’re just trying to figure out how can we contribute to the field of understanding what causes heterogeneity (differences) in anti-tumor immune responses,” she says.

The T cell solution

Wang, Woolaver and other cancer researchers on the Anschutz Medical Campus started the research by transplanting HNSCC tumors into genetically identical mice. Theoretically, their response to the cancer would be identical, but it turned out that 25% of the mice spontaneously rejected the tumor. The researchers started looking more closely at both the mice and the tumor cells to try to understand what was causing the mice to kill the cancer on their own.

Jing Hong Wang, MD, PhD © Anschutz

What they discovered is that it all depended on the types of the immune cells known as CD8 T cells that were present in the mouse. Even identical twins have different T cells due to the random DNA recombination event generating these T cells, Wang explains, so the genetically identical mice had different arrays of the T cells as well. The mice’s response to cancer depended on how their specific T cells matched up with the set of mutated proteins known as neoantigens that were present in the tumor they were fighting.

“Each of your T cells has a different receptor, and each T cell will be specific to a neoantigen,” Woolaver says. “If you have T cells that are specific to all of them or majority of them, you’re going to be able to get rid of your tumor and have a good anti-tumor immune response.”

What the researchers showed in the publication, Wang explains, is that the mice that spontaneously rejected tumors had vastly different T cell receptors from those that succumbed to tumor development.

Applications in immunotherapy

For the next phase of their research, Wang and her team members plan to study how to enable a cancer patient to develop a more diverse T cell response so they have a better chance of successfully fighting off a tumor.

“Because patient tumors are very heterogenous from each other, it’s very difficult to study them,” Woolaver says. “In our paper, we characterize a new model of tumor heterogeneity that has a lot of interesting immunological aspects that we can study to try to help improve the immune response to cancer.”

Wang adds that the research can be important in developing new types of immunotherapy.

“I don’t think it’s well recognized in the field that intrinsic differences in the immune system can make an impact,” Wang says. “Most people just focus on ‘Why are all the T cells not activated,’ or ‘The T cells are exhausted,’ or something like that. But maybe a patient doesn’t have the right T cells from the beginning. If they don’t have the right T cells that can recognize neoantigens, how can they have the effective anti-tumor immune response?”

Reference: Rachel Woolaver, Jing Hong Wang et al., “Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts”, Journal for Immunotherapy of Cancer, 9(1), 2021. https://jitc.bmj.com/content/9/1/e001615

Provided by University of Colorado Anschutz Cancer Center

‘Virtual Biopsies’ Could Replace Tissue Biopsies in Future Thanks to New Technique (Medicine)

A new advanced computing technique using routine medical scans to enable doctors to take fewer, more accurate tumour biopsies, has been developed by cancer researchers at the University of Cambridge. This is an important step towards precision tissue sampling for cancer patients to help select the best treatment. In future the technique could even replace clinical biopsies with ‘virtual biopsies’, sparing patients invasive procedures.

This study provides an important milestone towards precision tissue sampling. We are truly pushing the boundaries in translating cutting edge research to routine clinical care

Evis Sala

The research published in European Radiology shows that combining computed tomography (CT) scans with ultrasound images creates a visual guide for doctors to ensure they sample the full complexity of a tumour with fewer targeted biopsies.

Individual and combined biopsy scans © Evis Sala/University of Cambridge

Capturing the patchwork of different types of cancer cell within a tumour – known as tumour heterogeneity – is critical for selecting the best treatment because genetically-different cells may respond differently to treatment.

Most cancer patients undergo one or several biopsies to confirm diagnosis and plan their treatment. But because this is an invasive clinical procedure, there is an urgent need to reduce the number of biopsies taken and to make sure biopsies accurately sample the genetically-different cells in the tumour, particularly for ovarian cancer patients.

High grade serous ovarian (HGSO) cancer, the most common type of ovarian cancer, is referred to as a ‘silent killer’ because early symptoms can be difficult to pick up. By the time the cancer is diagnosed, it is often at an advanced stage, and survival rates have not changed much over the last 20 years.

But late diagnosis isn’t the only problem. HGSO tumours tend to have a high level of tumour heterogeneity and patients with more genetically-different patches of cancer cells tend to have a poorer response to treatment.

Professor Evis Sala from the Department of Radiology, co-lead CRUK Cambridge Centre Advanced Cancer Imaging Programme, leads a multi-disciplinary team of radiologists, physicists, oncologists and computational scientists using innovative computing techniques to reveal tumour heterogeneity from standard medical images. This new study, led by Professor Sala, involved a small group of patients with advanced ovarian cancer who were due to have ultrasound-guided biopsies prior to starting chemotherapy.

For the study, the patients first had a standard-of-care CT scan. A CT scanner uses x-rays and computing to create a 3D image of the tumour from multiple image ‘slices’ through the body.

The researchers then used a process called radiomics – using high-powered computing methods to analyse and extract additional information from the data-rich images created by the CT scanner – to identify and map distinct areas and features of the tumour. The tumour map was then superimposed on the ultrasound image of the tumour and the combined image used to guide the biopsy procedure.

By taking targeted biopsies using this method, the research team reported that the diversity of cancer cells within the tumour was successfully captured.

Co-first author Dr Lucian Beer, from the Department of Radiology and CRUK Cambridge Centre Ovarian Cancer Programme, said of the results: “Our study is a step forward to non-invasively unravel tumour heterogeneity by using standard-of-care CT-based radiomic tumour habitats for ultrasound-guided targeted biopsies.”

Co-first author Paula Martin-Gonzalez, from the Cancer Research UK Cambridge Institute and CRUK Cambridge Centre Ovarian Cancer Programme, added: “We will now be applying this method in a larger clinical study.”

Professor Sala said: “This study provides an important milestone towards precision tissue sampling. We are truly pushing the boundaries in translating cutting edge research to routine clinical care.”

Fiona Barve (56) is a science teacher who lives near Cambridge. She was diagnosed with ovarian cancer in 2017 after visiting her doctor with abdominal pain. She was diagnosed with stage 4 ovarian cancer and immediately underwent surgery and a course of chemotherapy. Since March 2019 she has been cancer free and is now back to teaching three days a week.

“I was diagnosed at a late stage and I was fortunate my surgery, which I received within four weeks of being diagnosed, and chemotherapy worked for me. I feel lucky to be around,” said Barve.

“When you are first undergoing the diagnosis of cancer, you feel as if you are on a conveyor belt, every part of the journey being extremely stressful. This new enhanced technique will reduce the need for several procedures and allow patients more time to adjust to their circumstances. It will enable more accurate diagnosis with less invasion of the body and mind. This can only be seen as positive progress.”

This feasibility study, involving researchers from the Department of Radiology, CRUK Cambridge Institute, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, and collaborators at Cannon, was facilitated through the CRUK Cambridge Centre Integrated Cancer Medicine programme.

The goal of Integrated Cancer Medicine is to revolutionise cancer treatment using complex data integration. Combining and integrating patient data from multiple sources – blood tests, biopsies, medical imaging, and genetic tests – can inform and predict the best treatment decisions for each individual patient.

The study was funded by Cancer Research UK and The Mark Foundation for Cancer Research.

Reference
Lucian Beer, Paula Martin-Gonzalez et al. Ultrasound-guided targeted biopsies of distinct CT based radiomic tumour habitats: proof of concept. European Radiology; 14 Dec 2020; DOI: 10.1007/s00330-020-07560-8

Provided by University of Cambridge

Researchers Create Framework to Help Determine Timing of Cancer Mutations (Medicine)

FINDINGS

UCLA Jonsson Comprehensive Cancer Center researchers studying cancer evolution have created a framework to help determine which tool combinations are best for pinpointing the exact timing of DNA mutations in cancer genomes. There are currently many different algorithms that researchers have developed to help determine the timing of mutations, but until now, it has been unclear which algorithm will work best for which cancer, and what common biases influence their results.

Fig. 1: Subclonal reconstruction workflow and pipeline construction.

BACKGROUND

Cancer is a disease of the genome. As a cancer develops, its DNA is constantly acquiring new mutations and the population of cancer cells is continuously evolving. Knowing the order of changes that have happened allows researchers to study the evolution of the cancer over time and see how the cancer cell population may have diversified, or became more uniform. The diversity or uniformity in the cancer cell population is related to patient response to therapy and reveals vulnerabilities that can be used to create highly targeted treatments.

METHOD

The study assessed 22 different pipelines for timing mutations in cancer genomes. Researchers tested the algorithms on a cohort of nearly 300 clinical prostate cancer samples to evaluate each pipeline and see how their results differed in various aspects. This allowed the team to see the variability across tools and have an unbiased view of how each performed.

IMPACT

Understanding when and why a tumor metastasizes, or spreads to other parts of the body, can influence how a person with cancer is treated. The framework developed in the study can help researchers decide which tool would be the most accurate for their case and generate a more personalized and targeted treatment plan for patients, minimizing the risk of cancer coming back in the future.

AUTHORS

The senior author is Paul Boutros, PhD, a professor of urology and human genetics at the David Geffen School of Medicine at UCLA who serves as associate director of cancer informatics at the UCLA Institute for Precision Health and director of cancer data science at the Jonsson Cancer Center. The first author is Lydia Liu, a PhD candidate at the University of Toronto and Visiting Graduate Researcher at UCLA, co-supervised by Dr. Thomas Kislinger at the University of Toronto and Dr. Boutros at UCLA.

JOURNAL

The study was published online in Nature Communications.

FUNDING

The work was supported in part by Prostate Cancer Canada, the Movember Foundation, the Canadian Cancer Society, the Canadian Institutes of Health Research and National Cancer Institute.

Reference: Liu, L.Y., Bhandari, V., Salcedo, A. et al. Quantifying the influence of mutation detection on tumour subclonal reconstruction. Nat Commun 11, 6247 (2020). https://www.nature.com/articles/s41467-020-20055-w https://doi.org/10.1038/s41467-020-20055-w

Provided by ULCA- Health Sciences

New Therapy to Target The Spread of Bowel Cancer (Oncology / Medicine)

For the first time, SAHMRI and University of Adelaide researchers are investigating gene therapy as an option to help people with metastatic bowel cancer.

Credit: South Australian Health and Medical Research Institute

Like most cancers, bowel cancer is surrounded by many normal cells that are corrupted to support cancer growth. Dr. Susan Woods, A/Prof Daniel Worthley and their team have been studying why some of these supportive cells (fibroblasts) assist cancer growth, while others actively work to stop it.

“In bowel cancer, we know that patients with the poorest prognosis have a lot of these corrupted or bad tumour supporting fibroblasts,” Dr. Woods said.

“Bad fibroblasts can promote abnormal growth of the tumour cells, while the good fibroblasts slow tumour growth and reduce tumour spread.”

The groups latest research study published in Gastroenterology, shows how cancers corrupt fibroblasts to support their growth and that virally-delivered gene therapy is able to reproduce good fibroblast signals within the tumour environment.

Dr. Hiroki Kobayashi, a key member of the team, generated a new gene therapy to deliver good fibroblast signals directly to the supporting cells.

“Most bowel cancers metastasise to the liver. In our preclinical models, the treatment works by injecting a virus that exclusively targets the liver. This generates more of the good cancer support cell signals in that organ, shrinking the tumour and ultimately extending lifespan,” Dr. Kobayashi said.

This sort of gene therapy has been used to treat blood disease in humans, but never in cancer.

The next step is to see whether this treatment is valuable for other cancers that also spread to the liver, such as lung and breast cancer and other gastrointestinal cancers, like oesophageal, stomach and pancreas.

References: Hiroki Kobayashi et al. The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis., Gastroenterology (2020). https://linkinghub.elsevier.com/retrieve/pii/S0016508520354007 DOI: 10.1053/j.gastro.2020.11.011

Provided by SAHMRI

New Type of Immunotherapy May Pave the Way For Better Cancer Treatments (Medicine)

Immunotherapy for cancer has made great advances and many patients can now receive effective treatments that were not available ten years ago. However, there are certain types of cancer that do not respond to existing immunotherapy. A study from Karolinska Institutet in Sweden published in Proceedings of the National Academy of Sciences (PNAS) reports on a new kind of immunotherapy that gives hope of more treatment options for cancer in the future.

From left: First author Silke Eisinger and last author Mikael Karlsson from Karolinska Institutet in Sweden. ©Mitch Eisinger

Cancer cells have the ability to reprogramme immune cells in a way that benefits tumour growth. After years of research it has been possible to exploit the immune system in the fight against cancer, whereby different antibodies can trigger immune system T cells to attack the cancer cells.

Macrophages are a different type of cells and play a crucial role in the immune system, where they recruit T cells to an area that has been affected by foreign organisms and regulate their function. Unfortunately, certain tumours develop ways to shut off the immune system, including making the macrophages in the tumour block the T cells.

“In our study, we’ve developed a new type of immunotherapy in which specific antibodies activate the macrophages so that they support the immune system and kill the cancer cells instead,” says the study’s last author Mikael Karlsson, professor in the Department of Microbiology, Tumour and Cell Biology at Karolinska Institutet.

The study also shows that NK cells, another important cell of the immune system, are primarily activated by this new immunotherapy to work alongside the T cells to kill the tumour, as opposed to existing immunotherapies, in which only the T cells are activated.

“It also turns out that when the NK cells are activated by macrophages, their cancer-fighting ability is hugely effective,” Mikael Karlsson says.

The study, which was conducted in collaboration with Rockefeller University in New York, was initially a modelling study. The researchers then applied their discovery to human skin tumours to assay the transferability of their results.

“We can also see that these specific antibodies trigger the human macrophages, which in turn activate the NK cells to kill the cancer cells,” Mikael Karlsson explains.

These findings therefore indicate that the new immunotherapy activates a different part of the immune system compared to previous therapies, and can hopefully be used in combination with existing treatments.

“The teamwork between the NK and T cells boosts their efficacy, which can help make more types of cancer treatable in the future,” Mikael Karlsson concludes.

References: “Targeting a scavenger receptor on tumor-associated macrophages activates tumor cell killing by NK cells”, Silke Eisinger, Dhifaf Sarhan, Vanessa F. Boura, Itziar Ibarlucea-Benitez, Sofia Tyystjärvi, Ganna Oliynyk, Marie Arsenian-Henriksson, David Lane, Stina L. Wikström, Rolf Kiessling, Tommaso Virgilio, Santiago F. Gonzalez, Dagmara Kaczynska, Shigeaki Kanatani, Evangelia Daskalaki, Craig E. Wheelock, Saikiran Sedimbi, Benedict J. Chambers, Jeffrey V. Ravetch, Mikael C.I. Karlsson, Proceedings of the National Academy of Sciences, online week of Nov. 23, 2020.

Provided by Karolinska Institute

A New Diagnostic Method Predicts Which Cancer Patients Will Respond To Immunotherapy (Medicine)

Banafshe Larijani, the Ikerbasque professor at the Biofisika Institute, leads the international team that has developed the tool.

Immunotherapy is a type of cancer treatment that helps the patient’s immunological system to combat it and has a hugely positive impact in cancer treatments, even though it does not work in all cases: it is highly successful in some patients whereas in others it has little or no effect. Given the risks inherent in these procedures, a growing need has emerged to specify which patients are more likely to benefit from them, thus avoiding unnecessary exposure of those who will not benefit.

Dr Banafshe Larijani, an Ikerbasque researcher seconded to the Biofisika Institute (UPV/EHU-University of the Basque Country, CSIC), leads the international group that has developed the new diagnostic method. ©Ikerbasque – UPV/EHU

Fellow researchers from other centres in the Basque Country (Biocruces, PIE, BCAM), in Europe and the company FASTBASE Solutions Ltd have participated in the group led by Dr Larijani, who is also the director of the Centre for Therapeutic Innovation of the University of Bath (United Kingdom). The new predictive tool has been developed by using an advanced microscopy platform that identifies the interactions between the immune cells and the tumour cells and also informs about the activation state of the immune checkpoints that buffer the anti-tumour response.

The team has published its findings in the prestigious journal Cancer Research. Dr Larijani’s team has analysed one immune checkpoint. In a healthy individual these checkpoints closely regulate the body’s immune response, acting as a switch to prevent self-immune and inflammatory diseases.

Specifically, the immune checkpoint analysed comprises two proteins: PD-1 (present in immune cells known as T-lymphocytes) and PD-L1 (present in other types of immune cells and on the surface of many different types of tumours).

As a rule, when PD-1 on the surface of T-lymphocytes joins up with PD-L1 on the surface of other immune cells, it efficiently switches off the immune function of the T cell. And that is what tumour cells do: when PD-L1 is expressed on their surface, PD-1 is activated in the T-lymphocyte, so their anti-tumour function is deactivated and the tumour is allowed to survive and grow. The inhibitors used in immunotherapy function by interrupting the interaction between PD-L1 on the tumour and PD-1 in the T cell, thus restoring the patient’s anti-tumour activity. This new tool determines the scope of the PD-1 / PD-L1 interaction in a tumour biopsy by predicting whether therapy using checkpoint inhibitors is likely to bring significant clinical benefits.

“Right now, decisions about whether to proceed with checkpoint inhibitor treatment are simply based on whether PD-1 and PD-L1 are present in the biopsies rather than in their functional state. However, our work has shown that it is much more important to know that the two proteins actually interact and, therefore, that they are likely to have a functional impact on the survival of the tumour,” said Prof Larijani.

References: Lissete Sánchez-Magraner, James Miles, Claire L. Baker, Christopher J. Applebee, Dae-Jin Lee, Somaia Elsheikh, Shaimaa Lashin, Katriona Withers, Andrew G. Watts, Richard Parry, Christine Edmead, Jose Ignacio Lopez, Raj Mehta, Antoine Italiano, Stephen G. Ward, Peter J. Parker and Banafshé Larijani
High PD-1/PD-L1 checkpoint interaction infers tumour selection and therapeutic sensitivity to anti-PD-1/PD-L1 treatment
Cancer Research 80(19): 4244-4257. https://doi.org/10.1158/0008-5472.CAN-20-1117
DOI: 10.1158/0008-5472.CAN-20-1117

Provided by University of Basque

Animation Reveals Secrets Of Critical Tumour Protein (Biology / Oncology)

The latest animation technology has revealed the molecular detail of how our bodies are protected from cancer by a key ‘tumour suppressor’ protein.

The new WEHI-TV animation visualises discoveries from more than 40 years of research to explain how the tumour suppressor protein p53 normally prevents cancer-causing changes in cells. More than half of human cancer cases involve faulty p53.

The animation was produced by WEHI.TV biomedical animator Ms Etsuko Uno, who worked closely with WEHI cancer researchers Professor Andreas Strasser and Dr Gemma Kelly to ensure the animation’s scientific accuracy.

At a glance

  • A new WEHI.TV animation explains how the ‘tumour suppressor’ protein p53 protects our body from cancer.
  • This animation is based on more than 40 years of research on p53 and includes recent discoveries from WEHI scientists.

Controlling cell life and death

In our bodies, p53 is an essential controller of cell division, cell death and DNA repair, ensuring that healthy cells can divide as needed, but forcing cells with damaged DNA to stop dividing and undergo repair – or die, if the damage is too severe. These processes are critical for maintaining good health; cancer is caused by damaged cells being allowed to persist and grow uncontrollably.

Cancer researcher Dr Gemma Kelly, who narrated the animation, said more than half of human cancers carry defects in p53.

“The most frequently mutated gene in human cancer is p53 – and it is, I think, the most important ‘tumour suppressor’ protein. Mutations of the p53 gene are particularly common in several prevalent cancer types with poor prognosis, including lung cancer, ovarian cancer and pancreatic cancer,” she said.

“Despite 40 years of intense research into p53, there is still a lot to learn about how this tumour suppressor works, in order to develop better therapies for cancers that have defective p53.”

Using animation to understand science

The new WEHI.TV animation was created to clearly explain the latest knowledge about p53, said its creator Ms Etsuko Uno.

“Working closely with our researchers, I was able to produce very complex pictures of p53 functioning within cells, which reflect the most up-to-date data about this tumour suppressor,” she said.

“This has been one of the most challenging proteins I have illustrated, because – unlike most other proteins I have tackled – this protein is largely unstructured. WEHI’s structural biology researchers provided valuable guidance on how to accurately depict it.”

“To create the detailed molecular shapes and movements, we turned to technologies used to make computer games, using a production software called Unity,” Ms Uno said.

Explaining p53’s function

The animation shows how p53 (in yellow) can attach to DNA (magenta and beige) to ‘turn on’ specific genes. ©WEHI, Australia

The new animation demonstrates how p53 responds to DNA damage in cells, ‘turning on’ the production of proteins that can repair the damage. It also stops the cells dividing, to allow time for this repair and prevent errors in genes being transmitted to new cells. However, if the damage is too severe, p53 delivers its final blow, directing the production of ‘cell death’ proteins that trigger the cell’s demise, by a programmed cell death process called apoptosis.

The animation also explains how malfunctions in p53 can lead to cancer development, by not adequately repairing DNA damage within cells.

Cancer researcher Professor Andreas Strasser said the animation provided a vivid and accessible explanation of how tumour suppressors within our cells work to prevent cancer developing. “It’s a wonderful educational resource, which clearly explains how p53 protects us from cancer,” he said.

“I am thrilled to see how it incorporates the latest discoveries about how p53 functions – including discoveries made by my own research group – incorporated in a dynamic and scientifically accurate way.”

Professor Strasser and Dr Kelly’s research into p53 has received substantial support from the Dyson Bequest, The Craig Perkins Cancer Research Foundation, the National Health and Medical Research Council, the Victorian Cancer Agency, Cancer Council Victoria, the Leukemia Foundation of Australia, the Redstone Foundation Bequest and the Victorian Government.

Provided by Walter and Eliza Hall Institute

Glioblastoma Nanomedicine Crosses Into Brain In Mice, Eradicates Recurring Brain Cancer (Medicine)

‘I’ve worked in this field for more than 10 years and have not seen anything like this.’

A new synthetic protein nanoparticle capable of slipping past the nearly impermeable blood-brain barrier in mice could deliver cancer-killing drugs directly to malignant brain tumors, new research from the University of Michigan shows.

The study is the first to demonstrate an intravenous medication that can cross the blood-brain barrier.

The discovery could one day enable new clinical therapies for treating glioblastoma, the most common and aggressive form of brain cancer in adults, and one whose incidence is rising in many countries. Today’s median survival for patients with glioblastoma is around 18 months; the average 5-year survival rate is below 5%.

In combination with radiation, the U-M team’s intravenously injected therapy led to long-term survival in seven out of eight mice. When those seven mice experienced a recurrence of glioblastoma, their immune responses kicked in to prevent the cancer’s regrowth–without any additional therapeutic drugs or other clinical treatments.

“It’s still a bit of a miracle to us,” said Joerg Lahann, the Wolfgang Pauli Collegiate Professor of Chemical Engineering and a co-senior author of the study. “Where we would expect to see some levels of tumor growth, they just didn’t form when we rechallenged the mice. I’ve worked in this field for more than 10 years and have not seen anything like this.”

The findings suggest that the U-M team’s combination of therapeutic drugs and nanoparticle delivery methods not only eradicated the primary tumor, but resulted in immunological memory, or the ability to more quickly recognize–and attack–remaining malignant cancer cells.

“This is a huge step toward clinical implementation,” said Maria Castro, the R.C. Schneider Collegiate Professor of Neurosurgery and a co-senior author of the study. “This is the first study to demonstrate the ability to deliver therapeutic drugs systemically, or intravenously, that can also cross the blood-brain barrier to reach tumors.”

Five years ago, Castro knew how she wanted to target glioblastoma. She wanted to stop a signal that cancer cells send out, known as STAT3, to trick immune cells into granting them safe passage within the brain. If she could shut down that pathway with an inhibitor, the cancer cells would be exposed and the immune system could eliminate them. But she didn’t have a way to get past the blood-brain barrier.

She attended a workshop at the Biointerfaces Institute, which Lahann leads, and the two discussed the problem. Lahann’s team began working on a nanoparticle that could ferry a STAT3 inhibitor past the blood-brain barrier.

A protein called human serum albumin, which is present in blood, is one of the few molecules that can cross the blood-brain barrier, so Lahann’s team used it as the structural building block for their nanoparticles. They used synthetic molecules to link these proteins up and then attached the STAT3 inhibitor and a peptide called iRGD, which serves as a tumor homing device.

Over the course of three weeks, a cohort of mice received multiple doses of the new nanomedicine, extending their median survival to 41 days, up from 28 days for those untreated. Following that success, the team performed a second mouse study using the drug alongside today’s current standard of care: focused radiotherapy. Seven of the eight mice reached long-term survival and appeared completely tumor-free, with no signs of malignant, invasive tumor cells.

The researchers say their synthetic protein nanoparticles could be adopted, after further development and preclinical testing, to deliver other small-molecule drugs and therapies to currently “undruggable” solid-based tumors.

References: Gregory, J.V., Kadiyala, P., Doherty, R. et al. Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy. Nat Commun 11, 5687 (2020). https://www.nature.com/articles/s41467-020-19225-7 https://doi.org/10.1038/s41467-020-19225-7

Provided by University of Michigan