Worldwide Cancer Research Menu

Could a natural dietary component help improve the effects of common chemotherapy drugs?

Professor Kevin Ryan and his team in Glasgow are investigating a potentially very simple way to improve survival rates for standard chemotherapy treatments.

“Despite the advent of targeted therapies, conventional chemotherapy remains the standard of care for many patients with cancer,” explains Professor Ryan. “And many patients are still receiving drugs that have not changed over decades.”

“For these patients, survival rates have generally little improved. New strategies to enhance the responses to these drugs are therefore greatly needed and hugely overdue.”

Professor Ryan and his team have spent years searching for compounds which could potentially help improve the effectiveness of chemotherapy treatments, and now they think they have found one.

“In our laboratory we have discovered that higher levels of a naturally-occurring component of our diet might enhance the activity of two widely-used cancer drugs. We will now use this new funding to understand how this works. We will then conduct pre-clinical studies to determine the potential of this dietary component to enhance the effectiveness of drugs used to treat specific cancer types.”

“We hope that our studies will ultimately lead to human clinical trials aimed at improving therapy responses for long-term patient benefit.”

A new DNA-based therapeutic to block enzymes which cause cancer progression

Dr Filichev and his team are developing a novel way of blocking DNA-damaging enzymes that are linked to cancer progression.

APOBEC3 enzymes are a helpful part of our immune system- they protect us by destroying the DNA of invading viruses and bacteria. However, several APOBEC3 enzymes are also linked to DNA changes that increase the risk of cancer progression.

The researchers want to make a new DNA-based therapeutic which inhibits the action of one of the APOBEC3 enzymes linked to cancer. The enzyme usually attacks and destroys single-stranded DNA found in invading cells, but ignores the double-stranded DNA found in healthy human cells. They want to exploit this difference by basing the new therapeutic on a chemically modified version of single-stranded DNA.

“We think that blocking the enzyme in this way will effectively suppress one of the main pathways that helps cancer to progress, but will not disrupt normal cells,” explains Dr Filichev. “But first we need to find out exactly how the enzyme normally interacts with single-stranded DNA. That’s what we are doing in this project.”

“I think with this work we will really advance knowledge about how APOBEC3 interacts with DNA, which in turn will accelerate drug discovery of novel compounds that inhibit cancer progress.”

Targeting chromosomes in cancer

Dr Maria Blasco is searching for new drugs which could kill cancer cells by altering their chromosome structure.

Chromosomes are tightly coiled strands of DNA in the cell. Telomeres, which cap the end of the chromosome work much like a cap on the end of a shoelace- stopping the DNA ends from unravelling. Telomeres help keep the chromosome stable and protect it from damage. Without long enough telomeres the chromosome will quickly degrade and the cell will die.

In this project Dr Maria Blasco and her team are searching for novel anticancer compounds which can block the mechanisms needed to keep telomeres stable in cancer cells. They are using high-throughput cell-based systems to screen for suitable candidates, which will then be investigated for their anticancer activity using a number of tests in the lab.

Understanding the molecular mechanisms that allow cancer cells to keep on growing

Dr Sara Sigismund is investigating how cancer cells manage to keep growing, bypassing safety checks meant to stop them.

In healthy cells, the epidermal growth factor receptor (EGFR) on the cell surface works as an antenna: it receives signals from the organism and instructs cells to survive and grow. However, if it is not correctly switched off, EGFR signalling can cause abnormal cell growth leading to cancer.

One mechanism that switches off EGFR signalling is endocytosis, a process where receptors are removed from the cell surface and internalized into the cell by inclusion into tiny membrane-bound structures called vesicles.

Dr Sigismund and her team have discovered a novel type of vesicle that exclusively directs EGFR to degradation. The EGFR is captured into these vesicles only when cells receive a high amount of signal. Importantly, blocking this mechanism causes EGFR signalling to be persistently turned on.

The researchers think that this mechanism represents a crucial ‘safety check’ that protects cells from overstimulation, and suspect that that cancer cells might turn it off so they can keep growing. In this project they will study the cell proteins involved in this specific process. They envisage their work will open the way to the identification of novel mechanisms used by tumour cells to escape the cell’s defences against excessive growth.

 

Testing a new drug development strategy

The accurate division of cells to grow, replenish tissues or repair wounds is a highly complex process. It requires thousands of proteins to be made in the correct shape, built into functional machines and then regulated in an accurate and timely manner to ensure that cell division occurs without error.

Central to this process are ‘chaperones’, a diverse family of proteins that act as ‘cellular guardians’. These associate with newly made proteins to ensure that they are properly folded and correctly assembled into intricate biological complexes.

One group of chaperones is the ‘heat shock proteins’ or HSPs that protect cells from the ‘shock’ of high temperatures. They do this by helping proteins maintain their correct shape despite the increased temperature. However, HSPs do much more than simply protect cells from ‘heat shock’. They also ensure the survival of cells exposed to other stresses, such as the imbalances in protein content that can arise in various disease states.

Not surprisingly, HSPs are very important in human cancer, ensuring the survival of cancer cells within the stressful environment of a tumour. Consequently, there is major interest in the development of HSP inhibitors (drugs which inactivate HSPs) as novel anti-cancer therapies that can effectively eradicate and overcome drug resistance typical of tumours.

Professor Andrew Fry told us “We have discovered that one particular set of HSPs, called Hsp70, is essential for division of human cancer cells. The purpose of this research project is to use cutting-edge molecular and cell biology techniques to explore how Hsp70 contributes to cell division and design strategies that will block Hsp70 pathways specifically in cancer cells.

The award of this grant from Worldwide Cancer Research gives us a really exciting opportunity to test the idea that cancer cells have specific vulnerabilities not present in normal cells. If targeted appropriately, this would allow selective killing of tumour cells while leaving normal cells unharmed. This would enable patients to benefit without suffering the debilitating side-effects associated with traditional chemotherapeutic approaches "

Visualising where drugs attach to their targets inside cancer cells

How can we see what goes on inside cells? Developing miniscule cameras to go inside of the cells isn’t physically possible, neither is building a machine similar to the one featured in the film ‘Honey I shrunk the kids’. Instead, Professor Carolyn Moores is developing state of the art electron microscopy to visualise where drugs bind to their target molecules in cancer cells.

Professor Moores explains “Tightly controlled cell multiplication is essential for replacing old cells and to repair wounds. However, mutations or malfunctions in this process can lead to out-of-control cell growth, a hallmark of cancer.

The purpose of this research is to study the machinery of cell multiplication in order to find potential drugs that can block it. Such drugs can act as “spanners in the works” of the out-of-control machinery and thus have the potential to be used as cancer treatments.

Our focus will be on a major component of this machinery called microtubules. Microtubules are long cylindrical structures that provide support and strength to cells. Within the multipliation machinery, microtubules act as tracks along which many different molecular motors - called kinesins - can move. We will study the way individual kinesins step along microtubules and how their movement can be blocked specifically by potential drugs.

We will use a very powerful microscope - an electron microscope - to take pictures of individual microtubules bound by drug-blocked kinesins. Revolutionary new imaging technology means that our pictures will provide unprecedented detail, from which we will calculate the three-dimensional shape of our samples.

Knowing what the motors look like helps us to determine the most precise way to block them. This precision is important because drugs that act on the wrong piece of cellular machinery could be poisonous to non-cancer cells. This technique could potentially revolutionise the way drug discovery is carried out and our findings could be used to design specific drugs that can be further developed to improve treatments for cancers in the future. It is an exciting time to be an electron microscopist and we are thrilled that Worldwide Cancer Research is supporting our research in this area.”

Can upside down cell division promote cancer development?

Dr Angeliki Malliri is studying why it is so important that cells grow and divide in the correct direction/orientation. Many tissues, such as kidney, breast and lung, consist of hollow spheres surrounded by a single layer of cells. New cells form side-by-side in the tissue. Potentially, if new cells form above or below the tissue layer, this may contribute to tumour formation. Many questions remain about the process for orientating cell divisions (so new cells know to grow side by side and not up or down).

Dr Malliri explains “We have recently identified a role for the protein CASK in this process. When CASK is depleted in normal kidney or breast cells, cell divisions are misorientated, and astral microtubules (the molecular cables within the cell which help orient cell divisions) are fewer and shorter. These cells then divide to form spheres with multiple centres - reminiscent of an early stage of breast cancer. Reintroducing CASK protein back into these cells restores normal spheres with single centres. To better understand how these abnormal structures form, we will use state-of-the-art microscopes to image live cells containing fluorescent proteins and watch as they form normal and abnormal spheres.

Another protein, Dlg1, whose loss causes tumour growth in other biological models and which binds CASK, is reduced when CASK is depleted. We will investigate whether depletion of Dlg1 gives rise to abnormal structures and misorientated divisions. We will also study how CASK is able to stabilise Dlg1 and investigate the importance of their binding.

To address the role of CASK in tumour formation and progression, we will examine human breast cancer tissues for reduced CASK and Dlg1 levels. Moreover, we will see whether breast cells with reduced CASK are more able to form tumours when introduced into mouse models.”

Developing a way to visually track immunotherapy treatments inside patients

Dr Gilbert Fruhwirth at King’s College London is developing a way to observe immunotherapy treatments at work inside patients.

Immunotherapy is a relatively new treatment which is based on ‘training’ the immune system to attack cancer, and which has already had spectacularly good results in some early clinical trials.

Dr Fruhwirth and his team are interested in CAR immunotherapy, a promising type of personalised treatment which involves genetically modifying some of the patient's own immune cells to recognise and kill cancer cells. The ‘souped-up’ immune cells, called CAR T-cells, are then transferred back to the patient and let loose on the cancer.

The trouble is, it’s hard to follow what these ninja T-cells do next.

“CAR immunotherapy is a live-cell therapy,” says Dr Fruhwirth, “so we’d really like to be able to actually monitor what’s happening in the patient. If we can track in real-time the arrival of CAR T-cells at the tumours, for example, and measure how many get there and how long they stay active against the tumour, it will be much easier for us to judge how well the treatment is working.”

Dr Fruhwirth aims to insert a gene into CAR T-cells that will make them visible to highly sensitive imaging techniques when they are inside a patient’s body. During this project he will test out his concept in the lab, gathering evidence that will form the basis of later human trials. “If successful, we can start a new Phase I clinical trial to test this technology in humans. We believe this project will ultimately help improve how we monitor CAR immunotherapy, and ensure its safety”

A new approach to stop cancer cells dividing

Dr Daniel Fisher is trying to block a protein present in dividing cells called Ki-67 in order to study its effects on tumour cell survival. He explains “At the root of all cancers is a deregulated cell proliferation where cells multiply rapidly forming a tumour. Most cancers are graded by laboratory analysis of a protein only present in proliferating cells called Ki-67. Whether or not this protein is merely a marker for cell proliferation, or whether it is required for cell proliferation and cancer, is not known.”

He continued "We have recently found that Ki-67 is dispensable for cell proliferation. However, it acts indirectly by organising the genome (DNA) within the cell nucleus, and for reasons that we don’t yet understand, it appears to be required for cells to survive inside a tumour. This suggests that it could potentially be used as a therapeutic target for cancer treatments.

Many cancer drugs target cell proliferation directly, and these can be toxic for healthy cells. We would like to find a drug that either prevents Ki-67 from appearing in cells without affecting cell division, or blocks its functions. In this project, we will use mouse genetic models to analyse whether blocking Ki-67 can protect against liver and colon cancers. We will further analyse how Ki-67 allows tumour cell survival. Finally, we will investigate whether its downstream effectors, that control gene activity, can explain its pro-tumour functions."

Deciphering why cancer occurs more often in some organs than others

Dr Ruben van Boxtel is deciphering DNA changes in different parts of the body to explain why cancer arises in some places more often than others.

Cancer incidence varies enormously among organs in the human body, for example it is rare in the small intestine and liver, more common in the pancreas and kidney, and very common in the breast, prostate and lung. It has long been known that specific changes in the DNA sequence of cells may cause cancer but it is unclear what determines this variability in different organs.

It is possible that the variation in cancer incidence in the organs may result from different organ-specific processes. These processes can be identified by studying characteristic ‘footprints’ they leave behind in the DNA sequence.

Dr van Boxtel told us “I am studying these ‘footprints’ in the DNA of adult stem cells, specialized cells that can change into a range of different cell types. DNA changes in adult stem cells have the largest impact on human health. Because they allow organs to self-renew and repair upon injury, so if the stem cells are altered, so are all the cells that they give rise to. I have gathered adult stem cells from post-mortem tissue samples obtained from people who donated their bodies to science. The changes present in the DNA will be determined by analyzing their complete DNA sequences and characteristic organ-specific footprints will be determined. Finally, computational analyses will help identify the processes responsible for generating DNA changes. By comparing the footprints of adult stem cells from different organs, I will be able to identify organ-specific cancer-initiating processes.

This research will increase our understanding of processes that cause cancer via DNA changes and how these differ between organs. Ultimately, this research may benefit cancer prevention. My work would not be possible without the generosity of people who leave their bodies to scientific research so I am very grateful to them and their families.

"I am currently trying to establish an independent research group and this grant will help me to reach that goal. With my career I want to figure out if and how the processes that are responsible for cancer-causing DNA changes can be stopped before the onset of disease. This grant will help me to start this research."