Tag Archives: #childhoodcancer

Scientists Use Tiny Bubbles To Help Treat Common Childhood Cancer (Medicine)

Researchers at UCL have developed a new way to deliver drugs that can shut down cancer-promoting mutations in neuroblastoma. The findings in mice, show the method, which uses tiny bubbles to deliver therapies directly to tumour cells, reduced tumour growth and improved survival.

Neuroblastoma is the most common solid tumour found in children and accounts for about 15% of all cancer-related deaths in children. Tumours develop from certain types of nerve cells and are most commonly found in the abdomen. Children who are diagnosed above the age of one often fail to respond to treatment or relapse at a later time, meaning that there is an urgent need for new treatment options. 

The research, published in Advanced Functional Materials and funded by Worldwide Cancer Research, now offers a new potential treatment approach. MYCN is a gene that is associated with poor prognosis and is found to be mutated or overactive in about 20% of neuroblastoma cases. The gene is usually expressed during foetal development and is involved in cell growth and development. Neuroblastoma cells continue to express too much MYCN, leading to uncontrolled cell growth and division and preventing cancer cells from dying.

Researchers at UCL Great Ormond Street Institute of Child Health have now found a way to silence MYCN by delivering a certain type of genetic material called siRNA, directly to the tumour cells. They developed nanoparticles – or tiny bubbles – that use the leaky blood vessels around the tumour and certain features that are only present on tumour cells to home in on the tumours.

The vast majority of nanoparticles, which were delivered via injection, located to the tumour and successfully shut down the MYCN gene causing the cancer. The treatment caused the tumours to grow at a slower pace and prolonged the time that the mice survived the cancer.

Senior author, Professor Stephen Hart, UCL GOS ICH, said: “These findings show that this approach with MYCN siRNA delivered by a nanoparticle is a new potential therapy for neuroblastoma. The next steps would be to develop methods of scaling up production to clinical grade, and to show that the treatment is safe. Current therapies such as surgery, radio and chemotherapy are effective at removing the primary tumour but, unfortunately, in many cases the tumour will return at other sites in the body, which is much harder to treat. We hope that this therapy might augment conventional therapies and provide a way of targeting the therapy to these new tumour sites.”

Dr Helen Rippon, Chief Executive at Worldwide Cancer Research said: “Each year about 100 families in the UK receive the devastating news that their child has developed neuroblastoma. Unfortunately, the cancer is often detected at a relatively late stage and intense treatment is needed.

“We are funding researchers, like Professor Hart, to start new cancer cures and this innovative research shows just how important investment in early-stage discovery research is. Using new methods, such as nanoparticles, to deliver treatment straight to the heart of cancer is an incredibly exciting area of research. These new results now offer hope to patients and their families by paving the way for effective new treatment options.”



  • UCL Great Ormond Street Institute of Child Health

Provided by UCL

Childhood Cancer Discovery May Stop Tumour Spread Before it Starts (Medicine)

New understanding of how Ewing sarcoma tumours travel through the body has the potential to prevent metastatic spread in a number of cancer types

A new discovery in Ewing sarcoma, an aggressive and often fatal childhood cancer, has uncovered the potential to prevent cancer cells from spreading beyond their primary tumour site.

The breakthrough provides new insight into what triggers the process that allows cancer cells to survive while traveling through the body in the bloodstream.

Researchers with the University of British Columbia and BC Cancer have learned that Ewing sarcoma cells–and likely other types of cancer cells–are able to develop a shield that protects them from the harsh environment of the bloodstream and other locations as they search for a new place to settle, or metastasize. The study has just been published in Cancer Discovery.

“You might think that a tumour cell could readily survive in the bloodstream, but it’s actually a very harsh environment,” said the study’s senior author Dr. Poul Sorensen, a distinguished scientist at BC Cancer, professor of pathology and laboratory medicine and director of the faculty of medicine’s newly-created Academy of Translational Medicine at the University of British Columbia.

“What we found was that Ewing sarcoma cells are able to develop an antioxidant response that shields them and allows them to survive as they circulate,” said Dr. Sorensen. “This is similar to a person in the Arctic having to put a thick coat on before they go outside. If they don’t shield themselves, they are exposed to dangerously harsh conditions under which they may not survive.”

Metastatic disease, which occurs when cancer has spread throughout the body, is the single most powerful predictor of poor outcome for cancer patients of all ages and has been a difficult process for researchers to study or for clinicians to target.

“What’s exciting about this study is if we can target the cells in circulation then maybe we can prevent metastasis from occurring. So that’s the really big goal of this research,” said Dr. Sorensen.

Not a lot of cells are able to become metastatic. While there has been research into genetic reasons a tumour mutates and spreads, what these researchers found is that Ewing sarcoma cells turn on the expression of a naturally-occurring gene on the surface of the cell, known as IL1RAP, to create a protein protective shield.

“This study is the first to show that the surface protein, IL1RAP, is rarely expressed in normal tissue, but is upregulated in childhood sarcomas” said Dr. Haifeng Zhang, a UBC postdoctoral fellow in Dr. Sorensen’s laboratory at BC Cancer and first author of the study. “This is a really good thing because it means we can develop treatments to target IL1RAP without producing toxic side effects in non-cancer cells.”

Drs. Sorensen and Zhang’s colleagues, who are members of the St. Baldrick’s Foundation-Stand Up To Cancer Pediatric Dream Team as well as the National Cancer Institute Pediatric Immunotherapy Discovery and Development Network (PI-DDN), have been developing antibodies that can target IL1RAP.

“These powerful antibodies can bind to the outside of the cell and we show in our research that these reagents can actually kill Ewing sarcoma cells. So not only have we discovered an interesting pathway, but we are well on our way to developing a clinical-grade immunotherapeutic treatment for Ewing sarcoma,” said Dr. Sorensen.

“We are optimistic that we can work towards clinical trials in the next year or two,” added Dr. Zhang.

Research is underway to investigate whether the same shielding behaviour can be found in other cancer cell types, including acute myeloid leukemia, melanoma, pancreatic adenocarcinoma, central nervous system tumours, and in some types of lung and breast cancers.

Reference: Hai-Feng Zhang, Christopher S Hughes, Wei Li, Jian-Zhong He, Didier Surdez, Amal M El-Naggar, Hongwei Cheng, Anna Prudova, Alberto Delaidelli, Gian Luca Negri, Xiaojun Li, Maj Sofie Orum-Madsen, Michael M Lizardo, Htoo Zarni Oo, Shane Colborne, Taras Shyp, Renata Scopim-Ribeiro, Colin A Hammond, Anne-Chloe Dhez, Sofya Langman, Jonathan KM Lim, Sonia HY Kung, Amy Li, Anne Steino, Mads Daugaard, Seth J Parker, Ramon I Klein Geltink, Rimas J Orentas, Li-Yan Xu, Gregg B Morin, Olivier Delattre, Dimiter S. Dimitrov and Poul H Sorensen, “Proteomic screens for suppressors of anoikis identify IL1RAP as a promising surface target in Ewing sarcoma”, Cancer Discovery, 2021. DOI: 10.1158/2159-8290.CD-20-1690

Provided by University of British Columbia

Multimodal Therapy May Hold Key To Treating Aggressive Childhood Cancer (Medicine)

Research led by scientists at Children’s Cancer Institute and published this week in the international journal, Clinical Cancer Research, has found a combination of therapies that appears to be highly effective against high-risk neuroblastoma and other forms of aggressive childhood cancer.

Up to half of all cases of neuroblastoma newly diagnosed in children are ‘high-risk’, meaning the cancer grows aggressively and is difficult to treat. Despite receiving intensive treatment, most children with high-risk disease die within five years of diagnosis, while those who survive are often left with serious long-term health effects.

Professor Michelle Haber AM, a senior author on the paper and co-head of the Molecular Targets and Cancer Therapeutics theme at Children’s Cancer Institute, said children diagnosed with high-risk neuroblastoma have less than a 50-50 chance of survival. “That is a devastating prognosis. We are absolutely determined to find better ways to treat this disease and improve that survival rate.”

The research focuses on two different types of therapies, both of which have been found to be effective against high-risk neuroblastoma in the laboratory. The first, CBL0137, is a compound called a curaxin, structurally similar to antimalarial drugs. The second is panobinostat, a new type of compound known as a histone deacetylase inhibitor. In the new research, the scientists tested whether the two therapies could work synergistically when used together, each enhancing the anticancer effect of the other.

The researchers found that the two compounds did indeed work well together, effectively inhibiting the growth of cancer cells in culture, as well as in mice bred to develop human high-risk neuroblastoma. As an added bonus, the therapies also jointly acted to heighten the body’s immune response to cancer, which is important since immunotherapy in neuroblastoma is currently challenging.

“In our experiments, we found that the combination of CBL0137 and panobinostat resulted in remarkable growth suppression and an immune response that was tumour-specific,” said Professor Haber. “This is very encouraging, because ideally you want a cancer treatment to specifically target cancer cells and leave healthy cells unharmed, reducing the problem of side effects.”

Dr Lin Xiao, joint first author and Research Officer in the Experimental Therapeutics Group at the Institute added, “When we used these two compounds together in mice with high-risk neuroblastoma, we saw complete and lasting tumour regression, with minimal ill-effects on the mice. Our results suggest that this combination could work well as a type of immunotherapeutic approach to treating high-risk neuroblastoma.”

Further research at Children’s Cancer Institute has shown that this type of multimodal therapy is also effective against other high-risk childhood cancers, including some forms of brain cancer. Together, it is hoped these results will lead to a new therapy for aggressive childhood cancer.

This work was supported by funding from Cancer Institute NSW, Neuroblastoma Australia, the Kids Cancer Alliance (KCA), Tenix Foundation, Anthony Rothe Memorial Trust, the National Health and Medical Research Council (NHMRC), the Goodridge Foundation, Stanford Brown, Inc (Sydney, Australia), Cancer Council NSW and Tour de Cure.

This science news is confirmed by us from Children’s Cancer Institute

Provided by Children’s Cancer Institute

About Children’s Cancer Institute

Originally founded by two fathers of children with cancer in 1976, Children’s Cancer Institute is the only independent medical research institute in Australia wholly dedicated to research into the causes, prevention and cure of childhood cancer. Forty years on, our vision is to save the lives of all children with cancer and improve their long-term health, through research. The Institute has grown to now employ over 300 researchers, operational staff and students, and has established a national and international reputation for scientific excellence. Our focus is on translational research, and we have an integrated team of laboratory researchers and clinician scientists who work together in partnership to discover new treatments which can be progressed from the lab bench to the beds of children on wards in our hospitals as quickly as possible. These new treatments are specifically targeting childhood cancers, so we can develop safer and more effective drugs and drug combinations that will minimise side-effects and ultimately give children with cancer the best chance of a cure with the highest possible quality of life. More at http://www.ccia.org.au.

Researchers Identify Gene Implicated in Neuroblastoma, a Childhood Cancer (Medicine)

 A new study by Mayo Clinic researchers has identified that a chromosome instability gene, USP24, is frequently missing in pediatric patients with neuroblastoma, an aggressive form of childhood cancer. The finding provides important insight into the development of this disease. The study is published in Cancer Research, the journal of the American Association for Cancer Research.

“Neuroblastoma is a highly aggressive cancer that nearly exclusively affects young children,” says Paul Galardy, M.D., a pediatric hematologist and oncologist at Mayo Clinic. Despite the use of multiple treatment approaches, Dr. Galardy says many children die of this disease every year.

To identify new therapeutic approaches, Dr. Galardy and his colleagues examined the role of a set of enzymes known as deubiquitinating enzymes (DUB) in this disease. They chose this family of enzymes because they could be targeted using drug therapy.

“Little is known about the role of DUBs in neuroblastoma,” says Dr. Galardy. “We used a computational approach to determine the effect of too much or too little of a gene on the outcome of a variety of human cancers to identify DUBs that may play a role in treating neuroblastoma.”

Dr. Galardy and his team used this method to identify two genes ― USP24 and USP44 ― with the biggest potential to affect the outcomes of young patients with neuroblastoma. “These genes were the ones most closely implicated as being important for accurate cell division,” he says.

Dr. Galardy says that his team found that USP44 plays an important role in cell division and was associated with poor outcomes in lung cancer. Therefore, the team shifted its attention to USP24 to understand how it might contribute to neuroblastoma.

“Little is known about how USP24 functions,” says Dr. Galardy. “We observed low levels of USP24 in children with neuroblastoma whose tumors were highly aggressive, leading to early progression or recurrence of the disease.” He says low levels of USP24 occur commonly with other markers of aggressive disease, including amplification of the MYCN cancer gene and a loss of a large segment of chromosome 1.

The team also found that USP24 is not simply a marker for aggressive disease. Using genetically engineered mice that lack the USP24 gene, they found that USP24 plays an important role in protecting cells against errors in chromosome distribution that take place during cell division.

“When we compared cells with normal or deleted USP24, and examined the levels of proteins in dividing cells, we found that mice lacking even one of the two copies of USP24 were more prone to developing tumors,” says Dr. Galardy. “This helped lead us to our conclusion that USP24 may play a role in ensuring accurate cell division, and that a loss of USP24 in mice leads to tumor formation and may also contribute to the development of aggressive neuroblastoma tumors in children.” 

Featured image: International Childhood Cancer Awareness Day © Mayo Clinic

Reference: Tibor Bedekovics, Sajjad Hussain, Ying Zhang, Asma Ali, Young J Jeon and Paul J Galardy, “USP24 is a cancer-associated ubiquitin hydrolase, novel tumor suppressor, and chromosome instability gene deleted in neuroblastoma”, Cancer Research, 2021. https://cancerres.aacrjournals.org/content/early/2020/12/22/0008-5472.CAN-20-1777

About Mayo Clinic

Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news and Mayo Clinic Facts for more information about Mayo.

Researchers Identify Potential Revolutionary New Drug Treatment For Fatal Childhood Cancer (Medicine)

Every year around 20 Australian children die from the incurable brain tumour, Diffuse Intrinsic Pontine Glioma (DIPG). The average age of diagnosis for DIPG is just seven years. There are no effective treatments, and almost all children die from the disease, usually within one year of diagnosis.

A paper published today in the prestigious journal, Nature Communications, reveals a potential revolutionary drug combination that – in animal studies and in world first 3D models of the tumour – is “spectacularly effective in eradicating the cancer cells,” according to lead researcher and paediatric oncologist Associate Professor David Ziegler, from the Children’s Cancer Institute and Sydney Children’s Hospital.

In pre-clinical testing in mouse models, the researchers found that the promising drug combination led to survival in two thirds of the mice and that the drug combination completely halted growth of these highly aggressive tumours in these mice.

Importantly, the drug therapy, which is currently in early trials in adult cancer, is the most effective treatment ever tested in laboratory models of this incurable childhood cancer. The treatment is a combination of two drugs: difluoromethylornithine (DFMO), an established drug, and AMXT 1501, an investigational agent being developed by Aminex Therapeutics.

DFMO is increasingly getting attention as a treatment for difficult-to-control cancers like neuroblastoma, another aggressive childhood cancer, and colorectal cancer in adults. DFMO works by targeting the polyamine pathway – an important mechanism that allows tumour cells to grow.

Associate Professor Ziegler has shown for the first time that the polyamine pathway is critical to the growth of DIPG cells. Ziegler and his team developed Australia’s first research program into DIPG by using tumour cells donated by the parents of children who have passed away from the disease. From these, they created the first laboratory models of the tumour in order to test new drugs. These models have been used to show that DIPG can bypass the activity of DFMO by pumping polyamines into the cancer, essentially allowing the tumour to continue growing despite treatment with DFMO. They have now made the breakthrough discovery that treatment with a new developmental drug, AMXT 1501, potently blocks the transport of polyamines into the DIPG cancer cell. Treatment with AMXT 1501 was found to re-sensitize the DIPG cells to DFMO leading to what Associate Professor Ziegler said, “was a spectacular response in animal models, with a significantly increased survival and minimal toxicity (side effects)”.

Associate Professor Ziegler said that clinical trials of the drug combination in DIPG are planned to begin this year in children in a global study led by the Children’s Cancer Institute and the Kid’s Cancer Centre at Sydney Children’s Hospital.

The Australian DIPG Tumour Database was started by the Children’s Cancer Institute in 2011. Australia’s first DIPG tumour data base has allowed Associate Professor Ziegler and colleagues to make great inroads into solving this disease. “Since establishing the tumour bank we have been able to grow this very aggressive cancer in our laboratories to allow us to screen hundreds of drugs to find those that are effective at killing the cancer cells. Its due to this capacity that we have been able to discover what we hope will be the first effective treatment for DIPG,” he said.

Rachael Gjorgjijoska was the first parent to agree to donate DIPG tumour tissue following the death of her daughter Liliana at just 4 years old, 15 months after her diagnosis. Rachael comments “We made the difficult decision to donate Liliana’s tumour because we wanted to make a difference, there were no treatments to save Liliana from this devastating disease, but if her cancer cells help advance research so there be new treatments for children in the future, this will be a lasting memory of our little girl.”

Dr. Mark R. Burns, the Founder, President and Chief Scientific Officer at Aminex Therapeutics, and inventor of AMXT 1501 said “the dramatic results against this devastating disease demonstrated by Dr. Ziegler and his team adds greater fire to our motivation to see these findings duplicated against human cancers. We share hope that this treatment will make a difference in the lives of those with DIPG and other aggressive cancers.”

This work was supported by grants from the National Health and Medical Research Council, Cancer Institute NSW, the DIPG Collaborative, the Cure Starts Now, Cure Brain Cancer Foundation, Levi’s project, Benny Wills Brain Tumour Research fund, Tour de Cure, Isabella and Marcus Foundation’s Gemma Howell Scholarship and drug supply from Aminex Therapeutics, Inc.

View the article at https://www.nature.com/articles/s41467-021-20896-z

Featured image: David Zeigler © CCI

Reference: Khan, A., Gamble, L.D., Upton, D.H. et al. Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas. Nat Commun 12, 971 (2021). https://doi.org/10.1038/s41467-021-20896-z

Provided by Children’s Cancer Institute

About Children’s Cancer Institute

Originally founded by two fathers of children with cancer in 1976, Children’s Cancer Institute is the only independent medical research institute in Australia wholly dedicated to research into the causes, prevention, and cure of childhood cancer. Forty years on, our vision is to save the lives of all children with cancer and improve their long-term health, through research. The Institute has grown to now employ over 300 researchers, operational staff and students, and has established a national and international reputation for scientific excellence. Our focus is on translational research, and we have an integrated team of laboratory researchers and clinician scientists who work together in partnership to discover new treatments which can be progressed from the lab bench to the beds of children on wards in our hospitals as quickly as possible. These new treatments are specifically targeting childhood cancers, so we can develop safer and more effective drugs and drug combinations that will minimise side-effects and ultimately give children with cancer the best chance of a cure with the highest possible quality of life. More at www.ccia.org.au

About Aminex Therapeutics

Aminex Therapeutics, Inc. is a clinical-stage biotechnology company focused on the development of a novel small molecule combination therapy for the treatment of broad range of cancer indications. Aminex has advanced AMXT 1501 + DFMO through target discovery, patenting, pre-clinical research and now into clinical development for the potential benefit of cancer patients. For more information, please visit www.aminextx.com

New Drug Targets For Childhood Cancer Neuroblastoma Identified (Medicine)

All neuroblastomas arise from developmental cells not normally found in children, making them a promising target for drug development

The largest single cell study to date of the childhood cancer, neuroblastoma, has answered important questions about the genesis of the disease. The researchers from the Wellcome Sanger Institute, Great Ormond Street Hospital (GOSH) and their collaborators, discovered that all neuroblastomas arise from a single type of embryonic cell called sympathoblasts.

The study, published today (5 February 2021) in Science Advances, sought to understand why neuroblastomas range in severity, with some easy to treat and others having relatively low five-year survival rates. The fact that all neuroblastomas arise from sympathoblasts makes them an attractive drug target, because these cells exist only in the tumour after the child is born.

Neuroblastoma is a rare cancer that generally affects children under five years old. It begins in the abdomen, usually in the adrenal glands – hormone-producing glands above the kidneys. Neuroblastoma is remarkable in that its severity can vary greatly between individuals. In some children the cancer will disappear without treatment, whereas in others the cancer is relentless. The five-year survival rate for neuroblastoma is one of the lowest of all childhood cancers*.

This varied outlook prompted the researchers to ask whether the range of severity could be caused by neuroblastomas arising from different cell types at different stages of the child’s development in the womb. This was made possible by the advent of single cell mRNA sequencing, a high-resolution technology that can identify different cell types present in a tissue according to the genes expressed by individual cells.

In this study, gene expression of 19,723 cancer cells was analysed and compared to a reference of 57,972 developmental adrenal cells in the hope of identifying the cell types from which neuroblastomas arise and to find novel treatment targets.

“What is most striking about our findings is that despite the great diversity of clinical behaviour of neuroblastoma, there is a patient overarching neuroblastoma cell type. The identification of sympathoblasts as the root of all neuroblastoma is an important step towards understanding how the disease develops and, hopefully, how we can treat it.”

— Dr Jan Molenaar, a senior author of the study from the Princess Maxima Centre for Pediatric Oncology in the Netherlands

Currently, many cancer treatments cause serious side-effects for the patient. But in recent years, technological advances have sped up drug development by allowing researchers to identify differences between the biological processes, such as the expression of a particular gene, within healthy human cells and those within cancerous ones. These differences can be exploited to attack cancer cells without affecting the patient’s healthy cells.

The presence of sympathoblasts, a developmental cell type not normally found in children after they are born, makes it a promising drug target for the treatment of neuroblastoma.

“Neuroblastoma is an unusual cancer in that some tumours resolve without intervention, yet the disease still has one of the lowest five-year survival rates of any childhood cancer. This study fills important gaps in our knowledge of what neuroblastoma cells are and revealed novel treatment targets. My hope is that new, less intrusive therapies can be developed by targeting sympathoblasts, a developmental cell type that exists only in neuroblastoma tumours after a child is born.”

— Dr Karin Straathof, a senior author of the study from Great Ormond Street Hospital

As well as facilitating the discovery of sympathoblasts as the root of neuroblastoma, the single-cell reference map of the developmental adrenal gland will also contribute to the Human Cell Atlas project**. The project aims to create comprehensive reference maps of all types of human cells – the fundamental units of life – as a basis for understanding human health and diagnosing, monitoring, and treating disease.

“Our study shows the power of looking at individual childhood cancer cells in revealing not just one, but a plethora of novel treatment ideas. This raises the exciting prospect that a single cell atlas of all types of paediatric tumours may transform our understanding of childhood cancer.”

Dr Sam Behjati, a senior author of the study from the Wellcome Sanger Institute and Cambridge University Hospitals

Featured image credit: Adobe stock

Reference: Gerda Kildisiute, Waleed M. Kholosy, Matthew D. Young, Kenny Roberts, Rasa Elmentaite, Sander R. van Hooff, Clarissa N. Pacyna, Eleonora Khabirova, Alice Piapi, Christine Thevanesan, Eva Bugallo-Blanco, Christina Burke, Lira Mamanova, Kaylee M. Keller, Karin P.S. Langenberg-Ververgaert, Philip Lijnzaad, Thanasis Margaritis, Frank C.P. Holstege, Michelle L. Tas, Marc H.W.A. Wijnen, Max M. van Noesel, Ignacio del Valle, Giuseppe Barone, Reinier van der Linden, Catriona Duncan, John Anderson, John C. Achermann, Muzlifah Haniffa, Sarah A. Teichmann, Dyanne Rampling, Neil J. Sebire, Xiaoling He, Ronald R. de Krijger, Roger A. Barker, Kerstin B. Meyer, Omer Bayraktar, Karin Straathof, Jan J. Molenaar, Sam Behjati, “Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell”, Science Advances 05 Feb 2021: Vol. 7, no. 6, https://advances.sciencemag.org/content/7/6/eabd3311 eabd3311 DOI: 10.1126/sciadv.abd3311

Provided by Wellcome Trust Sanger Institute

About Wellcome Sanger Institute

The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at http://www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.

Anti-depressant Repurposed To Treat Childhood Cancer (Medicine / Oncology)

A new study has found that a commonly prescribed anti-depressant may halt growth of a type of cancer known as childhood sarcoma, at least in mice and laboratory cell experiments. The findings, from researchers at Karolinska Institutet in Sweden and MD Anderson Cancer Centre in Texas, ignite hope of novel treatment strategies against this disease. The study is published in the journal Cancer Research.

Caitrín Crudden, former PhD student at the Department of Oncology-Pathology at Karolinska Institutet. ©Karolinska Institutet.

“Although this study was done in mice and we do not yet know how translatable the results are to humans, it gives us hope for repurposing common drugs for young cancer patients desperately requiring better treatment options,” says the study’s first author, Caitrín Crudden, a former PhD student in the receptor signaling pathology group at the Department of Oncology-Pathology at Karolinska Institutet.

The study examined commonalities between two large groups of cell surface receptors, the so-called G protein-coupled receptors (GPCRs) and the receptor tyrosine kinases (RTKs). GPCRs are targeted by more than half of all developed drugs to treat conditions such as allergies, asthma, depression, anxiety and hypertension, but have so far not been widely used to treat cancers.

RTKs, on the other hand, are targeted by drugs against cancers, such as breast and colon cancers, due to their implication in a variety of cellular abnormalities. One receptor in the RTK family that plays a key role in many cancers, including childhood sarcoma, is the insulin-like growth factor receptor (IGF1R). However, previous attempts to develop anti-cancer drugs against this receptor have failed.

In this study, the researchers scrutinised the IGF1R and found that it shares a signaling module with the GPCRs, meaning it may be possible to affect its function through drugs targeting the GPCRs. This strategy opens new possibilities of repurposing well-tolerated drugs to silence this tumour-driving receptor and thereby halt cancer growth.

To test their hypothesis, the researchers treated childhood (Ewing) sarcoma cells and mouse models with Paroxetine, an anti-depressant drug that impairs a serotonin reuptake receptor that is part of the GPCR-family. They found that this drug significantly decreased the number of IGF1R receptors on the malignant cells and thereby suppressed the growth of the tumour. The researchers also uncovered the molecular mechanism behind this cross-targeting.

“We have developed a novel strategy to control the activity of these tumour-driving receptors by striking the GPCRs,” says Leonard Girnita, researcher in the Department of Oncology-Pathology, Karolinska Institutet, and principle investigator of the study. “To our knowledge this represents a new paradigm for the entire class of cancer-relevant RTKs and could be used as a starting point for the rational design of specific therapeutics in virtually any pathological conditions. This is especially important considering the huge number of GPCR-targeting medicines already in clinical use and with low toxicity.”

Next, the researchers plan to develop their strategy to selectively cross-target multiple RTKs and to verify their findings in a clinical setting.

References: http://dx.doi.org/10.1158/0008-5472.CAN-20-1662

Provided by Karolinska Institute

Aggressive Childhood Cancer Could Be Treated By Combining DNA-Damage Targeting Drugs (Oncology / Medicine)

An aggressive form of the childhood cancer neuroblastoma could be treatable with two cancer drugs currently used in the treatment of colon and ovarian cancer, a study led by researchers at The Institute of Cancer Research, London, suggests.

Image: Neuroblastoma rosettes. Credit: Dr. Maria Tsokos, National Cancer Institute

A team led by researchers at the ICR modified neuroblastoma cells in the lab to silence a gene called ATRX, mutations to which are associated with a chemotherapy resistant form of the disease which is often fatal in children.

These ATRX-deficient cells were particularly sensitive to a combination of the drugs olaparib and irinotecan, which killed cancer cells by preventing DNA repair.

ATRX-deficient tumours in mice were also sensitive to the double treatment, including one derived from a child’s neuroblastoma tumour.

The research, published in the journal EBioMedicine, describes a new model for studying this aggressive form of neuroblastoma, and could lead to a new way of treating it.

Targeting DNA damage in aggressive childhood cancer

DNA damage is the underlying cause of cancer – but it is also a key weakness of cancer cells that can be exploited for treatment.

Knowing that the ATRX gene helps regulate DNA damage repair in healthy cells, the researchers reasoned that blocking other routes of DNA repair in neuroblastoma could leave cancers with ATRX mutations with a fatal level of DNA damage.

Using a gene editing technique called CRISPR, they first silenced ATRX in neuroblastoma cells, to generate a new model of the disease they could study in the lab.

They saw that ATRX-mutant neuroblastoma displayed key faults in a DNA damage repair mechanism called homologous recombination, which repairs double-strand breaks in DNA.

The researchers tested nearly 400 compounds that inhibit DNA repair in cancer cells, as well as DNA-damaging chemotherapy drugs.

They saw that ATRX mutant neuroblastoma cells were sensitive to a cancer drug called olaparib, which blocks an enzyme involved in DNA repair.

The drug is already used as a treatment for a range of adult cancers and is being studied in clinical trials for other forms of cancer in children.

Olaparib treatment was particularly effective when combined with the chemotherapy irinotecan, because it interfered with the cancer’s already weakened DNA damage repair mechanisms and pushed the cancer cells beyond repair.

Irinotecan and olaparib are already being used to treat cancer in adult patients, so the combination could be rapidly rolled out to treat children if clinical trials are successful.

This work was supported by a range of funders including the charities Christopher’s Smile, Neuroblastoma UK and Cancer Research UK.

Using readily available treatments for aggressive childhood cancer

Study leader Professor Louis Chesler, Professor of Paediatric Cancer Biology at the ICR and Consultant at the Royal Marsden hospital, said:

“ATRX-mutant neuroblastoma is a difficult to treat childhood cancer and there is a real need to identify new treatment strategies.

“Our research showed that combining two readily available cancer drugs, olaparib and irinotecan, could be an effective treatment for this form of the disease. Both drugs are already used as treatments for adult cancers, so if future trials of this combination are successful, they could be available as treatments relatively quickly.”

References: Sally L George, Federica Lorenzi, David King, Sabine Hartlieb, James Campbell, Helen Pemberton, Umut H Toprak, Karen Barker, Jennifer Tall, Barbara Martins da Costa, Marlinde L van den Boogaard, M Emmy M Dolman, Jan J Molenaar, Helen E Bryant, Frank Westermann, Christopher J Lord, Louis Chesler, “Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma”, 2020 DOI:https://doi.org/10.1016/j.ebiom.2020.102971

Provided by Institute Of Cancer Research