WIN 2016

Cancer organoids

Dr Robert Vries - Hubrecht Organoid Technology, Utrecht, The Netherlands

I’ll be talking an invention that we did in the lab of Hans Clevers a few years ago which allows us to grow stem cells and the differentiated cells of these stem cells of many different organs of people and also in case of, for instance, cancer of the diseased cells which basically means that we have what we call organoids, disease tissue in a dish that’s patient specific, and we can grow from virtually every patient.

What was the method?

Basically the method started off with stem cell biology, the identification of the stem cell and a process of identification of how this stem cell actually expands. Then with that we started building a biobank, we called it a living biobank, which basically is material that is either biopsies from cancer patients or resections. We take a very little bit of that, put it in our dish with the method of growing it and that basically expands these diseased or healthy cells of these different organs, intestines, kidney, lung etc., into a biobank, into an indefinite amount of material for science or drug development.

Could you tell me about LGR5 marker?

Basically the LGR5 marker was the starting point of the organoid. In the lab of Hans Clevers in the early 21st century they were looking for markers of stem cells. We knew about embryonal stem cells, we knew about haematopoietic stem cells but for adult stem cells for solid organs we had an idea that they were there and how they worked but we had no idea of which ones they were. So we were looking for a marker flag on these cells. LGR5 turned out to be a molecule of a specifically expressed on intestinal stem cells and later on we found that it was also true for liver and pancreas and various other organs. But basically it allowed us to identify this is a stem cell, an old stem cell, in the intestine and this is not.

What are the advantages of organoids in clinical practice?

What we found is that first of all, as we know from cancer research over the years, is that in cell lines when we grow them they undergo multiple changes in order to allow them to grow in the lab in a dish. So basically what we are growing is not necessarily representative of the cancer that we’re studying. Furthermore, it’s very difficult to establish the cell line so we have only a few thousand cell lines available to us on all the different diseases that we are studying. With the organoids we have on the one hand a system that allows us to expand unlimited cells of a cancer or other diseases but they are genetically stable as far as the disease goes, cancer in itself obviously being genetically unstable. But we basically preserved the identity it had when it came out of the body. Also very important, that doesn’t work one in a thousand or one in a hundred, it actually works for almost every patient. So on the one hand you have a stable growth in your dish, you have something that looks like the patient, and on the other hand you can actually do that for every patient that you want to look at. So the change is basically that before when you studied something in a dish it is a resemblance maybe of the patient whereas now we have actually the patient in the dish.

What were the challenges you faced?

So initially, of course, when we develop something new it is more expensive. In the case for organoids the reagents are more expensive than what we are used to for cell lines. On the other hand by now we have obviously gotten better at it, we grow the reagent better. That means that it’s actually very comparable to a normal cell line and especially when we compare to the more advanced models that we’re currently using, including xenograft models and animals etc. The organoids, which are in the end just cells in a dish, are actually not so expensive at all.

What have been your successes?

In the organoid successes at the moment most of them are actually in cystic fibrosis, the disease that we are most advanced where we have started treating the first patients based on an organoid result. So with the organoids we were able to identify in this disease that has over 2,000 different mutations, of course of most of them we have no idea how they’ll respond to drugs and there are a very, very limited number of patients to study. What we did there is we made organoids of these patients and we have a specific assay to show if these samples respond to drugs. With that we could identify some patients that were actually very good responders to certain new CF drugs and the interesting thing was that, because they were unique mutations of really like one, two or three different individuals in the world, those were patients that were otherwise not eligible for treatment because obviously there is no clinical trial for two patients. So with that we basically have started treating patients and indeed that showed very good response. With cancer we’ve just started our trials to do the same thing which we call a clinical validation trial basically to see what happens with our organoids when we treat them in our dish and what happens to the patient in parallel and to see if that indeed is predictive. At the moment we have started our inclusion, we have about 20-30 patients in it so we have to probably next year, I think about a year it will take for us to definitively show whether the organoids for cancer are also indeed predictive in a clinical outcome. On the other hand, though, in the preclinical side of things the organoids are obviously a new model and most of the models in breast cancer, for instance hormone sensitive tumours, in pancreas cancer where we had very few models, so the organoids have already added an enormous amount of new model systems for us to use to do drug development. That was our first implementation before we started thinking is it also valid in the clinic itself.