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Delivering immunotherapy to the heart of lung cancer

Non-small cell lung cancer (NSCLC), the most common type of lung cancer, has no cure and the overall survival rate is estimated to be only 20 per cent. It’s therefore critical that research uncovers new ways to treat the 1.7 million people diagnosed with NSCLC each year. Immunotherapy, a treatment that acts by turning the patient’s immune system against the tumour, holds real promise for treating NSCLC, but is held back by our inability to target the treatment directly at the tumour.

Professor Kairbaan Hodivala-Dilke has previously found that by using low doses of a drug originally designed to cut off the blood supply to a tumour, they are, counterintuitively, able to increase blood flow to the tumour and increase the level of chemotherapy that reaches the tumour. This odd finding has led Professor Hodivala-Dilke to investigate if a similar approach could be used to target the cancer-killing effects of immunotherapy directly at the tumour.

Professor Hodivala-Dilke and her team, based at Queen Mary University of London, England, aim to test a new drug in pre-clinical studies to see if it can boost the effects of immunotherapy in NSCLC. If successful, her team hopes that they will be able to take the new drug forward into clinical trials to treat lung cancer patients.

Identifying new drugs for the treatment of lung cancer

Non-small cell lung cancer (NSCLC), the most common type of lung cancer, has no cure and the overall survival rate is estimated to be only 20 per cent. It’s therefore critical that research uncovers new ways to treat the 1.7 million people diagnosed with NSCLC each year.

Dr Simona Polo and her team based in Milan study a network of proteins, called the ubiquitin network, and the role it plays in cancer. They are particularly interested in a group of enzymes in the network called E3 ligases, which help cells to coordinate how they respond to different stimuli in a precise and selective manner.

In this project, Dr Polo’s team are investigating one of these enzymes, called NEDD4, which is overactive in some lung cancer cells and thought to contribute to the growth and division of cells. They aim to develop chemical inhibitors that block the NEDD4 enzyme from working, as well as furthering our understanding of how this enzyme is linked to cancer. The results of Dr Polo’s research will be the first steps towards a brand new targeted therapy for NSCLC.

Developing a new approach to targeting lung cancers

Dr Silvestre Vicent is working hard to develop a new approach to targeting lung cancers with mutations in a gene called KRAS.

Worldwide, nearly 1.83 million new cases of lung cancer were estimated to have been diagnosed in 2012 and it is the leading cause of death from cancer in Europe. Non-small cell lung cancer (NSCLC) is the most common type and represents about 80% of total lung cancers. In these NSCLC tumours, KRAS is the most commonly mutated cancer-causing gene (oncogene), found in over 20% of patients."

Dr Vicent told us “Since KRAS mutations are directly responsible for NSCLC, KRAS represents an ideal target to try and turn off in order to prevent NSCLC development. Yet, efforts to develop therapeutic inhibitors against KRAS have failed for over 20 years. Thus, it is critical to identify targets of oncogenic KRAS that could unveil new therapeutic candidates.

A previous search for molecules downstream of activated KRAS led to the identification of a series of up-regulated ‘microRNAs’. MicroRNAs (miRNAs) regulate expression of key genes in normal and cancerous cells. We hypothesize that these microRNAs play a key role in cells harboring KRAS mutations.”

He added “The goal of this work is to carry out proof-of-concept testing on the role of the miRNAs afected by activated KRAS. We expect to identify miRNA target genes involved in cancer development driven by KRAS. Eventually we hope to apply these findings to develop new therapeutic strategies targeting KRAS in NSCLC patients.”

He concluded "This grant from Worldwide Cancer Research is of paramount importance to consolidate our research group and increase its visibility to the scientific community.”

The project is an excellent opportunity to test whether KRAS-regulated miRNAs represent functionally relevant targets for which novel therapeutic strategies could be eventually developed".

Lung cancer treatment boosted by simple blood pressure drug

A common blood pressure drug may make a type of lung cancer treatment more effective, suggests a new study partly funded by Worldwide Cancer Research and published this week in the journal Cell Discovery.

Worldwide Cancer Research scientist and lead author Professor Michael Seckl said “Although these are very early-stage results, and are yet to be applied to patients in trials, they suggest the addition of a very cheap diuretic may extend the amount of time we can use the lung cancer drug erlotinib. This could potentially provide patients with more treatment options and save money in financially challenged health services.”

Almost 2 million people are diagnosed with lung cancer every year worldwide and it is the biggest global cancer killer. There are two types, the rarer small cell lung cancer and the more common non-small cell lung cancer.  The drug erlotinib is prescribed to between 10 - 30 per cent of patients with non-small cell lung cancer who carry a particular genetic mutation on their cancer cells.  Erlotinib blocks this mutation and halts cell growth.  However, the cancer cells quickly evolve resistance to the drug’s deadly effects and within a matter of months patients no longer benefit from the drug.

Although alternative drugs are available once erlotinib stops working, these are much more expensive – and they can also stop working, again due to cancer cells developing resistance.

Previous studies have found that, in at least half of cases, the cancer cells become resistant to erlotinib by developing a second mutation. But scientists only partially understood how this additional mutation protected the cancer cells from dying.

In this study, the team found the second mutation lowers levels of a naturally-occurring antioxidant called glutathione.  If glutathione levels were raised in cancer cells in the lab, it reversed resistance to the drug erlotinib, and the treatment was once again able to kill cancer cells.  Spurred on by their finding, the team then looked for medicines that raise glutathione levels.

They found the ‘water pill’ ethacrynic acid, a diuretic used for 30 years to treat swelling, fluid retention and high blood pressure, raised glutathione levels.  Studies in mice confirmed that using the diuretic alongside the cancer drug erlotinib reversed resistance to the drug, and enabled it to kill lung cancer cells.

“We urgently need new treatments for lung cancer patients, and this research suggests we can boost the effectiveness of an existing drug, rather than switch to another new expensive treatment. We want to start patient trials within the next three years” explained Professor Seckl.

The research was supported by the European Commission, Cancer Research UK, Worldwide Cancer Research, Cancer Treatment and Research Trust and the NIHR Imperial Biomedical Research Centre.

  • Full bibliographic informationDecreased glutathione biosynthesis contributes to EGFR T790M-driven 2 erlotinib resistance in non-small cell lung cancerHongde Li, William Stokes, Emily Chater, Rajat Roy, Elza de Bruin, Yili Hu, Zhigang Liu, Egbert F. Smit, Guus J.J.E. Heynen, Julian Downward, Michael J. Seckl, Yulan Wang, Huiru Tang, Olivier E. PardoCell Discovery, 26 September 2016

Image courtesy of pixabay.com, CC0 1.0 Universal (CC0 1.0).

Improving the power of the immune system to help beat mesothelioma lung cancer and melanoma skin cancer

Dr Peter Katsikis and his team are finding ways to help our own immune system target and attack tumours more efficiently. In this project his team will focus especially on the skin cancer melanoma, and a type of lung cancer called mesothelioma. Both of these types of cancer are prone to spread and can be very hard to treat once they do.

The researchers are especially interested in a CD8 T cell, a type of immune cell which usually helps to spot and attack tumours in the body. However these cells sometimes fail to find the tumour, or are suppressed and unable to attack. So Dr Katsikis and his team want to find new ways to help re-activate them. They are particularly interested in a set of molecules called miRNAs, which they think might help to regulate T cell activity in the body.

During this study they want to find exactly which combination of miRNA molecules will help to enhance and restore T cell action against tumours. The researchers hope that their findings will help design future anticancer T cell based immunotherapies for cancer patients.

New year, new research

We support research into all cancer types and this latest grant round was no exception. The projects contain a good mix of cancer types from mouth and lip to breast, lung, pancreatic, lymphoma and liver cancer to name but a few. And of course a large amount is being spent on understanding the very fundamental principles behind how our cells behave and what goes wrong in cancer. Keeping with our ethos of supporting the best research around the globe, the projects are taking place all over the world including England, Portugal, Greece, Spain, Australia, The Netherlands, France, Germany, USA and Canada.

Opening up about mouth cancer

Some of the projects that most excite us are Dr Guy Lyons from the University of Sydney, Australia. He is identifying genetic changes that occur when mouth cancer starts so that it can be diagnosed early, when treatment is more likely to be successful. You can read more about mouth cancer in our recent blog. Dr Lyons told us “The support of organisations such as Worldwide Cancer Research for research into the fundamental biology of cancer is essential for the discovery of new paradigms that enable new approaches in the clinic down the track.”

Developing new ‘super cameras’

Professor Carolyn Moores at Birkbeck University of London in England is developing state of the art electron microscopy to actually visualise where drugs bind (stick) to their target molecules inside the cancer cells. This is VERY cool.  She said “Revolutionary new imaging technology means that our pictures will provide unprecedented detail, from which we will calculate the three-dimensional shape of our samples. 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.”

Studying ‘bubbles’ to beating childhood brain cancer

We are also funding Dr Kasper Rouschop at Maastricht University in The Netherlands (pictured above) who is studying how ‘bubbles’ released by glioblastoma tumours encourage blood vessels to grow into the tumour. Glioblastoma’s are a type of brain tumour that commonly effects.  He told us “We anticipate that the results of this research will enable us to evaluate whether targeting these particular bubbles could be a potential new way to reduce the growth of brain tumours.  Our approach is highly innovative and is based on our previous identification of “bubbles” that are specifically released by hypoxic tumour cells. Without the support of Worldwide Cancer Research, evaluation of this promising approach would not be possible.”

And last, but by no means marking the end of my list of fab new projects, is Dr Ruben van Boxtel at the Hubrecht Institute in the Netherlands. He is trying to figure out why cancer arises in some parts of the body more than others. Great question to try to answer!

Our next grant round is already underway and our Scientific Committee will meet in March to decide who gets funded.  But this relies on donations, no money means no research.  If you would like to join team Worldwide Cancer Research and make a donation today just text WORLDWIDE to 70004 to donate £10. Thank you.

Image kindly provided by Dr Kasper Rouchop.

Studying the roles of Fra proteins in lung cancer

Transcription is continually happening within our cells to extract information from our DNA to make sure that our cells work properly. This is controlled through proteins that are called transcription factors. Two very similar transcription factors, Fra-1 and Fra-2, can be found in a large number of cancers. When cancer cells are studied in the lab, Fra proteins can cause the cell to change into a different type of cell; this change is sometimes associated with cancer development.

When extra high levels of Fra proteins are found in lung cells grown in the lab, these cells grow and move in a way that is similar to cancer cells. However, the Fra proteins alone cannot cause lung tumours in mice, which suggests that there must be other factors involved as well. Dr Wagner's previous results have shown that 3 proteins, including Fra-2, were present at high levels in samples taken from lung cancer patients as well as mice that have the disease.

Dr Wagner and his team will be using their Worldwide Cancer Research grant to make genetically modified mice, in which they can eliminate or produce more of the Fra-2 protein at different times during lung tumour development. This will help them to understand the roles that the Fra-2 proteins play in lung cancer. They will also try to look at some of the molecules that are controlled by Fra-2 during tumour growth or when it spreads to other parts of the body, a process called metastasis. They expect that this study will give a better understanding of lung cancer development and may lead to new treatments that are specific for lung cancer and metastasis.

Studying drug resistance in lung cancer

Lung cancer is the commonest cancer killer in the world, with non-small cell lung cancer accounting for more than 80% of all cases. The disease has usually reached an advanced stage by the time it is diagnosed, and less than half of people who receive chemotherapy benefit from the treatment. It is therefore important that new treatments are developed. Genetic studies have found changes in different types of lung cancer, which makes it possible to group patients according to the type of disease they have. It also means that new treatments can be designed specifically for these different types of lung cancer.

About 10% of patients with non-small cell lung cancer have a mutation in the gene that controls a protein called EGFR. Some drugs exist that work on this mutation, and these drugs are initially very effective in about 90% of these patients. Unfortunately the cancer quickly becomes resistant to the treatment, and it is therefore important to overcome this resistance to ensure that more people survive this disease.

In previous work, Professor Seckl and his team found that cancer cells that were resistant to one of these drugs had very low amounts of a protein called glutathione inside their cells, and when glutathione levels were raised in these cells, they were less resistant to the drug. Professor Seckl wants to study molecules that control glutathione levels in the cancer cells and determine how they relate to resistance to drugs that target EGFR mutations. These results will be used to test whether new drugs that raise glutathione levels can be used to stop drug resistance in pre-clinical models. The results should help us to overcome drug resistance in lung cancer patients with the EGFR mutations, and prolong their survival.

Finding ways to block the Ras pathway in lung cancer

Non-small cell lung cancer accounts for more than 80% of all lung cancers, and is the most common cancer type in the world, killing more than 1.4 million people each year. Nearly half of patients have mutations in a group of molecules called the Ras pathway. So far attempts at developing treatments that work on the Ras pathway have been unsuccessful; there is therefore a need to develop new treatments for lung cancer patients where the Ras pathway plays a role in the disease.

Professor Downward and his team have found that cancer cells that develop with Ras mutations are dependent on a protein called GATA2. They developed a mouse model which showed that when GATA2 was removed, lung tumours regressed (became smaller) dramatically. They will now explore the relationship between GATA2 and lung cancer, how the absence of GATA2 affects the tumour as well as the area surrounding the tumour, and whether tumours can evolve to survive without it. They hope that this work will allow them to understand the role of GATA2, and to find out what effect the treatments that might block GATA2 from working could have on lung cancers caused by mutations in the Ras pathway.

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 Worldwide Cancer Research project looks 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.