News and events from the Institute of Cancer Therapeutics
You can find notable news articles relating to the Institute of Cancer Therapeutics below.
It is with great sadness that we learned of the death on 25th September of Terry Jenkins at the age of 69. Terry was appointed to lead the new YCR Laboratory attached to the Clinical Oncology Unit, the forerunner of ICT when based at All Saints Rd. The legacy of the YCR labs lives on in the Medicinal Chemistry facilities of ICT
Terry graduated, with a BSc and PhD in Chemistry, from Chelsea College, University of London. After posts including the MRC Radiobiology Unit at Harwell, he joined the Institute of Cancer Research in Sutton where he rose to team leader and senior lecturer. He moved to Bradford as Yorkshire Cancer Research Chair of Drug Design in 1999. He played key roles in the integration of drug discovery into cancer research in Bradford and the establishment of the University Analytical Centre.
Terry was a fantastically knowledgeable scientist and full of enthusiasm for his work. A dedicated laboratory worker who achieved excellence across the interfaces of synthetic Medicinal Chemistry, Biophysics and computer-aided drug design. Through this he built a global network of collaborators and friends and made significant contributions several anticancer prodrugs reaching clinical trial. He was author of about 150 publications, most of which included data generated himself. He stayed at the bench to the end of his career and maintained a distinct intolerance of bureaucracy and managerialism.
Terry was a kind and generous friend and colleague always keen to offer help and support and whose company brought laughter and fun. He had a well-developed, possibly over-developed, sense of humour and a sharp wit - word games and puns were his speciality.
The Institute of Cancer Therapeutics has a number of fantastic opportunities for people looking to gain experience in research and laboratory work.
To be eligible for the Kickstart programme you will need to be;
- aged 16-24yrs when starting your kickstart placement
- unemployed and receiving Universal Credit
- available to work for 25hours per week
- referred by your Jobcentre Work Coach
To find out more about an individual role please click on the links below:
Dr Peter Nicholls, a researcher at the Institute of Cancer Therapeutics recently presented his work at the Children’s Oncology Fall Group Meeting. Dr Nicholls’ talk was focused on identifying the genes that confer risk of Germ Cell Tumours (GCTs) in mice.
One strain of mice is particularly susceptible to GCTs, though the reason for this was previously unknown. Through a genetic screen, Dr Nicholls’ has identified regions of the genome that are critical for tumour development.
The Children’s Oncology Group (COG) partners with research scientists from around the world in an effort to understand the causes of cancer and find more effective treatments for children. For more information, please visit the COG Homepage.
Dr. Peter Nicholls a researcher at the ICT commented that the genetic studies in mice find parallels to human biology.
“These studies in mice find many similarities with the development of these tumours in young children. A clearer picture of the origin of these tumours may help us to better treat, and ideally, prevent disease.”
The ICT business development team at the University of Bradford, Dr Jason Jones and Dr Gill Westgate are delighted to announce they will be attending the BioEurope 2021 Digital conference between 25th-28th October.
The conference offers excellent partnering opportunities via its digital platform. The ICT team will be seeking industry partners for progression of ICTs IP portfolio of drug development candidates to the clinic and for collaborative research opportunities in the field of preclinical pharmaceutical development of cancer therapeutics and early clinical trials GCP support.
For more information on BioEurope 2021
ICT BD Team Dr. Gill Westgate and Dr. Jason Jones
Work set to begin on developing new drugs soon
Scientists from the Institute of Cancer Therapeutics have discovered a DNA protein ‘switch’ that could help in the treatment of cancer and dementia.
They involve the identification of a mechanism that regulates the creation of something called R-loops, which are part of our DNA. R-loops are very ‘brittle’ and prone to breaking. Too many R-loops can lead to cell death, whereas not enough causes disruption of protein production.
Now for the first time, a process by which R-loops are regulated in our DNA has been identified. The work follows five years of research.
Prof El-Khamisy said: “It is significant because it has not been clear until now how those structures are regulated in our cells. Also by identifying these proteins that regulate R-loops and the link between them, we can design drugs to manipulate the process in the way we want. We are getting one step closer to finding drugs that can modify the progression of some diseases including cancer, dementia and conditions which affect co-ordination, like ataxia and Huntington’s Disease, which are associated with perturbed R-loops.”
What do the findings mean?
The lead author, Prof El-Khamisy said they had now discovered a mechanism to control the regulation of R-loops.
“We have identified three main proteins in a ‘pathway’ that work together in a team to regulate the levels of R-loops and make them the optimum that’s needed for making proteins but also not big enough to induce DNA damage. This regulation is driven by a small molecule that’s added to proteins in our body called ubiquitin. In other words, we have found the protein that puts in the signal and the protein that takes it away.”
He said the findings could lead to new drugs to treat a variety of conditions.
First author, former PhD student and current post-doctoral fellow, Mat Jurga said: “From day one, it’s been an exciting and fast-paced project - starting at the University of Sheffield and finishing at the University of Bradford. I think it is very lucky that we finished in the Institute of Cancer Therapeutics, as it is the perfect place to take the project forward and develop new drugs for cancer and dementia.
Not only have we shown how human cells fine-tune R-loops, but also how they deal with a loss of a protein - an event commonly found in cancer. Therefore, I’m looking forward to working with researchers from ICT and the University of Bradford to build on our findings and develop new drugs.”
Professor Sherif El-Khamisy is a Wellcome Trust Investigator and a Fellow of the Lister Institute of Preventive Medicine. He is theDirector of the Institute of Cancer Therapeutics in Bradford and the Associate Dean for Research and Innovation.
Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment. In this study, ALDH1A3-selective candidates were designed based on the physiological substrate resemblance, synthesized and investigated for ALDH1A1, ALDH1A3 and ALDH3A1 selectivity and cytotoxicity using ALDH-positive A549 and ALDH-negative H1299 cells. Two compounds (ABMM-15 and ABMM-16), with a benzyloxybenzaldehyde scaffold, were found to be the most potent and selective inhibitors for ALDH1A3, with IC50 values of 0.23 and 1.29 µM, respectively. The results also show no significant cytotoxicity for ABMM-15 and ABMM-16 on either cell line. However, a few other candidates (ABMM-6, ABMM-24, ABMM-32) showed considerable cytotoxicity on H1299 cells, when compared to A549 cells, with IC50 values of 14.0, 13.7 and 13.0µM, respectively. The computational study supported the experimental results and suggested a good binding for ABMM-15 and ABMM-16 to the ALDH1A3 isoform. From the obtained results, it can be concluded that benzyloxybenzaldehyde might be considered a promising scaffold for further drug discovery aimed at exploiting ALDH1A3 for therapeutic intervention.
Co-Lead author Dr Klaus Pors Senior Lecturer at the Institute of Cancer Therapeutics commented “this study is part of a research programme focussed on studying the biological importance of a class of aldehyde dehydrogenase (ALDH) enzymes. The long-term aim is to develop therapeutics to treat cancer and other diseases, which are characterised by abnormal expression of ALDH isoforms including ALDH1A3.”
Ribonucleoside monophosphate (rNMP) incorporation in genomic DNA poses a significant threat to genomic integrity. In addition to repair, DNA damage tolerance mechanisms ensure replication progression upon encountering unrepaired lesions. One player in the tolerance mechanism is Rad5, which is an E3 ubiquitin ligase and helicase. Here, we report a new role for yeast Rad5 in tolerating rNMP incorporation, in the absence of the bona fide ribonucleotide excision repair pathway via RNase H2. This role of Rad5 is further highlighted after replication stress induced by hydroxyurea or by increasing rNMP genomic burden using a mutant DNA polymerase (Pol ε - Pol2-M644G). We further demonstrate the importance of the ATPase and ubiquitin ligase domains of Rad5 in rNMP tolerance. These findings suggest a similar role for the human Rad5 homologues helicase-like transcription factor (HLTF) and SNF2 Histone Linker PHD RING Helicase (SHPRH) in rNMP tolerance, which may impact the response of cancer cells to replication stress-inducing therapeutics.
Lead author Prof Sherif El-Khamisy Director of the Institute of Cancer Therapeutics commented “the misincoporation of ribose in DNA is now believed to be the most abundant source of genome instability. Here, we describe a mechanism for tolerating this threat which opens the door for new therapeutic targets".
Dr. Hannah Moody from the ICT presented at the “Action Meso Day” on Friday 2nd July 2021. The event was concentrated on scientists and clinicians communicating their research to patients, and how important patient involvement in research is within mesothelioma. Dr Moody’s presentation was focussed on resistance to chemotherapy in mesothelioma and how we may be able to overcome it, through targeting specific chemotherapy transport pathways in cells.
Dr. Moody commented “I am a passionate advocator for patient involvement in research and how we should work with patients to design and discuss projects to ensure they are relevant. “
For more information please visit Action Meso Day
Dr Hannah Moody: Lecturer in Cell and Molecular Biology at the ICT
Professor Sherif El-Khamisy, Director of the Institute of Cancer Therapeutics at the University, said: "Naked mole rats are fascinating creatures, not least because they are so long lived compared to other rodents of the same size. They also do not suffer from -- what we call in humans -- age associated disorders, such as cancer, dementia and neurological decline.
"What we're trying to do is to understand what makes them so resistant and then to try to harness that knowledge to come up with new treatments for cancer and conditions like dementia in people.
"This is not about extending life but extending the quality of life."
Prof El-Khamisy, from the University's Faculty of Life Sciences, is the lead author of a paper, DNA Homeostasis and Senescence: Lessons from the Naked Mole Rat, recently published in the International Journal of Molecular Sciences.
The Naked Mole Rat
"Lessons from the Naked Mole Rat" states: "As we age, our bodies accrue damage in the form of DNA mutations. These mutations lead to the generation of sub-optimal proteins, resulting in inadequate cellular homeostasis and senescence. The build-up of senescent cells negatively affects the local cellular micro-environment and drives ageing associated disease, including neurodegeneration.
"Which processes show an increased burden as naked mole rats age may identify novel biological targets to mitigate our own degeneration."
Hyperthermia enhances the effectiveness of chemotherapy and radiotherapy by inhibiting DNA repair pathways, leading to persistent DNA damage. In contrast hyperthermia protects cells from topoisomerase targeting through an unknpwn mechanism. In a recently published article in Cancers, the research team uncovered that hyperthermia inhibits the nonspecific repair of DNA damage by nucleases, which consequently channels repair to the alternative error-free pathways mediated by a class of enzymes known as TDPs. This new effect of hyperthermia subsequently led to suppression of therapy induced chromosomal translocations and hallmarks of inflammation.
The Lead author, Sherif El-Khamisy, said “The mechanistic impact of heat stress on the widely used anti-cancer topoisomerase targeting therapeutics has remained unknown for quite sometime. Here, we showed that heat stress acts as a pathway switch favouring the error-free repair of DNA damage induced by the anti-cancer drug. The consequent suppression of error-prone repair pathways reduces hallmarks of therapy associated chromosomal instability (secondary cancers) and inflammation”
A partnership between Covance by Labcorp, based in Harrogate, and the Institute for Cancer Therapeutics (ICT) at the University of Bradford, will strengthen research into chronic diseases and enhance learning opportunities.
It will begin by running a ‘boot camp’ this year to enable postgraduate students to shadow professional lab technicians and scientists. From next year, some postgraduate students will be offered up to nine months paid employment with the firm as part of the new 12-month postgraduate Master by Research (MRes) degree at the ICT. The company will also play an active role in helping design parts of the taught curriculum.
The MRes programmes in the School of Pharmacy and Medical Sciences, comprises one-third taught element and two thirds University lab or industry lab-based research project. There are currently six specialisms within the MRes programme in: Cancer Drug Discovery, Cancer Pharmacology, Drug Toxicology & Safety Pharmacology, Molecular & Cell Biology, Chemical Biology, and Pharmaceutical Technology.
To read the full press release
Some anti-cancer drugs are not very water soluble. This can cause problems when injecting intravenously into patients. This article published in Nanomedicine and co-authored by Professor Paul Loadman from the Institute of Cancer Therapeutics describes the use of a lipid-based nanoemulsion formulation termed Lipid-Oil-Nanodroplets (LONDs) for the encapsulation of a poorly soluble drug called Combretastatin A4 (CA4) to help in its administration. This formulation was tested in human colon tumours in mice. Using very sensitive analytical techniques (mass spectrometry) we showed that giving the drug using LONDs at four times lower dose than when giving the drug alone achieved the same drug concentrations in the tumour. The drug containing LONDS were also attached to microbubbles (MBs) and targeted to the blood vessels of the tumour causing a reduction in tumour blood flow in these treated tumours.
To read the full article
To learn more about the technology visit the Leeds Microbubble Consortium
Prof. Paul Loadman from the ICT said "Overall this study suggests that LONDs, either alone or attached to targeted microbubbles, have the potential to significantly enhance tumour-specific delivery of poorly soluble drugs."
Unlike many other cancers, germ cell tumours are most common in children and young men. In a new publication, academics at the ICT sought to better understand the origin of these tumours.
In the embryo, our cells are separated into those that build the body, and those that are set aside to later produce gametes (either eggs or sperm). However, before these cells become eggs or sperm, for a short window of development, they can be coaxed into making almost any type of cell.
In this new publication, Dr Peter Nicholls looks across different species to understand how these embryonic cells normally lose their ability to make any type of cell. Comparing this with the clinical behaviour of germ cell tumours, the team pinpoint that these tumours arise from errors occurring at a specific stage of embryonic development.
A deeper knowledge of these tumours is important for understanding their rising incidence in recent decades, and in developing new diagnostic and therapeutic strategies.
Co/Lead-author Dr. Peter Nicholls a researcher at the ICT commented that this work is a first step to better reconciling clinical data with our knowledge of development. “Decades of research across the globe has given us an increasingly deeper knowledge of the clinical behaviour of these tumours. Integrating these clinical findings with data from other species, such as fish and mice, we identify that these tumours can arise when cells stray from normal development".
Long Service Award to ICT Research team Member
Tricia Cooper, who is currently a Senior Scientist working at the Institute of Cancer Therapeutics has been recognized by the University for her long service at a recent ceremony. Tricia came to work at (what was at the time) the Cancer Research Unit when it was based on All Saints Road in 1995 and has ever since been a valuable member of the research team at the ICT, contributing to in vitro and in vivo research on new cancer drugs which have progressed to the clinic. She has also passed on her expertise and helped train and supervise several PhD, Masters and BSc students who have spent time in the cancer research laboratories.