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Novel drugs targeting the cells circadian rhythm offer new hope for future treatment of brain cancer

A study in mice shows how a new experimental drug could be a highly targeted treatment for brain cancer. The research, co-funded by the charity Worldwide Cancer Research and published in the journal Nature, establishes a path forward for generating a novel class of drugs that could also be used for a wide range of other cancers.

The researchers show that the drugs effectively starve the cancer cells to death by attacking their ability to sustain the high metabolic demand they need for continuous growth and replication.

The drug molecules, which are able to cross the protective barrier around the brain, reduced the growth of brain tumours, called glioblastomas, and lengthened survival time of mice. Results at this stage are similar to what is expected with the current standard of care for glioblastoma but with no toxicity or side effects.

In laboratory tests, the drugs also demonstrated selective cancer killing ability against breast, colon, leukaemia, brain and melanoma cancer cells with no apparent effects on normal cells. This data suggests that these drugs are a novel pharmacological tool for targeting cancer cells with high selectivity and low toxicity, against possibly a wide spectrum of tumours.

The researchers, led by Dr Satchindananda Panda at the Salk Institute for Biological Studies in La Jolla, California, found that the drugs work by interfering with the circadian rhythm (the internal “clock”) of cancer cells. The drugs activate a molecular component of the cellular clock, called REV-ERBs, which causes the cells to die.

Dr Panda, an associate professor in the Salk Institute’s Regulatory Biology Laboratory and senior author of the new paper, said: “We’ve always thought about ways to stop cancer cells from dividing. But once they divide, they also have to grow before they can divide again, and to grow they need all these raw materials that are normally in short supply.”

“Targeting REV-ERBs seemed to work in all the types of cancer we tried. That makes sense because irrespective of where or how a cancer started, all cancer cells need more nutrients and more recycled materials to build new cells.”

The researchers found that cancer cell death was induced because activating REV-ERBs led to the cells being unable to cope with the high metabolic demand created by their constant drive to grow and divide. They also found that the drugs could kill pre-malignant cells – or cells which are not yet proliferating uncontrollably but act as the seed to kick-start tumour growth – suggesting that treatment could be effective at eradicating those hard-to-treat, dormant cancer cells.

Dr Helen Rippon, Chief Executive of Worldwide Cancer Research, said: “Cancer cells often seem to have a broken internal ‘clock’. Not only does this disrupt the cells’ daily rhythms, but can also turn on molecular circuits that drive tumour growth.”

“Understanding these underlying faults at the root of cancer is essential if we are to develop completely new treatments that are more effective and have fewer side effects.  We are delighted that this research is already leading towards new treatments for brain tumours and that early results suggest it could be a fruitful approach for other cancers too.”

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

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.