Two researchers try to predict which fundamental research paths are most likely to improve the life of cancer patients in the future
How fundamental oncology will shape future cancer treatment
“I very much doubt if we will ever find a new chemotherapeutic agent that works on a very large population or on different cancer types,” says Jeanine Roodhart, medical-oncologist at UMC Utrecht. “All the low hanging fruit has already been harvested. New medicines will have to target smaller subpopulations and work in a more precise manner.”
To make this work and find novel therapies, more and detailed knowledge on tumour biology is necessary. Fundamental oncology, the focus point of Oncode, will be key in this, but what are the most promising pathways scientists are looking into to improve cancer treatment? Roodhart, together with Henk Verheul, professor of Medical Oncology at the VU medicinal centre and member of the Oncode Clinical advisory board, give us a peak in what they work on and what they think or hope will make splash in the coming ten years.
Better understanding tumour – host interactions
Traditionally, during the 20th century, cancer treatment was determined by the location of the tumour. There were lung cancer medicines for lung cancer, and breast cancer medicines for breast cancer. This changed after the sequencing of the human genome early 2000s, when researchers discovered that tumours in different locations had similar mutations, making mutation specific drugs all the rage. Scientist expected that mutations were the key drivers of cancer development, and mutation specific treatment would make it possible to cure cancer or at least make it a chronic disease instead of a death sentence.
Tumours with similar mutations, but in different organs or in different persons, still might need dissimilar treatment...
But as always, biology turned out to be more complicated. “We now know that genetics and the host environment interact in a tumour,” Verheul says. “It means that tumours with similar mutations, but in different organs or in different persons, still might need dissimilar treatment, because of variations in for instance the growth of connective tissue or veins in and surrounding the tumour. This impacts the accessibility and treatability of the cancer.” Roodhart adds: “There are examples where therapies work on colon cancer originating from the left side of the bowel, but not on right sided tumours, and we have no idea why. If we better understand how tumour genetic and the host environment interact, we can adapt therapy accordingly.”
In 2013, the prestigious scientific journal Science hailed immunotherapy, where the body’s own immune cells are specifically amplified or supressed to combat cancer, as its breakthrough of the year. Since then several immunotherapies reached the market, especially for blood cancers. “But immunotherapy still doesn't work in 90 percent of the cases,” Verheul says. “This might either be because the tumour isn't immunogenic enough, which means immune cells can't detect it, or because immune cells are unable to reach the tumour, because it has shielded itself with connective tissue. With more research we might be able to tweak the immune cells in such a way that they do recognise or reach the tumour. Immunotherapy is a very powerful treatment option, and I hope its use can be broadened soon.”
Picking up metastasis in an early stage
Recent decades, science has made good progress on survival of patients with solid tumours, but once metastatic, treatment remains elusive. Roodhart hopes this will change with techniques that are able to pick up metastasising cells in the blood before they settle down and become tumours. “Technological breakthroughs have made it possible to zoom in on to single cell level. This means we can pick up and analyse single floating tumour cells and circulating tumour DNA in a blood sample, hopefully making it possible to very early start with treatment, thereby stopping metastasis in its track.”
The progress in single cell microscopy also makes it possible to monitor tumours during treatment, as to pick up resistance,” tells Verheul. “This makes it possible to quickly adjust therapy accordingly.”
Drug repositioning is a very efficient way of improving therapy.
Verheul expects a lot from drug repositioning, the broadened use of medicines which are already on the market. “Most medicines have been tested in large random controlled trials, which means they only pass if they work very broadly,” he says. “But we now know that for instance colon tumour comes in many variants. It might well be that we dismissed drugs which do work, but only in a subpopulation.”
Similarly, many experiments are on the way to test if drugs for one tumour might also work for others, maybe in different regimes or concentrations. “We recently found the particular kinase inhibitors can be applied broader to other cancer types, when you administer them in a higher concentration at once.” says Verheul. Roodhart adds: “If there is a hit, those medicines can hit the market very fast, because all the safety tests have already been performed. Drug repositioning is a very efficient way of improving therapy.”
Currently, patients undergoing treatment still have an approximately 40 percent chance a drug doesn't respond. This means the patient doesn't get any better but does experience the side effects. Of course, it also means a lot of money goes down the drain. “Ultimately, doctors would like to be able to make a personal profile of a tumour, to individually determine what the best treatment is,” Roodhart says. Together with colleagues she investigates and optimises the use of so-called organoids for the clinic. These are 3D-models of tissue, be it healthy or tumour, which can be used to determine the best treatment option and develop new combinations of treatment. “We can grow organoid tumours from a biopt, and then test the response to various drugs. We hope to prevent unnecessary treatments, side effects and costs, and eventually also improve the survival of patients.” Now it is not yet possible add veins or other host factors to the tumour, it solely consists of cancer cells. If this will be developed in the future, organoids can serve as an even better predictor of treatment success.