Projects starting from June 2013 - June 2016
Grant Holder: Dr Jeremy Jones
Institution: Beckman Research Institute of the City of Hope, Duarte, California, USA
Grant award: £199,438 for 3 years
Project title: Developing new prostate cancer treatments for men who have become resistant to current therapies
Prostate cancer cells normally only grow and divide in the presence of the male sex hormone androgen. Androgen switches on a molecule called the androgen receptor when the two stick together, like a key in a lock opening a door. The main drug treatments for prostate cancer work by either competing with the androgens to stick on to the androgen receptor, like the wrong key blocking the lock, or they prevent androgen being made, like preventing the manufacture of the key. However, in advanced prostate cancer the cells become able to multiply without androgens, meaning the drugs no longer work and it is incurable. The lock is broken so the door can be opened without any level of control. Therefore new drugs that switch off the androgen receptor and keep the door shut in a different way are needed.
Dr Jones and his team have recently found a chemical that can stop the androgen receptor from being switched on. Instead of working like traditional treatments, this chemical stops the androgen receptor in a unique way – like adding a Yale lock. The team are using their AICR grant to firstly determine exactly how this chemical is working. This will include pinpointing exactly where it is sticking to, what other molecules are involved and how effective it could be when given in small amounts. This is an exciting project that, if successful, holds great promise for future prostate cancer patients who have become resistant to current treatments.
Grant Holder: Professor Michael Threadgill
Institute: University of Bath, England
Grant Award: £201,922 for 3 years
Project Title: Designing new anti-cancer drugs
Professor Threadgill and Dr Nathubhai are using his AICR grant to make potential new anti-cancer drugs that will act on proteins called Tankyrase-1 and Tankyrase-2 to stop them from working. Designing, making and testing drugs is an extremely long process and this grant is a continuation of a previous AICR grant awarded to Professor Threadgill. He plans that the drugs will stop the growth of cancer cells through three different mechanisms, to increase the effectiveness. The tankyrases are present at abnormally high levels in cancer cells, which makes them good targets to selectively kill cancer cells, while leaving healthy cells relatively unharmed. The specific shapes of the Tankyrases are already known and Professor Threadgill is using computer software to design potential new drugs in “virtual reality”, making the discovery process more efficient and cutting out laboratory work on those chemicals which can be predicted to be ineffective. Potential drugs which appear to fit well into these proteins in the computer model will be made in his chemical laboratory. He will then test them to see if they actually do work on the Tankyrases but on no other useful proteins. Then further testing will show if they actually do stop cancer cells growing. The researchers hope that the completion of this project will provide one or more potential anti-cancer drugs which work by new mechanisms of action. These would then need to be developed further and tested for their safety and effectiveness before being tested in patients.
Grant Holder: Professor Massimiliano Mazzone
Institution: VIB Flanders Institute for Biotechnology, Leuven, Belgium
Grant Award: £158,409 for 3 years
Project Title: Investigating the role of podoplanin in allowing breast cancer to spread.
The cancer microenvironment consists of the space in between the cancer cells within the tumour mass. Among other components, it contains cells of the immune system including some cells called macrophages. These immune system cells are produced in order to attack the tumour and try to destroy it. However, in some types of cancer, such as breast cancer, the cancer cells "convince" immune cells to work for their own benefit, favouring tumour growth and spread. One of the things that makes cancer so dangerous is this ability to grow and spread away from the original tumour and into surrounding tissues and organs. These secondary tumours can stop key organs from working which can make successful treatment much more difficult.
In an initial study Professor Mazzone and his team have found that, when exposed to a tumour like environment, macrophages are able to regulate many things, including levels of a molecule called podoplanin. Podoplanin is known to be found at high levels in cancer cells. Professor Mazzone is now using his AICR grant to better understand the role of podoplanin in breast cancer, with a particular focus on the part played by macrophages in allowing the cancer cells to invade the lymphatic system and spread. The team will start their work using cells grown in the laboratory but will then use mouse models, some with podoplanin and some without. Using mouse models like these are essential to study how cells can move around the body. Professor Mazzone hopes that his findings will shed new light on how breast cancer cells can spread which, in the future, could possibly help with the development of new treatments to stop this process.
Grant Holder: Dr Salvador Aznar-Benitah
Institution: IRB - Institute for Research in Biomedicine, Barcelona, Spain
Grant Award: £269,177 for 3 years
Project Title: Identifying and characterising the cells in tumours of the mouth and lip that allow the development of secondary tumours.
One of the main factors making tumours so dangerous is their ability to spread, known as metastasis. Individual cancer cells squeeze between the normal cells nearby and push their way through the tissue. They are then carried in the blood stream or lymphatic system and can form new tumours in other parts of the body, known as secondary tumours or metastases. These tumours can stop key organs from working which can have dire consequences for the patient and make successful treatment much more difficult.
There is still much that scientists don’t understand about the tumour cells that are able to break away from the original tumour. Dr Benitah is therefore using his AICR grant to study these cancer cells in tumours in the lining of the mouth and lips. The team have already identified a group of cells within these tumours that may be the cells of origin. They are using this grant to further investigate what makes these cells unique from the rest of the tumour cells and what characteristics enable them to break away and start new tumours. The team will be using mouse models of the disease as well as studying cells from samples taken directly from human tumours of the mouth and lip lining. As this project involves studying how cells move from the mouth and lip to other places in the body it simply would not be possible without the use of mouse models. If Dr Benitah is able to identify how these tumour cells break away and start new ones his team, or other scientists, could then work on finding ways to stop the process from happening. If scientists were able to stop tumours from spreading, successful treatment would be much easier to achieve.
Grant Holder: Dr Auli Karhu
Institute: University of Helsinki, Finland
Grant Award: £146,380 for 3 years
Project Title: Investigating pituitary gland tumours
The pituitary gland is a small organ located at the base of the brain and it has a vital role in producing hormones. These hormones are involved in many processes from regulating growth to stimulating milk after childbirth. Dr Karhu is using her AICR grant to study the development of tumours in the pituitary gland. In particular she is focusing on molecules called AIP and Gα proteins. Gα proteins are involved, for instance, in the regulation of hormonal signals inside the cell. Defective Gα protein signalling has been linked to the development of pituitary tumours. Therefore, it is possible that an altered or damaged Gα gene may predispose a person to pituitary tumour. If a faulty Gα gene is inherited from parents, it means that all family members who carry the same mutation have an increased risk to get a pituitary tumour. Dr Karhu is also investigating what factors make some people respond so poorly to current treatments for pituitary tumours and she thinks a fault Gα signalling may also play a role in this. The team hopes that their findings could help future patients with pituitary tumours.
Grant Holder: Professor Paolo Salomoni
Institute: University College London, England
Grant Award: £210,946 for 3 years
Project Title: Investigating acute promyelocytic leukemia (APL)
Professor Salomoni and his colleague Professor de The are using their AICR grant to study Acute Promyelocytic Leukaemia (APL). APL is a cancer of our white blood cells, in this case myeloid cells. White blood cells are a vital part of our immune system where they help fight infection. APL is a type of Acute Myeloid Leukaemia but is treated differently and it is very aggressive and progresses quickly. It is rare in young children but can affect adults of any age which is unusual as most cancers occur in older people. Around 200 adults are diagnosed with APL every year in the UK alone.
Every cell in our body contains thousands of genes that control most of the activities in the cell. In some cancers, including leukaemia, one gene can become fused or ‘glued’ to the end of another one, creating a hybrid gene. Professor Salomoni will be looking at one of these hybrid genes and a molecule called DAXX and their role in causing APL. DAXX has been implicated in other human cancers, such as tumours of the pancreas and brain, and works by modifying the way the DNA is packed in the cell. APL is one of the success stories of cancer therapy, with the majority of people with APL now surviving the disease. However, by better understanding how APL develops, in the future, scientists can then take this information and try to find ways to stop it from occurring or detect it earlier or to better treat it. Furthermore, this information will potentially provide new clues on how to treat other cancers characterized by similar disease mechanisms.
(*Statistics from Leukaemia & Lymphoma Research)
Grant Holder: Dr Colin Clyne
Institute: Prince Henry’s Institute of Medical Research, Melbourne, Australia
Grant Award: £210,816 for 3 years
Project Title: Studying breast cancer resistance to tamoxifen
Most breast cancers rely on a hormone called oestrogen to grow. These cancers can be treated with anti-oestrogen therapies that stop the hormone from working, such as the drug tamoxifen. However, resistance to hormone therapy is very common, and most patients experience the cancer coming back, called a relapse. We do not yet fully understand how cancer cells become resistant to tamoxifen. A protein was recently identified that predicts whether patients treated with tamoxifen are likely to relapse or not. This protein is found in much higher numbers in tamoxifen-resistant breast cancer cells, but it is not yet known how the protein functions and is able to distinguish between cancers that are affected by tamoxifen and those that aren’t. Dr Clyne and his team plan to investigate how the protein affects the growth and behaviour of breast cancer cells. They hope that this work will identify new functions for this protein and help us to understand how resistance to tamoxifen happens at a molecular level.
Grant Holder: Dr Helen Dooley
Institution: University of Aberdeen, Scotland
Grant Award: £202,566 for 3 years
Project Title: Creating new antibodies to overcome drug resistance in HER2-positive breast cancer
In about a quarter of women with breast cancer, the cancer cells have a very high amount of a protein called HER2 on their surface. This is referred to as HER2-positive breast cancer. The HER2 protein helps cancer cells to grow. As a result, a number of treatments have been developed that stop HER2 from working properly. One such drug, Herceptin® works by a molecule called an antibody attaching to and blocking the HER2 protein, stopping it from working properly and preventing the cancer cell from growing. Unfortunately, cancer cells often become resistant to this treatment. Research suggests that when HER2 is blocked it causes an increase in the level of a similar molecule called HER3, which is on the cancer cell surface, and that is a major cause for drug resistance. Scientists are now trying to find ways to block HER3 along with HER2, thereby providing a way to treat tumours that have become resistant to Herceptin®.
A special type of antibody has been discovered in sharks; part of it is much smaller than human antibodies and so can block its target and therefore work in a very different way. For this reason, scientists believe shark antibodies may work better than the current antibodies for the treatment of HER2-positive breast cancer. Scientists at the University of Aberdeen led by Dr Helen Dooley have been awarded a grant from AICR to find shark antibodies that can attach to the HER2 and HER3 proteins and stop them both from working. They will then investigate whether these antibodies can stop cancer cells from growing using lab-based tests.
Grant Holder: Dr John Maher
Institution: King’s College Hospital, London, England
Grant Award: £197,614 for 3 years
Project Title: Manipulating the immune system to fight prostate cancer
The immune system is part of our body’s response to infection and disease. It includes T cells, which have the ability to recognise foreign molecules – such as those on bacteria, viruses and even some cancer cells. Once a foreign body has been detected the immune system is able to attack and kill it. But cancer cells have a wide range of ways to prevent the immune system from recognising or attacking them. Dr Maher is developing a new way of using the immune system to attack prostate cancer cells. He is specifically looking at prostate cancer in men where the cancer cells have stopped responding to the usual drugs and have spread to other parts of the body, known as metastatic castration-resistant prostate cancer (mCRPC). For these men there are few treatment options remaining so new ones are being urgently sought.
In the laboratory, Dr Maher will genetically alter T cells that specifically recognise prostate cancer cells, taken from men with mCRPC. He will then inject a large number of these altered T cells into mice with prostate tumours. Once the T cells stick to a prostate cancer cell, the T cells are designed to make genes which help the body destroy the cancer cells, whilst leaving healthy cells unharmed. The team hope that one of genes will also ensure that the T-cells can produce more T-cells by taking advantage of the environment in which the tumour is located, which is altered by the prostate cancer. Depending on his findings in mice, Dr Maher is hoping that his T-cells could be used in a human clinical trial in the next few years. He is already doing a clinical based on findings from his previous AICR grant for patients with head and neck cancers and we are excited at the thought that this may also be possible for prostate cancer patients one day.
Grant Holder: Professor Christine Clarke
Institution: University of Sydney, Australia
Grant Award: £200,004 for 3 years
Project Title: Studying the role of progesterone and synthetic progesterone in breast cancer
Progesterone is a hormone produced by the ovaries. It is essential for the development and function of the female breasts and reproductive system and has a wide range of effects in these tissues. During the menopause some hormones, including progesterone, are no longer produced.
Hormone replacement therapy (HRT), used to reduce the symptoms of menopause, replaces these missing hormones, including a synthetic version of progesterone, called a progestin. However, progestin in HRT increases a woman’s risk of breast cancer. Progesterone sticks to a molecule called a receptor (PR) within a cell. There are two types of progesterone receptor, PRA and PRB, which are found in normal cells. In the early stages of breast cancer there are much higher numbers of PRA and PRB in breast cancer cells. When progesterone sticks to PRA or PRB the receptor attaches itself to specific sequences of DNA and controls the activity of key genes. The types of DNA sequences that PR binds to is also different in normal breast cells compared to cancerous cells. Professor Clarke and her team have found that the DNA sequences are different again when progestins from HRT attach to the receptor. They plan to use their AICR grant to study well defined models of breast cancer and normal breast tissue to identify what causes PRa and PRB to interact differently with DNA in the breast, as well as studying the role of progestins from HRT in increasing the risk of breast cancer.
Grant Holder: Dr Laura Soucek
Institution: Vall d’Hebron Institute of Oncology, Barcelona, Spain
Grant award: £195,479 for 3 years
Project Title: Developing “Omomyc” as a new cancer drug
One of the best advances in cancer treatment over the last decade has been the advent of what are called ‘targeted’ therapies. These treatments are designed specifically to attack individual proteins in or on cancer cells that are driving the cancer to grow. Unfortunately, scientists are finding that treating cancer with targeted therapies can be rather like building a dam across a stream; the water stops for a while but eventually it finds a way around the blockage.
Dr Soucek is working on one way to tackle this problem, by blocking a protein called myc. Myc is common to many cancers and is a component of so many cell growth pathways. Dr Soucek’s group have developed a myc-blocking protein fragment called omomyc that has been shown in animal models to be very effective at stopping cancer growth. But the problem that prevents it from being used in humans is that omomyc is not able to get into cancer cells easily, a crucial property that any cancer drug must have. This AICR project will look specifically at how omomyc might be chemically modified so that it can move easily into cancer cells by itself. Modified omomyc protein fragments will then be tested to see if they can eliminate lung cancer in a mouse model. This project represents a crucial step in the drug development process that will, if successful, turn omomyc from scientific tool to potential new cancer drug, and open up the prospect of future clinical trials.
Grant Holder: Professor Marc Vooijs
Institution: University of Maastricht, The Netherlands
Grant Award: £210,462 for 3 years
Project Title: Working to improve standard treatment for non-small cell lung cancer
Lung cancer is the most common cause of cancer related death in the world. The majority of lung cancers (80%) are non-small cell lung cancers (NSCLC). Standard care treatment for NSCLC is chemotherapy and radiotherapy combined but sadly the 5 year survival is only 5-15%. The reason treatment is so unsuccessful is due to the complex biology of the lung cancers and the environment surrounding the tumour. Another reason they are so hard to treat is due to the presence of cancer stem cells. These cells often do not die when the rest of the tumours cells do and, like a criminal on the run from the police, they are then able to escape and travel around the body where they can form secondary tumours, known as metastases. Professor Vooijs has found that a communication pathway inside cells, called the NOTCH pathway, is often deregulated and over-active in NSCLC. This deregulation of NOTCH is associated with resistance to treatment and decreased survival for patients. Conversely, switching off NOTCH stops tumour growth and so finding a way to do this could be a potential new way to treat NSCLC patients, either alone or along with standard chemotherapy and radiotherapy. This is the focus of Professor Vooijs’ AICR grant and he will also be looking for a way to identify which patients could respond well to this type of treatment and which would not benefit as much.
Grant Holder: Dr Carl Goodyear
Institution: University of Glasgow, Scotland
Grant Award: £157,953 for 2 years
Project Title: Targeting bone disease in myeloma
Multiple myeloma is a cancer of the blood, but as it progresses the blood cancer cells collect in the bone marrow, the spongy centre of bones like the spine, pelvis and ribs. Here they release molecules that cause bone to be broken down, weakening it, causing pain and eventually the bone to fracture and collapse. The damage caused by myeloma cells inside bones is known as myeloma bone disease and it is the most debilitating symptom of this type of cancer. Almost all patients with myeloma get bone damage and all are put on treatments to try to contain it.
Current treatments for myeloma bone disease can slow it down, but they cannot stop it. Dr Goodyear will use his AICR grant to investigate what he thinks could be a new way of preventing myeloma cells from causing bone damage. His laboratory has discovered a type of antibody complex, called SIC, that is able to dock onto the surface of the bone-damaging cells and quench their activity. He will test this potential new treatment in a mouse model of myeloma, and investigate whether it might also help stop the myeloma itself as well as control the bone damage.
If successful, this line of research might not only lead to a new treatment for myeloma, it could also be important for other cancers that often spread to the bone, like breast and prostate cancer.
Grant Holder: Dr Kim Jensen
Institution: University of Copenhagen, Denmark
Grant Award: £228,761 for 3 years
Project Title: How are stem cells involved in the progression of bowel cancer?
Worldwide, an estimated 1.24 million new cases of bowel cancer are diagnosed each year. As with most cancers, the earlier it is diagnosed the more successful the treatment. But there is still much that scientists do not understand about how it develops and this is what Dr Jensen is working on changing.
All tissues within our bodies have a small population of stem cells. These are amazing 'starter cells' which have the unique ability to multiply and change (differentiate) into a variety of other cells, depending on where they are located in the body. Dr Jensen is using his AICR to study bowel stem cells and how they may grow rapidly and out of control when they are in the presence of abnormal levels of growth factors, leading to cancer.
Studies using biopsies from bowel cancer patients have already indicated that levels of a molecule called Lrig1 changes during bowel cancer progression. Now Dr Jensen will be using human cells, patient samples and mice, which have had Lrig1 removed, to study in detail what Lrig1 does and how it may prevent cancer. Dr Jensen hopes that by knowing more about how bowel cancer develops this will aid the development of better ways to diagnose patients earlier and lead to better patient care.
Grant Holder: Dr Robin Lovell-Badge
Institution: National Institute for Medical Research, London, England
Grant Award: £164,678 for 3 years
Project Title: Understanding the role of stem cells in tumours of the brain and pituitary
All normal tissues within our bodies have a tiny population of stem cells. These are amazing 'starter cells' which have the unique ability to multiply and change into a variety of other cells depending on the tissue in which they are located in the body. The worrying discovery of a small group of cancer cells with stem cell properties, known as cancer stem cells, in several different types of cancer has profound implications for cancer treatments. It is thought that these cancer stem cells could be responsible for the progression, spread and reoccurrence of cancers as they seem to be able to escape death when treated with anti-cancer drugs.
Some cancer stem cells are thought to originate from tissue stem cells and it is therefore important for scientists to identify and understand the differences between these 'good' tissue stem cells which can be helpful in regenerative medicine and 'bad' cancer stem cells which need to be killed. Dr Lovell-Badge has identified two proteins called SOX2 and p27 which he thinks are involved in normal
stem cells and which, when altered, have a detrimental role in creating cancer stem cells. Dr Lovell-Badge is therefore using his AICR grant to investigate the part played by SOX2 and p27 in the development of brain tumours called glioblastomas and in pituitary adenomas.
Grant Holder: Dr Grant Stewart
Institution: University of Birmingham, England
Grant Award: £215,052 for 3 years
Project Title: Determining the role of a molecule called USP7 in repairing damaged DNA
Cancer can be caused by damage to the DNA inside our cells. This damage can be from many things such as UV in sunlight or mistakes when the DNA is being copied. All healthy cells have mechanisms to repair this damage. However, these repair mechanisms can sometimes become faulty, which allows the DNA damage to remain. This damage can contribute to, or even cause, the cells to become cancerous and allow tumours to develop.
When a piece of damaged DNA is detected, signals are sent to recruit a vast array of molecules that act as a repair kit. One if these molecules is Ubiquitin. Ubiquitin is special because, amongst other things, when attached to another molecule it can signal for it to be destroyed. To counteract this, molecules called de-ubiquiting enzymes (DUBs) are able to remove the ubiquitin tags and prevent unwanted destruction. Dr Stewart is looking at a specific de-ubiquiting enzyme called USP7. USP7 removes ubiquitin from a DNA repair kit molecule called Rad18 which has a key role in efficient DNA repair. If USP7 is absent or inactive, Rad18 is tagged for destruction by ubiquitin. The subsequent low Rad18 levels can then prevent correct repair of DNA damage. Dr Stewart is using his AICR grant to further understand how USP7 can help regulate the levels of Rad18. This work is particularly relevant as new drugs which block the activity of USP7 are being developed as anti-cancer treatments.
Grant Holder: Dr Loretta Dorstyn
Institution: University of South Australia, Adelaide, Australia
Grant Award: £206,542 for 3 years
Project Title: Studying the role of caspase-2 in preventing cancer
Tumour suppressor genes, as the name suggests, are genes that act to suppress the development of tumours. They are able to control a number of functions within our cells to prevent cancer from developing. Cancer-causing genes, called oncogenes can counteract this anti-cancer effect and are often present at much higher levels in cancer cells. In order to prevent tumours, tumour suppressor genes can sometimes kill cells through a process of programmed cell suicide, called apoptosis. Apoptosis is driven by a group of molecules called caspases which act like cellular scissors, chopping up molecules and proteins. Dr Dorstyn and her team have recently shown that one of these caspases, caspase-2, has a direct role in stopping cancer development that is being driven by oncogenes. They also found that low levels of caspase-2 means that DNA damage is not being detected and repaired the way it should be, to prevent cancer from developing. The team believe that caspase-2 can act as a tumour suppressor by protecting against DNA damage. They will use their AICR grant to study whether caspase-2 works as a suppressor of tumours that are caused by oncogenes. They will also investigate genes and molecules that are affected by the absence of the caspase-2 gene. This will give us a better understanding of the role of caspase-2 in preventing cancer, and might identify possible new ways of treating the disease.
Grant Holder: Dr Eva Petermann
Institution: University of Birmingham, England
Grant Award: £190,295 for 3 years
Project Title: Investigating how tumour-promoting genes cause DNA damage
Cancer can be caused by damage or alterations to our DNA which makes up our genes. This damage can be caused by many things such as from UV from sunlight or mistakes when the DNA is being copied, in a process called DNA replication, as the cells grow and divide. Cancer can also be driven by the ‘switching on’ of tumour-promoting genes, called oncogenes, which themselves can allow mistakes when the DNA is copied as cells grow and divide.
DNA is a special code but in order for it to make sense, it must first be decoded and put into a different code called RNA. This is like having instructions for flat packed furniture that were written in a foreign language so you first have to copy the instructions into the correct language before you could build the furniture, or in this case, proteins. This important decoding process, called transcription, can be altered by oncogenes. The loss of control over transcription can cause physical problems between the two sets of machinery that are making new DNA and transcribing it and this can also lead to damaged DNA. Dr Petermann is using her AICR grant to unravel this extremely complex relationship between DNA replication and transcription which is being driven by oncogenes. This work is important as drugs which work by stopping transcription are being developed as anti-cancer treatments. It is therefore important scientists understand what is happening inside cancer cells and how the drugs may then work and what effects they will have inside the cell, thus improving the efficiency of the drugs.
Grant Holder: Dr Marianne Farnebo
Institution: Karolinska Institute, Stockholm, Sweden
Grant Award: £199,768 for 3 years
Project Title: Investigating DNA repair in cancer and its link to non-coding RNA
Every cell carries a complete set of blueprints called genes. Genes are coded instructions to make proteins which then carry out activities within the cell. However, in order to be of any use, the genetic code must first be decoded and turned into something called RNA. The resulting RNA can then be used to make proteins. Recent findings show that some RNA, called non-coding RNA, do not help make proteins. Instead, these non-coding RNAs have several roles inside the cell, such as controlling the RNA that make proteins and it is thought they also do other things. Dr Farnebo is using her AICR grant to investigate a process not currently proven to involve non-coding RNA - the repair of damaged DNA.
If DNA damage is not repaired correctly this can lead to the development of a cancerous cell. Dr Farnebo is therefore investigating what role non-coding RNAs, and the proteins that stick to non-coding RNAs, play in the correct repair of DNA. She is also looking at what happens if changes occur to either of these non-coding RNAs or the associated proteins and how that may impact DNA repair. Basic research, like that carried out by Dr Farnebo, is important as there is still so much for scientists to learn about how healthy cells work and what goes wrong to cause cancer. It is much harder to try to fix something if we don’t understand exactly what is broken. Projects like this help scientists unravel the complex details of what goes wrong to cause cancer so they can then build on this knowledge to try to find ways of preventing or treating cancer in the future.
Grant Holder: Professor Neil Perkins
Institution: University of Newcastle, England
Grant Award: £209,608 for 3 years
Project Title: How does NF-kappaB turn off the anti-cancer molecule p53?
The NF-kappaB family of proteins are switched on by stress signals and help the cell adapt to threats from the environment and infection. They have an important role in regulating our immune system and inflammation. NF-kappaB proteins are also found to be incorrectly switched on in many types of cancer, meaning the active form can have cancer-promoting properties, including turning off the anti-cancer molecule p53. In response to cell stresses, chronic inflammation or genetic alterations
there are two main communication pathways that can lead to the switching on of NF-kappaB. Communication pathways are similar to a line of dominoes. As one ‘domino’ falls, the message gets passed from one molecule, to the next until it reaches the final one, who then gets switched on and performs a task. However, if a domino is removed or falls at the wrong time this can lead to the wrong message being communicated and this can lead to cancer. Professor Perkins has recently found a new mechanism, which helps regulate one of these NF-kappaB communication pathways. This pathway allows NF-kappaB to switch off the anti-cancer molecule p53, which can prevent damaged cells from entering a dormant state. Entering this dormant state provides a mechanism for normal cells to escape becoming cancer cells. Professor Perkins will be using his AICR grant to investigate this mechanism in more detail. He hopes that by learning more about it we can prevent NF-kappaB switching off p53 and so find a way to treat the cancers in which this pathway has been activated.
Grant Holder: Dr Allison Bardin
Institution: Institut Curie, Paris, France
Grant Award: £197,530 for 3 years
Project Title: Using fruit flies to understand how cancer begins
Most tissues within our bodies have a small population of stem cells that can renew these tissues when old cells die. These are amazing 'starter cells' which have the unique ability to multiply and change (differentiate) into a variety of other cells, depending on where they are located in the body. The recent discovery of cancer cells with stem cell properties, known as cancer stem cells, in several types of cancer has profound implications for cancer treatments. It is thought that these cancer stem cells could be responsible for the progression, spread and reoccurrence of cancers as they seem to be able to escape death when treated with anti-cancer drugs.
Dr Allison Bardin is using her AICR grant to better understand how stem cells and tissues cope with genetic damage from environmental factors. For example, human stem cells suffer from exposure to ultraviolet radiation from the sun or cigarette smoke. She will also look at how the cells stop being able to repair the damage and how cancer can begin to develop. Dr Bardin will be using fruit flies for her research as the genes that control the growth and death of fly cells are almost identical to those found in human cells, making their findings highly relevant to what goes on in the human body. Since fly cells are less complicated, grow quickly and they are easier to study than human cells they enable
scientists to see changes more quickly.
Grant Holder: Dr Jeffrey Arbeit
Institution: Washington University in St Louis, Missouri, USA
Grant Award: £200,145 for 3 years
Project Title: Studying mTORC protein complexes to target blood vessel growth in cancer
For tumours to grow bigger than a millimetre or two they need to establish their own blood supply otherwise they cannot get enough oxygen. Not surprisingly, trying to find ways to stop blood vessels growing in tumours is an important line of cancer research. Although some anti-blood vessel drugs are already available for cancer treatment, they do not work as well as originally hoped because we now know that the process of blood vessel growth in tumours is much more complicated than first thought.
This project will look at two protein complexes, mTORC1 and mTORC2, and comprehensively examine the role they play in tumour blood vessel growth. Some preliminary studies in isolated cells have indicated that they are both important, but in order to know this for sure Dr Arbeit will study them using laboratory models that are a much better representation of real tumours.
Drugs that targeted the mTORC complexes are already in clinical development, so if the mTORC complexes are proven to be important regulators of blood vessel growth in cancer this project will help inform how these drugs could be used most effectively in cancer treatment.
Grant Holder: Professor Lena Claesson-Welsh
Institution: Uppsala University, Sweden
Grant award: £207,045 for 3 years
Project Title: Understanding how our bloody vessels can become leaky and identifying chemicals that can stop it happening.
In order for tumours to grow larger than about 1 millimetre across they must have their own blood supply to enable enough oxygen and nutrients to reach the cells. Tumour cells produce a hormone-like molecule called VEGF which encourages new blood vessels to grow towards the tumours. VEGF also causes blood vessels to become more porous and leaky, allowing tumour cells to get into the bloodstream and spread around the body. In addition, the leakiness causes fluid (mainly water) to build up around the tumor and cause swelling and discomfort for the patient. This swelling can also stop drugs from getting to the correct site of the tumour, making them less effective. With her AICR grant Professor Claesson-Welsh is going to investigate how VEGF is involved in causing the blood vessels to become leaky. She then plans to identify chemicals that could act as potential drugs to stop this excessive leaking. In order to do this she will be using mouse models to test the potential drugs for their ability to stop the leaking and to see if the drug can get to the correct place in the body without any unwanted side effects.