The doctoral candidate from Germany conducted his research under the supervision of Wilbert Zwart, professor at the TU/e Department of Biomedical Engineering and also the leader of the research group. Hormone-associated cancer of the Netherlands Cancer Institute (NKI). “In this group we focus on hormone-dependent types of cancer, mainly breast and prostate cancer, but in recent years we have also seen other types in which hormones play a role, such as lung cancer,” says Linder. He himself was involved in research into prostate cancer within this research group. This hormone-sensitive cancer is very common; In the Netherlands alone, about 12,000 men are diagnosed with this every year, and more than 3,000 die from it. “So we can still do a lot to improve the therapy for this group of patients.”
Resistance
“If the disease is only in the organ, we can remove the prostate surgically – with a so-called prostatectomy – or we can treat with radiotherapy,” Linder continues. “About 70 percent of patients are cured that way, which is fantastic. But the disease comes back in the remaining thirty percent.” These patients are often treated with hormonal therapy. The goal of this treatment is to slow down the production of male hormones, or androgens, that drive the growth of prostate cancer.
“In prostate cells, hormones activate a certain pathway that leads to the growth of cancer cells. So if you block the biosynthesis (building of biomolecules, ed.) of these hormones or switch off the molecule that needs the hormones to activate the pathway, you can inhibit the process,” explains Linder. In the beginning, these therapies are very effective, but the big problem is that the tumors become resistant to them quite quickly.
Smart cancer cells
“Cancer cells are very smart in a way,” he continues. “If you block the path they normally use, after a while they find a detour to eventually reach the same goal. Or they activate something else that can take over and drive the disease.” Unfortunately, sooner or later it is inevitable that the tumors will become resistant. And it is precisely this resistance that is the greatest overall challenge in the treatment of prostate cancer and other hormone-driven diseases.
The important question is: how do these tumor cells adapt to hormonal therapies? We need more fundamental understanding of these processes to prevent cancer cells from becoming resistant. “We have to outsmart them,” said Linder. During his research at the NKI, affiliated with the Antoni van Leeuwenhoek clinic, he focused on patients with primary, localized prostate cancer to gain more insight into the behavior of the cancer cells. “These patients received hormone therapy three months before surgery, and biopsies were taken before and after this treatment. In this way I was able to investigate what hormone therapy does to the cancer cells.”
The bigger picture
Linder used the so-called multiomics approach, in which a large amount of biochemical data is analyzed to obtain new and deeper insights. The second part of the term multiomics refers to various branches of molecular biology that end in “-omics” in English, such as genomics (the study of DNA), transcriptomics (the study of RNA) and proteomics (the study of proteins). “In multiomics we look at all molecules of the same species, let’s say DNA, in the same sample. So you don’t just look at one DNA sequence, but at all of them. You then do the same for the RNA – a kind of recipe for how the protein is made later – and for the proteins themselves.”
“With this broad multiomics analysis, you have a lot of small parts that you have to put together to form the bigger picture. It’s like a jigsaw puzzle with lots of little pieces that add up to something much bigger.” Linder analyzed all of these factors in the samples taken before and after therapy to see what was different and understand what is causing the resistance. The ultimate goal would be to find ways to block this mechanism and prevent the resistance, or even resensitize cells that have become resistant to the therapy.
Surprising discovery
After extensive analysis, he discovered that a protein that normally plays a role in a very general physiological process suddenly took on a completely new role in driving this resistance. “This protein normally plays a role in the circadian rhythm, the day and night rhythm that is present in every cell of our body and makes us more awake in the morning and sleepier at night,” he explains. “The interesting thing is that the circadian rhythm in cancer cells is often lost. But suddenly this protein took on a new role in prostate cancer cells. That was very surprising to us, because it has never been described in prostate cancer, and certainly not in connection with resistance to the hormonal therapy.”
Linder decided to dive in and then conducted more analysis to confirm this startling discovery. Not on patient samples anymore, but in vitro, so with a disease model that he grew up in the lab to see how the cells respond to the therapy. “That way we can model therapies, but also try to better understand the biology of these tumors,” he explains. These analyzes showed that resistant cells become sensitive again to the therapy when you prevent the production of this specific circadian rhythm protein, confirming the role of this protein in the resistance mechanism. “If you block the main route, the cancer cells find a detour to reach their target. But if we also block this alternative route, the cancer cells can no longer do anything and eventually they die.”
Out of the box
“It was very cool to see that these initially very broad analyzes with a lot of patient samples and a lot of data eventually led to one driver that could be validated in these models,” says Linder. Ultimately, he believes, these findings could lead to a new therapeutic approach for patients with prostate cancer. “Not today, but in the future,” he adds, as specific drugs must first be developed that target this circadian rhythm protein.
“I learned from this research project that you should never rule anything out in advance,” he continues. “If you had asked me beforehand what drives resistance in prostate cancer, I would never have put my money on the circadian rhythm, because is a normal physiological pathway. But now we know that cancer cells can even hijack proteins that normally play a role in a very normal process and use them to achieve their ultimate goal, which is to grow and survive. If we want to advance therapies and If we want to improve patients’ lives, we need to do more out of the box think.”
This article is written by Cursor.
2023-07-03 12:22:36
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