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Probing a group of proteins to develop novel ways to detect and treat cancer

The cells in our body produce a group of proteins called Kallikrein-related peptidases, or KLKs for short. It’s known that these proteins play an important role in a variety of biological processes involved in the development and progression of cancer, but researchers currently lack the technology to study KLKs accurately in cancer cells.

Professor Edward Tate, based at Imperial College London, is a chemical biologist who through his career has developed techniques to produce chemical probes to study the activity of proteins within cells. These probes allow scientists to measure how active specific proteins are in cancer cells and use this information to develop new ways to diagnose and treat cancer.

Professor Tate is now developing probes to study the activity of KLKs in prostate, ovarian and pancreatic cancer cells. His team will use their results to identify chemicals that can block KLKs in these cells with the goal to open up new avenues for cancer treatment. They will also test the probes in biological samples from cancer patients to understand if measuring KLKs could be used as a way to more accurately diagnose patients.

New genetic marker could help diagnose aggressive prostate cancer

Scientists have discovered a link between certain genetic mutations, the aggressiveness of prostate cancer, risk of developing the disease and poorer survival rates of patients. The gene, called ANO7, could play a vital role in improving diagnosis of prostate cancer patients. There are over 50,000 new cases and 11,000 deaths from prostate cancer each year in the UK.

There is currently no clear way to diagnose aggressive prostate cancer at an early-stage. Genetic mutations, such as those revealed in this study, could lead to the development of accurate diagnostic tests that will ultimately mean patients receive the best possible treatment, sooner.

The researchers studied the DNA from over 1,700 prostate cancer patients and a comparable number of healthy men to look for genetic mutations that were associated with the disease. They were particularly interested in studying mutations to the ANO7 gene because their previous research suggested this could be a gene of interest for prostate cancer.

Dr Johanna Schleutker, from the University of Turku, Finland, who led the study, said: “We found that small genetic changes to the ANO7 gene increase a patient’s risk of aggressive prostate cancer. One of the current biggest unmet needs in prostate cancer care is being able to diagnose aggressive cancers at an early stage. Genetic testing for ANO7 could help identify these patients sooner and may bring new opportunities for precision oncology in prostate cancer.”

The researchers found one particular genetic mutation that correlated with an increased risk of developing prostate cancer as well as the severity of the disease. They also found a separate mutation that correlated with shorter survival.

Analysis of tissue samples from prostate tumours revealed that mutations to ANO7 were associated with the gene being more active, suggesting that the biological function of ANO7 may play an important role in why these cancers are more aggressive. The function of ANO7 is not fully understood, but further research could lead to new ways to treat the disease.

Dr Helen Rippon, Chief Executive of the charity Worldwide Cancer Research, whose supporters helped fund the study, said: “Prostate cancer affects so many people so we desperately need to find new, clever ways to accurately diagnose patients sooner. Those with the more aggressive forms of prostate cancer have the bleakest outcome, but if we can devise tests to diagnose them early on in the disease process, we can do more to ensure they receive the best possible treatment. We are thankful to all the people that support Worldwide Cancer Research as they are the ones that make research like this possible.”

Although the study involved a large population, it is limited by the fact that it is primarily a Caucasian population from Northern Europe. Further research involving other demographics is needed to validate the findings. Worldwide Cancer Research, the Finnish Cancer Organisations, the Academy of Finland, the Juselius Foundation and the Research Funding of Turku University Hospital supported the research. The research was published in the International Journal of Cancer.

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Turning “sweet” on cancer – developing an entirely new way to fight cancer

Sometimes to push the boundaries of science you have to have a radical new idea. Dr Diego Laderach, based in Argentina, is using funding from Worldwide Cancer Research to pursue just that. His teams work is aiming to develop a brand new type of immunotherapy for prostate cancer by targeting a feature of cancer cells that has never before been tested.

Their potentially game-changing idea involves stimulating the immune system to target a specific molecule found in abundance on the outside of cancer cells. This molecule is also found on the surface of a special type of white blood cells called a suppressive T-cell, which contribute to cancer by suppressing the immune system from attacking rouge cancer cells. Dr Laderach proposes to trick the immune system into eradicating cells displaying the molecule using a ‘sugary’ form of the same molecule. The hope is that this will lead to a two-pronged attack on cancer that allows the full force of the immune system to be unleashed on the disease.

The teams work will focus on prostate cancer but Dr Laderach says that the impact of their work “…will significantly contribute to the design of novel therapeutic strategies which, in combination with current treatments, will be of paramount clinical benefit in patients with advanced prostate cancer and probably other types of cancer.”

Developing nanomedicines to treat prostate cancer

Dr Dufès and her team in Glasgow are developing nanomedicine carriers to help target hard-to-treat prostate cancers which have returned or spread.

Prostate cancer is one of the most common cancers in men, with 130 new cases diagnosed every day in the UK alone. Although effective treatments exist for early hormone-dependent prostate cancer, cancer which has returned or spread is harder to treat. New treatment approaches are therefore critically needed for these patients.

“Gene therapy holds great promise for the treatment of prostate cancer.” Says Dr Dufès. “However, its use is currently limited by the lack of safe and effective ways of delivering therapeutic genes to prostate tumours without secondary effects to healthy tissues.”

Tumours need iron to grow, and molecules which detect and transport iron into tumours are present in abundance on the surface of tumour cells. In earlier studies Dr Dufès and her team exploited this fact and used specially engineered iron ‘carriers’ to target genes specifically to tumours. “We found that that the use of iron-carriers linked to highly promising prototype gene therapies caused the disappearance of 60 per cent of prostate tumours in mice.” Says Dr Dufès.

“We now want to build on these promising results and develop new ‘seek-and-destroy’ systems incorporating what we have learned. This proof-of-concept research will hopefully help us develop an entirely new way to deliver gene therapy to hard-to-treat tumours in a safe, specific, and effective way.”

Developing new prostate cancer treatments

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 Worldwide Cancer Research 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.

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 Worldwide Cancer Research 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.

Improving prostate cancer screening

Prostate cancer is the most frequently diagnosed cancer among men in the UK. It is estimated that 5-10% of cases are due to faulty genes passed on from our parents. Faults in two particular genes called BRCA1 and BRCA2, appear to cause a higher risk of prostate cancer and men with faulty BRCA2 genes also tend to develop the more aggressive forms of the disease which have lower survival rates. The prostate specific antigen (PSA) test helps detect prostate cancer but it is not perfect. Although the test has helped decrease the number of deaths from prostate cancer by around 20% it also leads to over-detection and over-treatment for many men who would have continued living a normal and full life, usually when they have mild forms of this cancer. However, men at a higher risk of developing prostate cancer, and particularly the more aggressive form, for example those with faulty BRCA1 or BRCA2 genes, may be more likely to benefit from PSA screening. Professor Kiemeney is conducting a study looking at the use of the PSA test for men with different faults in their BRCA genes along with a second screening test for prostate cancer which detects the molecule PCA3 in urine. Professor Kiemeney will then evaluate the use of the PCA3 marker in screening high-risk families with the hope that if it is successful, it could be added to the screening programme for men with a higher risk of developing the disease.

Investigating how prostate cancer starts and spreads

Prostate cancer is the most common cancer in men in the UK and worldwide, around 899,000 men were diagnosed with prostate cancer in 2008. Despite the high number of men getting this disease there is still much to be known about how it starts and spread.  Worldwide Cancer Research has therefore recently awarded a grant to Professor Sette to investigate some of the molecules involved in allowing prostate cancer to start and spread.

Every cell in our body contains thousands of genes that are in control of all that happens within the cell.  Cancer is caused by changes to either the structure or activity of specific, key genes that control how the cells grow, divide and survive.  These gene changes cause the cells to multiply in a rapid and uncontrolled manner, forming a tumour.

A new way that cells control the activity of their genes involving molecules called long non coding (lnc) RNAs has recently been discovered. lnc RNAs have been shown to be involved in many human diseases, including prostate cancer.

Professor Sette has previously shown that a protein called Sam 68 is also involved in controlling gene activity in prostate cancer cells and is present at high levels in these cells.  Sam68 can control the activity of genes in several different ways, either directly or by effecting lnc RNAs which then control the gene’s activity.  With his new Worldwide Cancer Research grant he is aiming to understand exactly how Sam68 works with other molecules in the cell, including lnc RNAs, and what effects it has on prostate cancer cells.  A better understanding of Sam68’s role in cancer cells may help with the development of new prostate cancer therapies in the future.

How can prostate cancer spread to other organs?

One of the main factors that make tumours so dangerous is their ability to invade into surrounding tissues and organs and spread throughout the body. Individual cancer cells squeeze between the normal cells nearby and push their way through the tissue. They are then carried in the blood stream and can form new tumours in other parts of the body. The ability of prostate cancer cells to move and spread is controlled by many different proteins, including one called Met and a group called Rho GTPases. These proteins are usually tightly controlled but can become unregulated in cancer. With her Worldwide Cancer Research grant Professor Ridley is analysing how the Rho GTPases interact with the Met protein to allow the cancer cells to spread. She also hopes to identify other proteins that may be involved. This could lead to the design of new treatments in the future.

What is the link between obesity, cholesterol and prostate cancer?

Currently, there is a known link between prostate cancer, obesity and high cholesterol. How these conditions are linked remains unclear. A cell is covered by a cell membrane; this separates the inside of the cell from its external environment. Cholesterol is a component of this cell membrane that helps to organize the membrane into regions that are important for communication of the cell with the outside. One molecule that is controlled by cholesterol is called caveolin-1, and this molecule may play a role in aggressive prostate cancers. Dr Hill is using her Worldwide Cancer Research grant to investigate how caveolin-1 and high cholesterol are involved in prostate cancer. One theory is that the caveolin-1 molecule becomes altered in prostate cancer which causes changes in the way the cell membrane functions. These changes increase the ability of the prostate cancer cells to invade surrounding tissues and spread around the body, forming secondary tumours. Dr Hill and her team will test this theory using prostate cancer cells with or without caveolin-1 to mimic aggressive and non-aggressive prostate cancers, and study how these cells respond to changes in cholesterol in their environment. As the number of obese people increases and the population continues to eat a high cholesterol diet, a better understanding of how cholesterol and caveolin-1 contribute to prostate cancer is vital. Dr Hill's team will use this system to find new molecules that could be used in diagnosis and to enable scientists to design and develop better treatments for prostate cancer in the future.