Interview: Ariel Ruiz i Altaba on silencing cancer stem cells
"The silencing of the wolves" could be the title of an uplifting film based on the work of a team of biologists in Geneva. Their most recent discovery, published 28 March in Proceedings of the National Academy of Sciences of the USA, could shake the foundations of current approaches to cancer treatment.
"The survival rates for many cancers haven't really changed. Even though early detection has vastly improved and terminal patients live a little bit longet with current treatments, there is no cure for many cancer types, including glioblastoma – a deadly form of brain cancer, and metastatic tumors such as those of the prostate, lung or skin. We have nothing that cures cancer once metastis sets in," Ariel Ruiz i Altaba, professor of stem cells at the University of Geneva's medical school, who led the team of eight researchers. "We have only treatments that reduce the tumour burden with highly toxic and non-specific agents."
Ariel Ruiz i Altaba and his team in the University of Geneva stem cell laboratoryshow in the new publication that they have managed to silence human melanoma cells in mice. They were working with funds from the Jeantet Foundation, the Leenaards Foundation, the NIH, the Swiss Cancer League and other sources, together with collaborators at the HUG and the ISREC, who provided important materials for the study. Melanoma is an aggressive form of skin cancer and it is on the rise. Using a drug called cyclopamine that occurs naturally in the corn lily plant, the team has been able to prevent cancerous cells – including cancer stem cells – from proliferating, surviving and self-replicating. As a result, the cancer cannot grow or spread.
"Cancer kills you because you have too many cancer cells," says Ruiz i Altaba. "We think that cancer is a problem of patterning, of regulating cell number and form. With every single tumour treated in the last 10 years we have now shown that cyclopamine works."
Ruiz i Altaba's enthusiasm is quickly offset by the exacting scientist that he is: the researcher is quick to point out this does not mean we have a cure for cancer. He is a scientist, not a medical doctor, he notes, and the experiments with human cells in mice must now be followed by trials in humans, a lengthy but, he underscores, an urgent process.
His excitement is understandable, though. Significantly, the team has now shown that cyclopamine has been equally effective in stopping cell communication in several types of cancer cells – in prostrate and brain, for example. The Geneva researchers also attracted attention earlier in 2007 when they showed that cyclopamine is effective in killing glioma stem cells in mice Current Biology, 23 January issue. Glioma is a form of brain cancer that does not respond well to chemotherapy or radiation and its most aggressive form (also called glioblastoma multiforme) generally kills within a year. Given the difficulty of effectively treating it with current drugs and therapies, finding a way to kill it is an important research path. The side effects in mice were minimal, limited to treatable diarrhea in small mice.
The cyclopamine chemical interrupts a communication systems called Sonic Hedgehog (SHH)-GLI signaling that regulates the proliferation and survival of melanomas and other tumours. It is also used by normal melanocytes (cells responsible for skin pigmentation) and other cells in adults. In mice the team was able to interfere locally or systemically with this system and as a result to stop the growth, recurrence and metastasis of the cancer cells.
"The therapy we could develop for any one of these tumours could apply to the others," he notes. The Geneva group has been studying The SHH-GLI pathway in development and disease for 12 years "and the results have been getting better and better. I cannot know for sure that cyclopamine is going to cure these cancers but I think it's worth trying and the arguments against it are not strong," says Ruiz i Altaba. Major pharmaceutical companies are not at the moment, rushing to support the next stage of the research with cyclopamine, however, largely because "the IP is not clear," he believes. Intellectual property rights, or patents, provide the future income for pharma companies to repay their heavy research investments.
In this case cyclopamine was discovered over 30 years ago and the corn lily plant is considered a common, poisonous wildflower in the American Southwest. One-eyed lambs were born in Idaho and the US government spent the next 11 years trying to find out why. Richard Keeler Later it was found that cyclopamine specifically inhibits the SHH-GLI pathway, which is required in the embryo for normal brain and face development.
Ruiz i Altaba spends a large amount of time seeking funding for his group's research and looking for oncologists – cancer specialists – who can carry the research through the next stage, testing it on humans. The stem cell laboratory is part of the University of Geneva, but a very large part of its work is privately funded. Its basic mission is to study how and cell interact to build tissues and organs. Scientist still have many questions to answer, at the most basic level, he points out. "We are looking at the formation and maintenance of an organ. Cells get damaged and they must be repaired – we don’t yet understand how. Animals have organs of different shapes – we don’t know why. How are cells counted?"
The last question leads directly to cancer research, since the human body appears to lose its ability to count and control the number of cancer cells once they appear.
The laboratory works closely with doctors at the University Hospitals in Geneva. "We're lucky to have a very good hospital next door, world-class, and a very good relationship with them so that we can go from basic science to pre-clinical research." Ruiz i Altaba is happy about public support for stem cell research in Switzerland – "I don’t think there’s been a public referendum on this anywhere else in the world" – but he is concerned that the country is not investing enough in what he insists is the medicine of the future. Singapore, Australia, China and Canada are all investing massive amounts, he says, to create cutting edge stem cell science and medicine.
And while Ruiz i Altaba and his team are anxious to see stem cell research move ahead, he cautions that some of the early enthusiasm could leave people disappointed. "Embryonic stem cell research is exciting, scientifically and even artistically," says the biologist who is also a gifted artist whose works have appeared in several notable galleries and museums. "But let’s be realistic." The best way to find out what stem cells can do is to do the research, he adds - so let’s get on with it.