The ultimate way to target cancer is to nip the growth of malignant cells in the bud. To that end, the Schneider lab seeks to uncover what happens in the pre-stages of leukaemia - and to use that knowledge to try and prevent malignant blood cells from further developing and spreading.
The Rebekka Schneider Group
Rebekka Schneider MD, PhD is Associate Professor at Erasmus MC and Oncode Investigator
Nipping leukaemia in the bud
Although cancer remains a huge problem worldwide, scientific progress has improved the prospects for many forms of cancer. Unfortunately, this does not hold true for leukaemia and many other types of blood cancer. This cancer type originates in the bone marrow, when blood stem cells of the bone marrow either cannot mature into healthy ones or malignant ones are slowly outnumbering them.
Full-blown leukaemia’s are hard to treat. “Leukemic cells change and hide in the bone marrow, which is basically their home”, Schneider says. “Often, they can completely escape the treatment, whether this comprises chemotherapy or bone marrow transplant.”
Scientists typically study leukaemia when it’s already in a highly advanced stage. The Schneider Group decided to try a different route: examine the disease from the bottom-up.
Schneider, who is originally from Germany and trained in the U.S., explains the background of their research: “We seek to untangle what happens in the pre-leukaemia stage when blood cells already fail to develop in a normal way or are starting to turn malignant - but full-blown blood cancer hasn’t developed yet.”
The group’s research hasn’t been without results. Since its start 2.5 years ago, the team has made several discoveries that offer clues as to how leukaemia could be stopped in its tracks.
Reversal in mice
Nipping bone marrow fibrosis in the bud by eradicating Gli1+ cells is one such possible route. In bone marrow fibrosis, abnormal blood cells and fibers build up in the bone marrow to cause endless and unnecessary scar tissue, thereby slowly depleting the human body of all healthy blood cells - to the point of bodily collapse.
“Think of it as wound healing turned bad,” Schneider says.
Building upon earlier research findings that Gli1+ cells always grow massively around blood vessels in organs affected by fibrosis, Schneider suspected that this might be the case for fibrosis in the bone marrow too – et voila.
“There they are, these are Gli1+ cells,” points Schneider at a couple of cells that pop up on a screen connected to a microscope. Highlighted in bright pink and clustering together, they can be clearly distinguished from the other cells in the tissue.
Just how important Gli1+ cells are in bringing about the disease – and what the effects of blocking these could be – show enlarged images from a microscope that hang in Schneider’s office. The image to the left shows advanced scar tissue in the bone marrow of a mouse suffering from bone marrow fibrosis. The picture on the right displays the same part of the bone marrow, but is taken three weeks later, following a depletion of Gli1+ cells through a medicine. Nearly all the scar tissue is gone and new blood cells can be seen.
But it’s not just by trying to untangle bone marrow fibrosis that the Schneider group is trying to tackle the onset of leukaemia. They also do so by pro-actively studying myelodysplastic syndromes, a group of malignant blood disorders in which the bone marrow fails to produce healthy blood cells.
Leukemic cells change and hide in the bone marrow, which is basically their home. Often, they can completely escape treatment.
The joint focus on primary myelofibrosis and myelodysplastic syndromes, the creation of excessive scar tissue and malignant blood disorders in which the bone marrow fails to produce healthy blood cells, soon led to the team’s next discovery: it may be possible to target pre-leukemic cells based on their gene expression. This is the process by which the heritable information in a gene is translated into a protein or RNA, which in turn determines the function of a cell.
Post-doc Sergio Martinez-Hoyer, one of the team’s experts on myelodysplastic syndromes, explains in more depth how that works. He joined the group 18 months ago, thereby exchanging Vancouver for Rotterdam.
Leukaemia happens when the DNA of immature blood cells, mainly white cells, becomes damaged in some way. This causes these blood cells to grow and divide continuously, so that there are too many. This is also visible in myelodysplastic syndromes. “These are driven by a bunch of genetically distinct malignant blood cells, that grow at the expense of healthy cells,” Martinez explains. “These tumorous cells only make one copy of a gene that helps them to survive, called csnk1a1, which offers them access to useful proteins. Commonly, cells make two copies of genes that encode proteins.”
But while these tumorous cells may well derive their strength from this feature, it also comprises their Achilles Heel. “Low concentrations of a drug that inhibits Csnk1a1 cause the death of the tumorous cells, but keep the gene expression high enough for normal cells to survive.”
Like the rest of the team, Martinez-Hoyer is well aware that this is a huge challenge. “So far, medicines against myelodysplastic syndromes have proven to not be that effective. There is still a lot of puzzling to do to ensure that troublesome cells can’t find a stealthy way out and that a potential medicine won’t target other cells as well.”
Schneider couldn’t agree more. “It’s one of the reasons why I was so happy with the funding from Oncode Institute and other sponsors. When I started at the Erasmus Medical Center 2.5 years ago, it was just lab technician Inge Snoeren and myself. Now my team counts four post-docs, three PhD students and two lab technicians. Having more capacity to undertake the research is great.”
Interestingly enough, when it comes to the group’s actual research output, it’s not just the seven PhDs and post-docs who have contributed. Lab manager Inge Snoeren recently published an article in Leukaemia together with PhD student Flavia Ribezzo. Their findings show how multiple genes that play a role in myelodysplastic syndromes together induce the disease. They cause an overactivation of the immune system, which then leads to inflammation in the bone marrow. “During the early stages of the project when it was still just Rebekka and me, I wasn’t just facilitating the research, but also started my own projects,” Snoeren explains.
Snoeren and Ribezzo’s focus on inflammation isn’t coincidental. Untangling the impact of inflammation on leukaemia is another important research priority for the group.
“Inflammation creates an environment in which the malignant cells in myelodysplastic syndromes and bone marrow fibrosis can grow or even thrive,” says Schneider. “Pre-leukemic cells seem to be more resistant to stress caused by the inflammation, which gives them an edge over normal blood cells.”
Although it’s still early days, the Schneider Group hopes to turn their acquired knowledge into a viable medicine that could nip leukaemia caused by fibrosis or myelodysplastic syndromes in the bud. Such a drug would most likely combine the three remedies the team has been focusing on. “So, it would inhibit Gli1+ cells, either directly or by targeting their home in the bone marrow, block the csnk1a1 gene and try and stop excessive inflammation,” Schneider says.
But when could such a medicine be ready? Schneider hesitates. “A decade is a very short time in science. Also, because clinical trials may introduce new bottlenecks and issues. But we are all rooting it will be in ten years. The clock is ticking, after all, given the current lack of a feasible remedy for the early stages of bone marrow fibrosis and myelodysplastic syndromes – and thereby also for the blood cancers into which they can develop.”