Rosetrees researcher profile:Dr. Stuart Rushworth and Professor Kristian Bowles, Norwich Medical School, University of East Anglia
Who Rosetrees Trust is funding
Current treatment options for patients with acute myeloid leukaemia (AML), including curative cytotoxic chemotherapy, are limited by their intensity and side effects. They are most commonly used to treat younger, fitter patients, but this is a disease mainly of older people. Therefore, in addition to these existing treatment options, patients that are older and less fit would require alternative therapy options that can be better-tolerated. Even in younger patients treatments need to be improved to increase survival and reduce side effects.
by the Norwich team and others shows that there is a high dependence of AML on
external signals from bone marrow stromal cells (BMSC) for its survival. So, tumour
cell-to-cell interactions and the microenvironment represent a potential target
for novel treatment strategies.
Previously, Dr. Stuart Rushworth and Professor Kristian Bowles and the team at Norwich Medical School have investigated how AML survives the cellular challenges of its rapid growth and chemotherapy. With Rosetrees support the team further investigated what makes the bone marrow microenvironment, in which the leukaemia grows, so important in this process. The aim of the work is to ultimately exploit these interactions between the blood cancer and the cells that surround it, in order to identify a novel tumour-specific treatment strategy that can be used for all patients with AML patients.
How Rosetrees Trust have supported Dr. Stuart Rushworth and Professor Kristian Bowles
The team in Norwich received their first Rosetrees Trust grant in 2015. This project funded PhD student Chris Marlein who completed his degree in the Autumn of 2018.
What the outcomes are of Rosetrees Trust-funded research from Dr. Stuart Rushworth and Professor Kristian Bowles
The team, including Dr. Rushworth, Professor Bowles, and Chris Marlein, the PhD researcher on this project, have identified new key interactions between non-malignant cells of the bone marrow microenvironment and leukaemia cells. Furthermore, they discovered how these processes support the energy requirements of the cancer cells.
AML cells require large amounts of energy to grow and survive chemotherapy. It had not been fully understood how, and to what extent, the bone marrow microenvironment supports the energy requirements of the leukaemia cells. The team in Norwich have shown that functional mitochondria (energy generating organelles) are transferred, via nanotubes, from non-malignant stromal cells to the malignant cell. This process significantly enhances the growth capacity of the cancer cell, whilst at the same time providing chemoresistance. This output from this Rosetrees-funded work has been reported in a number of publications, including the following Cancer Research, Leukemia, Blood and Haematologica (Epub ahead of print).
Rosetrees Trust support on this project has helped the team secure further funding from the Wellcome Trust, the MRC and the Big C, totalling almost £1 million. Furthermore, Dr. Rushworth has led expansion and development of the lab as a whole, and Dr. Chris Marlein has launched his academic career.
Written by: Dr. Rebecca Downing, Dr. Stuart Rushworth, and Professor Kristian Bowles
Rosetrees researcher profile: Dr. Pascale V Guillot, UCL
Who Rosetrees Trust is funding Dr. Pascale V Guillot’s research is about a rare disease called brittle bone disease, also known as osteogenesis imperfecta (OI). OI affects around 10,000 births and in average 70 babies per year in the UK. It inflicts painful bone fractures which start to occur in the womb and continue throughout a person’s lifetime, as well as a deformed skeleton and reduced height. There is currently no cure for this condition.
The Guillot lab aims to improve the quality of life of people with OI by developing innovative therapeutics to strengthen the bones, and therefore reduce the number of fractures.
“Our team is passionate about improving the quality of life of children with unbreakable spirit but suffering from bone fragility by developing the next generation of therapeutics.”
How Rosetrees Trust have supported Dr. Guillot Dr. Guillot is a Rosetrees Trust-funded Associate Professor at University College London (UCL) who has received funding from Rosetrees Trust for two projects, starting in 2014. She has also started her third grant with Rosetrees Trust funding.
What the outcomes are of Rosetrees Trust-funded research from Dr. Guillot The Guillot lab has found that transplantation of stem cells counteracts the fragility of the bones by secreting factors that stimulate the bone-forming cells to produce bone of better quality. These findings have a significant economic and social impact, not only for the treatment of people with OI, but also for those suffering from osteoporosis.
Dr. Guillot has recently been awarded a 3-year £870,000 grant from the MRC using her Rosetrees Trust-funded findings.
Written by: Dr. Rebecca Downing and Dr. Pascale V Guillot
Rosetrees researcher profile: Professor Sejal Saglani, Imperial College London
Who Rosetrees Trust is funding Professor Sejal Saglani leads the childhood severe asthma research programme at the National Heart & Lung Institute, Imperial College London. Her research focuses on investigating how childhood asthma starts, and finding new treatments to treat, but also to prevent asthma.
Asthma is predominantly a childhood onset disease and affects over 1 million children in the UK. It results in symptoms of difficulty in breathing, breathlessness and wheezing and acute attacks which frequently require hospitalisation. In studies that have followed children from birth, approximately one-third of all preschool children under 5 years have suffered from wheezing attacks, usually caused by common cold viruses, and one-third of those preschool wheezers progress to develop asthma in later life. The children that develop asthma suffer a reduction in lung function, and this loss never recovers even into adulthood. Children with asthma, especially those with severe asthma, therefore go on to develop a lifelong illness.
It is known that certain environmental exposures are protective from the development of asthma, this includes being raised on a farm with traditional cattle farming practices. Professor Saglani is investigating which components of the “farmyard environment” are protective.
Professor Sejal Saglani’s lab is aiming to find new treatments that can stop progression of wheezing in preschool children to asthma and also to stop the permanent loss in lung function to adult life.
“We want to know what it is about the cattle farm environment that stops children from getting asthma, so that we can make it into a preventive asthma treatment for use in the UK.”
How Rosetrees Trust have supported Professor Sejal Saglani Professor Sejal Saglani is a Rosetrees Trust-funded researcher at Imperial College London who has received funding from Rosetrees for 1 project, starting in 2018.
What the outcomes are of Rosetrees Trust-funded research from Professor Sejal Saglani Professor Sejal Saglani has previously shown that specific bacteria that are inhaled from the farmyard environment are protective in a mouse model of “asthma” (Science Immunology, 2018). She is now investigating how this protection occurs, and also whether it occurs in children with virus infections and wheezing. The aim is to find the component of the farmyard bacteria that confers protection and formulate this into a compound that may achieve prevention of childhood asthma.
Written by: Dr. Rebecca Downing and Professor Sejal Saglani
Professor John Sayer and his team have recently completed a Rosetrees Trust-funded project which aimed to further develop their nephronophthisis (NPHP) mouse model, and subsequent treatment opportunities, at Newcastle University. NPHP is an early onset cystic kidney disease, and it is the lethal component of an incurable, inherited disorder known as Joubert syndrome. Currently, treatment options for NPHP are limited to symptomatic therapy. Therefore, Professor Sayer’s research will help bring treatments for NPHP to the clinic.
In their latest paper, published in the Proceedings of the National Academy of Sciences (PNAS), Rosetrees Trust funding has helped support their research on the identification of a “modifier gene” involved in cystic kidney disease. Using their mouse model, they showed for the first time that the single locus, Barttin, is a modifier. Then, in a cohort of patients, they also showed that the human homolog plays a similar role in disease. These findings provide researchers with a novel potential target to exploit in their model systems, which could have future use in patients. Through altering levels of modifier genes, this may alleviate the effects of Joubert syndrome.
Professor Sayer said: “We have elegantly shown using mouse and human DNA samples that Barttin modifies the severity of kidney disease in Joubert syndrome. This is the first time that a modifier gene for cystic kidney disease has been identified. This information will improve diagnoses and will be used to develop therapies to reduce the severity of kidney disease in affected patients.”
“Our research is a major step forwards proving the power of using mouse models to study rare human inherited disease and in the future we may be able to offer a therapy that switches on the protective modifier gene and reduces the development of genetic kidney disease.
“This work paves the way towards personalised therapies in patients with the inherited kidney disease.”
Overall, this research offers new hope to understanding the genetic, and mechanistic, basis of rare diseases to ultimately improve diagnoses and treatment options.
Written by: Dr. Rebecca Downing and Professor John Sayer
Professor Alexander Binshtok is a Rosetrees Trust-funded researcher who has been receiving funding from Rosetrees Trust since 2011, for two closely-related projects, at Hebrew University Jerusalem. These projects involve the development of novel “natural” drug-delivery systems, to selectively target pain and cancer cells.
Recently, Professor Binshtok, who is head of the Pain Plasticity Research Group, and his team, have published in Frontiers in Pharmacology about their novel method for delivering chemotherapy selectively into tumour cells, sparing healthy cells. Their method exploits the targeted delivery by activating specific proteins on the surface of tumour cells which are not present on normal cells.
They have identified that tumour cells express a protein known as transient receptor potential (TRP) channel V2, and this protein can be used to specifically import chemotherapy into the tumour cells. Furthermore, the team showed that co-application of TRP activators such as cannabidiol (CBD) or 2-APB, with chemotherapy, enhanced chemotherapy uptake into tumour cells, permitting usage of lower doses of chemotherapy drugs, thus reducing their side-effects.
Professor Binshtok and his team have therefore shown that their novel method for delivering chemotherapy may be potentially used to help patients in reducing the side-effects associated with cancer treatment. Their research may also act as a platform for further development of this natural drug-delivery system to target specific cell types.
Professor Binshtok said:
“Most anti-cancer treatments are not sufficiently specific, meaning they attack healthy cells together with the malignant ones they’re trying to get rid of. This leads to the many serious side-affects associated with chemotherapy. Eliminating cancerous cells while leaving healthy ones alone is an important step towards reducing patients’ suffering. It’s too early to make concrete predictions but we are hopeful this discovery will lead the way towards a new, more targeted delivery method for chemotherapy treatment.”
Written by: Dr. Rebecca Downing and Professor Alexander Binshtok
Dr. Jurre Kamphorst and Dr. Grace McGregor have recently completed a Rosetrees-funded project at the Beatson Institute, Glasgow. Their research involves investigating metabolic pathways in more detail, and how this can be exploited in cancer. In this project, they were specifically interested in the mevalonate pathway and drug repurposing of statins to target cancer cells.
Grace worked on this project as part of her PhD research. In the early stages of their project, Jurre and Grace identified that the coenzyme Q branch of the mevalonate pathway was highly active in pancreatic, breast and prostate cancer cells. They next used statins to successfully block coenzyme Q synthesis, which led to reduced cancer cell proliferation. This finding was particularly interesting as much of the literature has focussed on the use of statins to target cholesterol synthesis. However, using stable-isotope tracers and a novel high-resolution mass-spectrometry approach, Grace and Jurre explored the mevalonate pathway and found this was not the mechanism of action in cancer cells. Taking their observations further, they mapped the metabolic compensation that occurs as a result of decreased coenzyme Q synthesis. Their most striking observation was of reduced oxidative phosphorylation and significantly elevated reactive oxygen species production. Jurre and Grace then tested a combination therapy strategy in cancer cells to target these changes and metabolic vulnerabilities that occur in cancer cells, when treated with statins. They showed that statins synergised with the MEK-inhibitor (AZD6244), which lowers xCT cystine transporter levels, to produce a robust anti-tumour response.
From this, Grace conducted in vivo metabolism studies to explore the pathway in a pancreatic mouse tumour model. Excitingly, the in vitro results held up in vivo, and indeed a synergistic dual drug treatment significantly increased tumour cell death compared to the control and single arm treatments. Their findings have been published in Cancer Research.
This is what Grace had to say,
“I absolutely loved my PhD and I am incredibly grateful for the support I received from Rosetrees and Cancer Research UK. I had the unique opportunity to explore metabolism in vivo and learn the vastly complex technique of mass-spectrometry. I didn’t quite realise how rare such a skillset was until I attended the Keystone Tumor Metabolism Conference in March 2019. It was here that I was offered a post-doctoral position in the prestigious lab of Professor Christian Metallo. I have taken everything I learned as a PhD student, from lab techniques to refining my approach to pushing a project forward, and I am now heading up my very own high-resolution mass-spectrometer. I am exploring complex lipid molecules in the context of breast cancer and hoping to develop this to look at breast cancer metastasis. I was ecstatic that a part of my thesis was able to culminate in a publication. Science is about communication and now I’ve put in my first piece of the cancer research puzzle I feel like a real scientist. I thank Rosetrees and CRUK for supporting me through my PhD, and I hope to continue laying puzzle pieces during my postdoc.”
Written by: Dr. Rebecca Downing, Dr. Grace McGregor, and Dr. Jurre Kamphorst