Aspirin could hold the key to supercharged cancer immunotherapy

Giving cancer patients aspirin at the same time as immunotherapy could dramatically boost the effectiveness of the treatment, according to new research published in the journal Cell.

Francis Crick Institute researchers, funded by Cancer Research UK, have shown that skin, breast and bowel cancer cells often produce large amounts of prostaglandin E2 (PGE2). This molecule dampens down the immune system’s normal response to attack faulty cells, which helps cancer to hide. It is a trick that allows the tumour to thrive and may explain why some immunotherapy treatments have not been as effective as hoped.

Aspirin is part of a group of molecules called COX inhibitors, which stop the production of PGE2 and help reawaken the immune system. Combining immunotherapy with aspirin or other COX inhibitors substantially slowed bowel and melanoma skin cancer growth in mice, compared to immunotherapy alone.

Study author Professor Caetano Reis e Sousa, senior group leader at the Francis Crick Institute, said: “We’ve added to the growing evidence that some cancers produce PGE2 as a way of escaping the immune system. If you can take away cancer cells’ ability to make PGE2 you effectively lift this protective barrier and unleash the full power of the immune system.”

Giving patients COX inhibitors like aspirin at the same time as immunotherapy could potentially make a huge difference to the benefit they get from treatment. It’s still early work but this could help make cancer immunotherapy even more effective, delivering life-changing results for patients.”

Professor Peter Johnson, Cancer Research UK’s chief clinician, said: “PGE2 acts on many different cells in our body, and this study suggests that one of these actions is to tell our immune system to ignore cancer cells. Once you stop the cancer cells from producing it, the immune system switches back to ‘kill mode’ and attacks the tumour.”

This research was carried out in mice so there is still some way to go before we will see patients being given COX inhibitors as part of their treatment. But it’s an exciting finding that could offer a simple way to dramatically improve the response to treatment in a range of cancers.”

Zelenay et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell, 2015; DOI: 10.1016/j.cell.2015.08.015 [Open Access]

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Key factor discovered in the formation of metastases in melanoma

Patients who visit the doctor because of malignant skin cancer often go too late – the aggressive cancer has already formed numerous metastases in their bodies.

This rapid, malignant metastatic formation of melanoma, was previously put down to the high mutation rate that is characteristic of melanoma, i.e. genetic changes that stimulate the growth of cancer cells. Various cancer drugs therefore target the signaling pathways activated in the process, some of which have recorded astonishingly positive results in the clinic and are able to prolong the lives of seriously sick patients.

Unfortunately, however, in most cases a kind of resistance develops: Eventually, the cancer cells no longer respond to the drug and the tumor spreads again. Evidently, the cancer cells have found new ways to grow. A team of researchers headed by Professor Lukas Sommer from the University of Zurich’s Institute of Anatomy has now found a possible explanation for this dynamic behavior in cancer cells: The scientists believe that, depending on the prevalent conditions, cancer cells are able to “read” different genes and use them to their own end.

A highly active epigenetic factor in cancer cells

The readability of genes is controlled by epigenetic factors, namely factors which do not influence the gene sequence directly, but rather cause certain genes and chromosomal segments to be packed in different densities – and thus make them accessible for reading. Consequently, the Zurich-based researchers studied whether epigenetic factors are especially active in melanoma cells – and stumbled across EZH2, an epigenetic control protein found very frequently in malignant melanoma cells compared to normal cells.

Joining forces with dermatologists and oncologists from the University Hospital in Zurich and backed by the University Research Priority Program “Translational Cancer Research”, Sommer’s team was able to demonstrate that, in melanoma cells, the epigenetic factor EZH2 controls genes that govern tumor growth as well as genes that are important for the formation of metastases. In their study, the researcher exploited this central position of EZH2 to combat the cancer: They used a pharmacological inhibitor to suppress the activity of EZH2. As a result, the researchers were able to prevent the growth and malignant spread of the cancer in the animal model and human melanoma cells.

To our astonishment, we were able to use the approach to influence the progression of the disease, even if tumors had already developed,” explains Sommer. Epigenetic factors like EZH2 therefore appear to be highly promising targets for future cancer treatments, especially combined with other drugs that are already available.

Zingg et al. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nature Communications, 2015. Doi: 10.1038/ncomms7051 [Abstract]

Researchers map paths to cancer drug resistance

A team of researchers have identified key events that prompt certain cancer cells to develop resistance to otherwise lethal therapies.By mapping the specific steps that cells of melanoma, breast cancer and a blood cancer called myelofibrosis use to become resistant to drugs, the researchers now have much better targets for blocking those pathways and keeping current therapies effective. The findings are published in two papers in the journal Science Signaling.

Clinical resistance to anticancer therapies is a major problem,” said lead author Kris Wood, Ph.D., assistant professor of Pharmacology and Cancer Biology at Duke. “The most logical way to solve the problem is to understand why tumor cells become resistant to drugs, and develop strategies to thwart these processes.”

In our studies, we developed a screening technology that allows us to quickly identify the routes cells can use to become resistant, and using that information, we were able to show that these mechanisms seen in the laboratory are actually also occurring in patients’ tumors,” Wood said.

Wood and colleagues conducted a broad survey of the known cell-signaling pathways that, when activated, have the potential to trigger resistance to drugs. Using this screening technology, they were able to corroborate the results of earlier drug-resistance studies, while also finding new pathways that had not previously been described.The new mechanisms they identified in the laboratory were also clinically relevant, appearing in tumor cells from patients who had grown resistant to therapies.

Interestingly, the mechanisms are quite similar among all three of the cancer types,” Wood said. “In breast cancer and melanoma, our findings suggest the same Notch-1 pathway as a potential driver of resistance to a wide array of targeted therapies — a role that has not been widely acknowledged previously.”

Wood said that in myelofibrosis, the researchers tracked a pair of separate signaling pathways downstream of an important signaling molecule called RAS. When activated, these pathways promote resistance to current standard-of-care targeted drugs by suppressing cell death. In the second Science Signaling paper, the researchers suggest that targeting the pathways downstream of RAS may sustain the potency of current therapies.

Together, these findings improve our ability to stratify patients into groups more and less likely to respond to therapy and design drug combinations that work together to block or delay resistance,” Wood said.

Martz et al. Systematic identification of signaling pathways with potential to confer anticancer drug resistance.Sci Signal. 2014;7(357):ra121. doi: 10.1126/scisignal.aaa1877 [Abstract]

Winter et al. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal. 2014;7(357):ra122. doi: 10.1126/scisignal.2005301 [Abstract]