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GROUNDBREAKING RESEARCH ALLOWS SCIENTISTS TO VISUALISE WHERE AGGRESSIVE SKIN CANCER MELANOMA WILL SPREAD, OPENING DOORS FOR NEW TREATMENTS

Scientists in Spain, partly funded by Worldwide Cancer Research, have found a way to detect skin cancer spread (metastasis) before the process even happens. The researchers at the Spanish National Cancer Research Centre (CNIO) developed special bioluminescent mice, called ‘MetAlert’ mice, which ‘glow’ to show how the skin cancer cells prepare the surrounding areas prior to beginning to metastasise.

The team also identified a protein called MIDKINE which is involved in metastasis and discovered that switching this protein off could be a potential way to treat skin cancer. These game-changing findings were recently published in prestigious journal NATURE and you can watch a short animated video demonstrating the key findings here.

The importance of an early diagnosis

Early detection is essential when it comes to cancer. If a tumour is detected when it is small and still in one place, treatment has the best chance of success and patients have the greatest chance of survival. This is especially true for cuteanous melanoma, the most aggressive type of skin cancer. Even when it reaches a thickness of a little more than one millimetre, the tumour may begin to spread, sending cancer cells to other parts of the body to set up new tumours, in a process called metastasis. When this occurs, the prognosis for the patient is usually poor as it is much harder to find and kill all of the cancer cells. Whilst treatment options have improved for many other types of cancer, there are fewer available for melanoma and number of deaths remain very high.

Lead researcher Dr Marisol Soengas explains "Here we have been able to discover unknown mechanisms in the development of melanoma, and to identify new markers of metastasis that we have validated in samples from patients. These results open up new avenues for treatments."

MetAlert mice

One of the novelties of this paper is the development of the MetAlert mice that can reveal how melanoma acts throughout the body, even before the occurrence of new tumours (metastases). The team used genetic modifications to produce special mice that emit light (bioluminescence) when there is activation of the lymphatic vessels. "These bioluminescent mice are ideal for studying melanoma" says researcher Dr Sagrario Ortega, "because the generation of lymphatic vessels, known as lymphangiogenesis, is one of the initial steps in the spread of this cancer."

The MetAlert system can guide researchers when looking for genes and molecules involved in tumour progression at the very earliest stage. It also helps study cancer relapses after surgery, or monitor the response to anticancer drugs. To date, the techniques available to use in animals required probes or markers that had to be injected into the area around the tumour, or were based on the detection of tumour cells once they were already present in other organs, i.e. once metastasis had begun. As Dr David Olmeda, who performed most of the experiments says "one of the major complications in tracking melanomas has been precisely the lack of sensitivity of the standard techniques but with our MetAlert mice we think we have overcome this."

New mechanisms of cancer spread

Using MetAlert, researchers detected the mechanisms that melanomas activate early on to create their own pathways of spread. This spread is in part through the lymph vessels and lymphatic system and is at a much greater distance from the original tumour than they originally thought. The cells can also spread without many of the proteins that were previously considered essential to activate lymphangiogenesis in the tumour. "These results indicate a paradigm shift in the study of melanoma metastasis," says Dr Soengas.

The group next investigated proteins produced by aggressive and non-aggressive melanomas. “We found many proteins produced specifically by melanomas that act at a distance, but in this paper, we focused on one in particular, called MIDKINE, because it was new and could represent an alternative therapeutic target in the future," explains Dr Olmeda.

MIDKINE: A key to melanoma metastasis and a marker of aggressiveness

Again using the MetAlert mice, the group showed that MIDKINE plays an essential role in cancer spread, to the point that MIDKINE’s activation actually determines the tumour's ability to spread through the body.

Following the studies conducted on mice, the researchers showed how important MIDKINE would be in patients. They analysed the levels of MIDKINE in non-cancerous moles and in melanomas at different stages of development. This demonstrated that patients with high levels of MIDKINE in their lymph nodes have a worse prognosis and lower chance of survival. This finding could lead to the use of MIDKINE as a potential biomarker of aggressiveness.

The paper has further implications, because when MIDKINE is blocked, metastasis is also blocked, as the team discovered in animal models.

"In MIDKINE we have found a possible strategy that is worth considering for drug development", says Dr Soengas. "MIDKINE is not the only target, of course, but as melanoma is one of the cancers with the highest number of mutations described, finding a protein that can serve to block metastasis is an important step.

The researchers predict that the discovery of MIDKINE is only the beginning.

"These metastasis-visualisation techniques are opening up new avenues of research regarding new tumour mechanisms and other preclinical studies," say Dr Soengas, Dr Ortega, and Dr Olmeda, "and they are very useful because they can be adapted to various types of cancer, not only to melanoma.”

Dr Gwen Wathne, Research Impact Manager at Worldwide Cancer Research said: “This innovative research provides exactly the kind of answers that melanoma patients desperately need. With treatments few and far between for this aggressive cancer, discovering MIDKINE and its role in melanoma spread, means that researchers can begin to explore its use as a marker of melanoma aggressiveness, and how targeting MIDKINE could be used to prevent melanoma spreading before it even starts. And that’s incredible news. We need to be supporting more cutting edge, innovative research like this to give the best chance of survival to patients.

The work was supported by a grant from Worldwide Cancer Research, the Ministry of Economy, Industry and Competitiveness, the L’Oreal Paris USA–Melanoma Research Alliance, the Spanish Association Against Cancer, the Mutua Madrilena Foundation, the 'La Caixa' Foundation, Immutrain Marie Skłodowska-Curie ITN and projects of the US National Cancer Institute.

This text was adapted from a press release by the CNIO communications office in Spain.

Reference: Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine. David Olmeda, Daniela Cerezo-Wallis, Erica Riveiro- Falkenbach, Paula C. Pennacchi, Marta Contreras-Alcalde, Nuria Ibarz, Metehan Cifdaloz, Xavier Catena, Tonantzin G. Calvo, Estela Cañón, Direna Alonso, Javier Suarez, Lisa Osterloh, Chandrani Monda, Julie Di Martino, Osvaldo Graña, Francisca Mulero, Diego Megías, Marta Cañamero, David Lora, Inés Martinez-Corral, J. Javier Bravo Cordero, Javier Muñoz, Susana Puig, Pablo Ortiz-Romero, José L Rodriguez- Peralto, Sagrario Ortega, María S. Soengas (Nature 2017).

DOI:10.1038/nature22977

Skin cancer research project we kick-started gets the boost it needs

We are thrilled to see that a skin cancer project that we kick-started at the University of Sussex and run by Professor John Spencer has received further funding from The Engineering and Physical Sciences Research Council (EPSRC) to take the research to the next step.

The team has been awarded a £428K grant to research a protein called PHIP(2) which is present in high amounts in melanoma.

Melanoma is a devastating cancer of the skin, the occurrence of which is on the rise. It can be treated surgically but long term survival tends to be poor and clinical treatments often prove too aggressive or ineffective.

Professor Spencer’s Lab, along with Paul Brennan and Frank von Delft at the Structural Genomics Consortium at Oxford University, will work to target the PHIP(2) protein with drug like molecules to try to stop the cancer’s progression.

The new project will enable the scientists to study the role the protein plays in the development of melanoma and other aggressive cancers.

Professor Spencer said: “If we are to understand melanoma better, it is crucial we find out why this protein is present in high amounts of this type of skin cancer.

This new project work stems from earlier grant funding from Worldwide Cancer Research where we found a new use from molecules that we’d initially made to target another cancer protein called p53.

“It pays to recycle molecules as it takes a lot of effort to make them so finding another, unexpected application is rewarding.”

The project will also include working with Dr David De Semir, from the California Pacific Medical Center, a world expert in PHIP(2) biology and Bio-Techne/Tocris Biosciences and Selcia industrial partners, who will help exploit the findings in order to make them widely available to cancer researchers.

Rob Felix, Head of Product Management for Tocris at Bio-Techne, said: “After many years of successful collaboration, Tocris Bioscience are delighted to now have the opportunity to work with the Spencer group on a project to develop truly novel and innovative chemical probes for cancer research.”

This text is adapted from a press release from the University of Sussex, written by Lynsey Ford.

Investigating a potential new druggable target in cancer cells

Melanoma is the most aggressive type of skin cancer. When diagnosed at an advanced stage, it means a poorer outcome for patients and new treatments are urgently needed. Professor Cano is investigating the role of LOXL3 proteins in melanoma.

She explains “Members of the lysyl oxidase (LOX) family of proteins, including LOX and LOXL2 have previously been implicated in cancer progression and metastasis (spread) of several cancers. But little is known about the role of Lox members in melanoma.

Our initial studies indicate that over-expression (increased switching on) of LOX3 is specifically linked to melanoma cell lines and melanoma primary and metastatic tumours. Moreover, an association of LOXL3 with mutations in BRAF/NRAS (the main activating mutations found in melanoma patients) has been found in melanoma cell lines.

The main aim of this project is to establish the role of LOXL3 in the initiation and malignant progression of melanoma. We want to unravel the underlying molecular mechanisms of LOXL3 action and explore the potential of LOXL3 as a new druggable target. We hope our studies can stir an interest in developing LOXL3 inhibitors that might be potentially beneficial for patients when combined with established RAS/BRAF/ERK pathway inhibitors.”

She concluded “This project is really exciting to us because it means that we can test if in vitro data on LOXL3 involvement in melanoma obtained from basic research can be translated to the melanoma patients in the near future through the design of new drugs to target LOXL3.”

Studying inherited skin cancer risk in affected families

Dr MacGregor told us “Melanoma skin cancer is the most dangerous form of skin cancer. A person’s genes, and more importantly mutations in these genes, influence their risk of getting melanoma. An inherited risk is one that can be passed on from their parents and can arise either from a single serious mutation in a critical gene or from the accumulation of lots of mutations in multiple lower risk genes (termed polygenic risk). We will assess the level of polygenic risk in families that have multiple members all with melanoma skin cancer. In those families with a low polygenic risk we will use sequencing, specifically exome sequencing, to search for serious mutations in critical genes."

He continued “We are excited to be able to conduct this work because it will provide certainty to some high risk families. In some families, we expect to show that the contribution of common polygenic risk is low or no different to the normal population. This will enable us to focus efforts on identifying rare variants of substantial clinical relevance to specific family members who inherit a high risk mutation. In such scenarios, individual members will be at a different risk, depending on the specific mutations they inherit.

In other families the observed familial clustering may be completely explained by multiple genes of small effect, reinforcing for the affected families that all members are at high risk. Since such families are unlikely to also carry rare mutations, family members need not undergo additional genetic testing. Knowing whether someone is at a high risk of developing melanoma, means they can take precautions to lower their risk and get monitored so it is caught early if it does develop.”

Recycle, recycle, recycle!

Worldwide Cancer Research funded scientist Dr John Spencer has unearthed a new role for seemingly redundant chemicals made in his lab during his cancer research experiments.

Along with his collaborators, Dr Spencer, from the University of Sussex has found a new purpose for molecules that were originally made for his Worldwide Cancer Research project. A series of oxazole fragments (small drug-like molecules) did not work as well as hoped on the original protein they were meant to target (a faulty form of p53 called p53-Y220C) which we discussed in a previous blog post.

However, undeterred, the team are big believers in ‘recycling’ (inside and outside the lab) and giving molecules a new purpose.  When a hunch made them test the potential drugs on a new ‘bromodomain’ they were amazed at the results.

Dr Spencer explains “Bromodomains are a class of druggable proteins (meaning scientists can make drugs that act directly on these proteins to only kill certain types of cells, such a cancer cells).  They are big targets in cancer and inflammation, and play an important role in the regulation of gene expression (turning genes on and off).

The molecules we had made were able to block a protein called PHIP(2).  PHIP2 is a biomarker – that is something that indicates that cancer is present in the body- and a potential target to treat melanoma skin cancer that has spread.”

Although these results are exciting, Dr Spencer added “They are preliminary findings, and the biological activity of the molecules is still rather weak, so more work is needed.  It is great, however, to show that we can recycle molecules and put them to exciting and unexpected new uses.”

The work, led by the Structural Genomics Consortium and Diamond Light Source partners (Paul Brennan and Frank von Delft), was recently published in the flagship Royal Society of Chemistry journal Chemical Science.
1. Transient Protein States for the Design of Small-Molecule Stabilizers of Mutant p53. Joerger, A. C.*; Bauer, M. R.; Wilcken, R.; Baud, M. G.; Harbrecht, H.; Exner, T. E.; Boeckler, F. M.; Spencer, J.; Fersht, A. R. Structure, 2015, 23, 2246–2255.
2. A Poised Fragment Library Enables Rapid Synthetic Expansion Yielding the First Reported Inhibitors of PHIP(2), an Atypical Bromodomain. Cox, O. B., Krojer, T.; Collins, P.; Monteiro, O.; Talon, R.; Bradley, A.; Fedorov, O.; Amin, J.; Marsden, B. D.; Spencer, J.; Von Delft, F.*; Brennan, P. E.* Chem. Sci. 2016, 7, 2322-2330.

Image: Image shows an oxazole fragment sat inside in the PHIP(2) bromodomain as described above.

 

Investigating new mutations in melanoma

Melanoma is the most dangerous type of skin cancer that is often associated with exposure to the sun or sunbeds. It is one of the most common causes of cancer in people aged 15-44, although incidences of the disease increase steadily with age.

Professor Gabrielli will be using his Worldwide Cancer Research grant to study new genome mutations that have been associated with melanoma. The genome consists of all the information that is needed to build and maintain a living organism. Advances in technology has allowed for more and more entire genomes to be studied, and increasing numbers of mutations are being identified in the 50 cancer genomes that are currently being analysed worldwide. Many of the mutations are uncommon, and therefore researchers are unsure of whether they play a role in cancer formation. The project will involve analysis of 250 new mutations that are found in melanomas, to identify those that directly lead to disease occurrence.

Understanding how CD4+ T cells react to tumours

Cells in our immune system are trained to recognise bacteria and viruses to attack and kill them. In some instances, our immune system will recognise tumour cells. The cells that normally attack and kill foreign bodies or cancer cells are called T cells. There are several different types of T cells, and until now, cancer research has mostly been studying CD8+ T cells, known for their ability to recognise and kill tumours. In recent years, another type of cell, the CD4+ T cell, has been shown to play a part in the immune response to cancer. The CD4+ T cells were sometimes found to help and enhance the immune response to the tumour, but in some cases the cells were shown to suppress the immune response.

Dr Quezada and his team recently showed, in a mouse model of melanoma (a type of skin cancer), that in addition to their normal helper and suppressive roles in the immune response, CD4+ T cells are also able to produce a very strong killer response, which leads to impressive rejection of large, fully established tumours. Killer CD4+ T cells have been found in patients with different diseases that are related to inflammation, or swelling, but we know nearly nothing about the possible role of these cells in helping or stopping tumour development.

With their Worldwide Cancer Research grant they aim to study what systems control these cells, and the signals that are involved in making them form an immune response against tumours. They also want to study the presence of these cells in human tumours to better understand the systems that control their behaviour within tumours, and if there are systems that prevent these CD4+ T cells from attacking tumour cells. This project should give us a much better understanding of the role of these T cells in human tumours and whether there may be ways to control an immune response against some tumours.

Searching for new treatments for skin cancer

Dr Wellbrock is using her Worldwide Cancer Research grant to investigate new treatments for melanoma skin cancer, the most dangerous type of skin cancer. Melanoma is usually resistant to many of the cancer treatments. Last year a new drug was shown to be highly effective in killing these type of tumours but sadly many patients became resistant to the treatment very quickly, meaning the drug no longer worked but it is still unclear why or how. Dr Wellbrock has discovered a new way this drug resistance may have occurred and is now searching for drugs that could turn this resistance mechanism off. She will test the drugs in a zebrafish model of melanoma which will also allow her to test other treatments at the same time. In the future, new drugs, like those being researched by Dr Wellbrock, could be given alongside other treatments to help kill the melanoma cells and prevent drug resistance.

Understanding the causes of melanoma skin cancer

Genetic information is like our cellular blueprint - it determines how our cells function. Cancer can be caused by changes to either the structure or activity of key genes that regulate how cells operate, divide and die. One way that cells control the activity of genes is to add specific chemical groups or 'tags' on to the genes themselves or the proteins which act as scaffolding for the genes to ensure proper regulation. The addition of these tags can lead to an increase or decrease in gene activity. This often happens incorrectly in cancers and changes in gene activity may drive the cell to grow and divide in an uncontrolled manner, forming a tumour.
Assistant Professor Emily Bernstein is using her Worldwide Cancer Research grant to study the role of tagging in malignant melanoma, the most dangerous type of skin cancer.

Investigating the genetic causes of malignant melanoma skin cancer

There are two main types of skin cancer; the more common and less dangerous non-malignant melanoma and the less common but more dangerous malignant melanoma.
Professor Newton Bishop and her team have collected one of the largest malignant melanoma sample and data sets in the world. They have recruited over 1,900 patients and are following their progress for at least 8 years. Such large collections are needed to understand such a complex disease.

Advanced malignant melanomas have always been difficult to treat.  There has been recent progress for some types of malignant melanoma; drug therapies are producing encouraging results in tumours that have genetic alterations in the gene called BRAF. However, in most patients these drugs gradually lose their effectiveness and much remains to be understood as to why. Also, for other types of malignant melanoma tumour the main genetic causes remain unknown.  

One of the problems when studying malignant melanoma is that the tumours are very small, meaning little material to use for research. Professor Newton Bishop’s team have developed ways of producing large amounts of genetic information from tiny samples of the tumours stored by hospitals as part of clinical care. Using these samples, Professor Newton Bishop aims to investigate the genetic types of malignant melanoma as well as identifying genetic alterations that may indicate whether or not the cancer is likely to come back.  She will also be investigating whether any such genetic alterations could be turned off using drugs.