Prostate cancer

ON THE HUNT FOR NEW AND SPECIFIC DRUGS TO FIGHT CANCER

Maréne Landström and her colleagues discovered a cellular signalling pathway that is only active in cancer cells. Now work is underway to produce a drug that specifically targets aggressive tumour-transformed cells, while healthy cells are left alone.

Prostate cancer is the most common type of cancer in men and is diagnosed in 10,000 Swedish men every year. Maréne Landström, Professor of Pathology at Umeå University and a clinical pathologist at Norrland University Hospital in Umeå, began her professional career as a nurse – where she met men who were very sick with prostate cancer.

“It made a strong impression on me. Because I wanted to understand more about the disease so that I could contribute, I trained to become a doctor and researcher – which is something I’ve never regretted,” she says.

Prostate cancer can be treated if discovered early, while the tumour remains within the capsule of the prostate gland. But if the cancer has spread, it is considerably more serious.

“Some of those whose cancer has spread only survive for six months or so once the spread has been found. It’s a cruel disease when it occurs in that form,” she says.

In her research she wanted to understand why prostate cancer spreads, and just over 10 years ago she and her colleagues made a crucial discovery.

“We found a signalling pathway that was only active in aggressive cancer cells and not in normal cells,” she says. They found that a receptor on the cell surface was itself part of the signalling pathway, in that it can send part of itself into the cell nucleus. This sets off a series of reactions that enables the cancer cell to invade surrounding tissue. The molecule that binds to the receptor concerned is a growth factor called transforming growth factor beta, or TGF-beta for short. Researchers have shown previously that TGF-beta is formed to a greater extent in tumour cells. Men with prostate cancer who have high concentrations of TGF-beta in their blood also had a poorer prognosis than those with lower concentrations.

“If we could block this specific signalling pathway in cancer cells, it could be a route to a new drug that prevents tumour cells from spreading,” says Maréne Landström.

The findings were published in the journal Nature Communications in 2011.

A couple of years later her research group began collaborating with the national SciLifeLab Drug Discovery Development platform in Stockholm and Uppsala. The aim was to produce antibodies that could block the signalling.

“They’ve been a fantastic support in the development work, and when they took on our project in 2014 I felt that this really could be turned into a new drug,” she says.

With the project Targeting the oncogenic TGFbeta signalling pathway – a novel cancer treatment strategy and drug development programme the work is now moving into a new phase.

From an initial 19 different candidate antibodies, by means of a series of tests the researchers have now narrowed this down to just one. To be able to

“If we could block this specific signalling pathway in cancer cells, it could be a route to a new drug that prevents tumour cells from spreading.”

Maréne Landströms is driven by wanting to be able to do something for patients who are severely ill. “Now I have good reason to believe that our work will be useful!”

be trialled as a drug it needs to be rebuilt and tested on human cancer cells as well as in various animal models before it can be given to patients.

In this work, the funding from the Erling-Persson Foundation is very welcome.

“We are enormously glad to have it, since it means we can continue to employ skilled individuals in the research group. The support means that we can take the next step and develop new, improved antibodies that do not need to be given in such high concentrations,” she says.

If the work progresses as planned, the first clinical trials could take place within three to four years, according to Maréne Landström. The researchers have patented the discovery and the development work is taking place in partnership with a biotech company. The hope is that the drug will not have many side effects, since it precisely targets cancer cells. Another advantage of the new approach is that it can be used not just for prostate cancer.

In 2016 Maréne Landström’s research group published in Oncotarget that they had found that the same signalling pathway is also active in a type of kidney cancer called clear cell renal cell carcinoma, for which there is currently no effective treatment.

“Within the framework of the project we will attempt to develop antibodies to this type of cancer too,” says Maréne Landström, continuing:

“I’ve always been driven by wanting to be able to do something for severely ill patients, and to succeed in that you have to jump in the deep end. Now I have good reason to believe that our work will be useful!”

10,000

Prostate cancer is the most common type of cancer in Swedish men, with around 10,000 people estimated to be given this diagnosis every year. Every year around 2,400 men die from prostate cancer.

90%

If the disease has not spread it can generally be cured through a combination of surgery, radiotherapy and hormone therapy. Long-term survival rates are then good – generally over 90 percent.

3–5

Once the cancer has spread, the diagnosis is considerably poorer. With cancer that has spread into the bones, patients live for three to five years on average.

ABOUT THE PROJECT Project Manager: Maréne Landström, Professor of Pathology at the Department of Medical Biosciences at Umeå University and clinical pathologist at Norrland University Hospital in Umeå.

Title: ‘Targeting the oncogenic TGF-beta signalling pathway – a novel cancer treatment strategy and drug development programme’.

What it involves: The researchers have been able to identify a signalling pathway unique to cancer cells that spread. In the project, the researchers will evaluate an antibody that is thought to be able to block the signalling pathway – a way to specifically target cancer cells while sparing heathy cells.

Funding: The Erling-Persson Foundation is supporting the project with SEK 2 million per year for three years, totalling SEK 6 million.

Read more: Nature Communications 2011: https://pubmed.ncbi.nlm.nih.gov/21629263/ Oncotarget 2016: https://pubmed.ncbi.nlm.nih.gov/27166254/