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2019 Research Grants

Taking back control of the immune system: Peptide directed binding to identify small molecule leads for immnue checkpoint therapy

Amount Funded:

42 month PhD starting October 2020
£84,505.37 (years 1-3 only)

Research Organisation:
School of Pharmacy, UEA

Grant Applicants:
Dr Andrew Beekman

Lay Summary of Research:

One of the hallmarks of cancer is its ability to evade the immune system. Cancer cells can over-produce proteins which turn off the immune system and under-produce proteins which turn it on. Two of the proteins which control this are Programmed Death-1 (PD-1) and Programmed Death Ligand-1 (PD-L1). Controlling how these two proteins interact has led to treatments for many cancers, called immune checkpoint therapy, and the award of the Nobel Prize in 2018. One way of controlling this interaction is using antibodies but these tend to be expensive and can have dangerous side effects. If small, drug-like molecules could be found which control this interaction then this treatment could become more widely available at a much lower cost. However, finding small molecules which control massive proteins is very challenging with current techniques. 

 

The aim of this project is to use a new technique, developed in our lab, to make small molecules which can control this interaction. Peptides (small protein-like molecules) which control the interaction of PD-1/PD-L1 will be used to design small, drug-like molecules. Peptides are smaller than antibodies but are still broken down by enzymes in the cell and often are unable to reach the target tumour. Small molecules are able to overcome these problems by penetrating into tumours and cancer cells. 

 

This study will take a peptide which controls PD-1/PD-L1 and separate it into two “semi” peptides, displayed in the picture below. Small drug-like fragments can be attached to the semi peptides to create peptide-small molecule hybrids. If these hybrids are able to bind to the protein then we can assume the small fragment in some way mimics a section of the peptide. This process can be done with both semi peptides, identifying many small molecule fragments which mimic a section of the peptide. The small fragments can then be joined together to create a small molecule which possesses fragments known to mimic a section of the parent peptide, creating a small molecule which controls PD-1/PD-L1.

 

This study will make new small molecules which target an protein interaction, PD-1/PD-L1. This research will lead to the development of small molecules which could replace expensive antibodies, making immune checkpoint therapy more widely available. Proving that this method works on important protein interactions will encourage other researchers to use this technology on a variety of problems.

 

This research will be carried out by a Ph.D. student, resulting in the training of a student to become an independent researcher with the skills and knowledge to pursue a career in cancer research.

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Distinguishing Aggressive from Non-Aggressive Prostate Cancer (The Tiger Test)

Amount funded:
£93,294 (24 month project starting April 2020)

Research Organisation:
Norwich Medical School, UEA

Grant applicant:
Prof Colin Cooper

Lay summary extracted from application: 

Prostate cancer is the most common cancer in men. Across North America and Europe 500,000 cases of prostate cancer are diagnosed annually. In the UK, we lose 11,000 men each year to this devastating disease.  What makes prostate cancer unique is that, unlike other cancers, most prostate cancers are harmless. The challenge that clinicians face is how to reliably distinguish between benign cancers and the 10% of aggressive, potentially fatal cancers at the point of diagnosis.  

Previously, many scientists have tried to develop a classification system for prostate cancer but this has always failed. In our work, we took a different approach to analysing existing data. When we take a tissue sample from?a patient it’s about the size of a pea. We put that in a fancy pestle and mortar and crush it up. In other words, you crush up all the structure and then get an average of everything in that sample. The problem is that the pea-sized sample is made up of several different components and all that information is mushed together and lost when you prepare it for analysis. We decided to use a different form of maths, an artificial intelligence approach, to reconstruct the original samples, which takes into account their heterogeneity or innate diversity. We discovered that prostate cancer is like a layered sweet with several different elements, rather than a single component like breast cancer, which could be likened to a marshmallow. What was shocking is that we?found one particular component that defines a distinct category of prostate cancer,?and when we linked that to the clinical data it always had a poor outcome. This component is called the ‘Tiger’ or ‘DESNT’ component. This had been completely missed because previously scientists were using the wrong maths.

Critically, DESNT provided new information in addition to that provided by conventional clinical markers such as Clinical Stage (how far the cancer has spread), Gleason Grade (how abnormal the cancer looks down a microscope) and PSA. 

We are currently engaged in a three-stage initiative to set up a clinical test that find if DESNT is present in a patients biopsy sample.  In Phase 1 we have already raised funds to set up a Diagnostic Laboratory at the University of East Anglia. We are now requesting funds to initiate Phase 2 of the project that will involve application of the test in high profile clinical series.  The outcome, once Phase 2 and Phase 3 are complete, will be an CE-mark ISO standard compliant test that can be used to direct treatment in patients diagnosed with prostate cancer. Ultimately, the Tiger Test will save lives by providing an accurate diagnosis of aggressive prostate cancer, whilst sparing tens of thousands of men with clinically irrelevant ‘pussycat’ cancers from unnecessary treatment that often results in life-changing side-effects, including impotence and urinary incontinence.

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Synthesis and evaluation of X-ray structure inspired ubiquitin ligase inhibitors as anticancer lead compounds

Amount funded:
£89,349 (36 month PhD starting 1 October 2020)

Research Organisation:
School of Chemistry, UEA

Grant applicant:
Dr G Richard Stephenson


Lay summary extracted from application:

Cancer is normally prevented inside healthy human cells by the presence of an important family of proteins known as Tumour Suppressor Proteins (TSPs). In previous work, we and others have identified a completely new process that causes the abnormal breakdown and disappearance of these vital TSPs, or ‘cancer brakes’. Furthermore, it has been shown that this occurs in many different types of cancer, but especially breast and prostate cancer. This process involves a family of enzymes known as Ubiquitin Ligases which present inside cancer cells. These Ubiquitin Ligases tag the ‘cancer brakes’ for destruction by the body. We now know that these enzymes are over-produced in cancer cells that are more prone to spread around the body, and we also now understand more about how these enzymes work and, in some cases, we know their exact overall 3-dimensional shape. In this project, we will capitalise on these key discoveries, and begin to develop new drugs targeting these ubiquitin ligase enzymes that can be used to prevent cancer outgrowth and spread. Recent developments have allowed us to identify how the drug molecules fit in the protein receptor. In the proposed period of doctoral research, the PhD Student project will make analogues of a molecule called 2805, to introduce additional binding interactions with the receptor and so provide a better series of second-generation inhibitors which can be evaluated by our recently established in-house methodologies. This information is very important as it will allow us to see which parts of the drugs are required for their activity, and which can be modified in later studies to reduce side-effects. The big advantage we have here at UEA to carry out this work is that it builds on an existing strong collaboration with experts in cancer, assay development, structural biology and chemical synthesis. The main outcomes of the project could also lead to the development of a new class of drug that could have a real impact on patient survival in the long-term.

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Real-Time PCR System for Gene Expression Studies

Amount funded:
£27,293 (36 month project starting 1 January 2020)

Research Organisation:
Norwich Medical School, UEA

Grant applicant:
Dr Yongping Bao


Lay summary extracted from application:
Polymerase chain reaction (PCR) is a core technique used in molecular biology to analyse genetic material from living cells. It has a multitude of applications in research and medicine from detecting cancer genes in tumours to analysing the presence of pathogens in patient samples. Reliable and high throughput analysis of samples is key for successful experimental approach.  

We are requesting funding for purchasing an Applied Biosystems (ABI) PCR machine called QuantStudio 3 to perform real-time, quantitative PCR analyses. This equipment will be located at the Bob Champion Research and Educational Building (BCRE) at University of East Anglia (UEA), and used on a daily basis by several groups investigating gene expression, genotyping and diagnosis of gut bacterial infections. This equipment will give us the capacity to perform large-scale quantification how human genes respond to chemicals in particular foods and anti-cancer drugs. We will examine the genes in relation to nutrients, bioactive compounds or drugs, and develop new treatments of prostate cancer and develop new therapies to treat osteoarthritis and rheumatoid arthritis. We will also be able to develop a real-time PCR test for diagnosis of human parasite infections.

The data obtained around human gene responses to foodstuffs will contribute to the understanding of the importance of prevention of chronic diseases including cancer and rheumatoid arthritis. This will help to form sound dietary advice to individuals at risk of cancer and lead to personalised nutrition, which could prevent cancer. In addition, the PCR System will be used to investigate gene expression in gut pathogenic and commensal bacteria and in human intestinal cells, thereby helping us to understand what is going on during infections of the gut and the influence of the gut microbiota on human health and/or disease. Finally, the PCR System will also allow us to obtain quantitative confirmation of gene expression data and form a basis for the development of new therapies to treat both chronic and infectious diseases.  

In summary, this QuantStudio 3, PCR machine will support several ongoing projects in the BCRE Lab in Norwich Medical School, at UEA.