Killing cancer

Living tissue samples could reveal which drugs kill cancer.

The Helsinki University Surgical Hospital performs surgeries on breast cancer patients from all over southern Finland. The surgery is deemed a success if all of the tumour can be removed. However, that only marks the beginning of the journey for the cancer itself.

First, diagnostic samples of the tumour are extracted for the pathologist. Then, cancer researcher Juha Klefström’s (@JuhaKlefstrom) group gets whatever is left. The researchers will take any trace of breast cancer, even a piece the size of a fingernail is enough.

The first challenge is to keep the cancer alive.

 “Because dead means dead. We can’t kill something that’s already dead,” Klefström explains.

And killing cancer is the primary target of Klefström’s group. The researchers work towards their goal by treating the samples with various substances.

They receive viable samples every few weeks. The researchers no longer have to rush from the hospital to the laboratory by cab, as they know that the cancer can easily survive the half-hour tram ride from the Surgical Hospital to Meilahti Campus.

Once they have arrived at Biomedicum, the tumour is ground up and placed in a body-temperature cabinet, on a specially formulated gel to generate conditions that mimic those of the patient’s original tissue as closely as possible. In this state, the cancer can survive for a week or two. After that it begins to transform, and is no longer of use to the researchers.

Klefström has researched and developed the gel media for a long time. He feels that the traditional method, in which cell lines are cultivated in a petri dish, reveals very little about how cancerous cells behave in the human body.

 “A cell line is a pale shadow of the tissue from which it is derived.”

The original tissue can be preserved in the gel, and the cells operate and communicate normally. It also allows researchers to see how the cancer cells react to the treatment.

An effective cocktail

Researcher Heidi Haikala points to a small container where cancer cells are growing. Haikala is treating some of them with different combinations of drugs, while others are being attacked by the patient’s own immune cells.

There is currently great interest in immunotherapies in cancer research. If a patient’s immune system can itself fight the cancer, the patient will avoid the adverse effects associated with many cancer treatments.

Many approved precision drugs already exist, but the effects of their combinations are currently unknown. Haikala, who will receive her doctorate in June, has made an interesting discovery. For her dissertation research, she tried a combination of well-known drugs on a cancer tumour, and it proved to be highly effective.

 “I was lucky that the drugs I used were very well-known and proven to be safe,” Haikala says.

The drug cocktail must still go through clinical trials, as the drugs may have unexpected harmful compound effects. However, that process is faster and easier than the trial process for completely new drugs.

The usual suspects

Klefström’s group is also testing new drug molecules developed by chemists. The group has an open channel to several pharmaceutical companies, so they can easily notify them if they find a previously unknown chemical that proves to be an effective cancer killer.

 “We have to find new solutions, as our current cancer medications are relatively ineffective on metastatic cancers. We can treat them, but usually not cure them,” Klefström says.

How do the researchers begin their work? They start by inspecting a graph depicting the signalling pathways of cancer cells.

 “It looks a little bit like a map of the underground – in London, not Helsinki. We think about what we would do if we wanted to block a particular pathway,” Klefström explains.

If they can halt cell metabolism using pathways that are vital to all cancer cells, they will be close to discovering a panacea for cancer.

Approximately 20 signalling pathways are important for cancers. Klefström says the results can be generalised beyond breast cancer.

 “It’s always the usual suspects, the ones we identified twenty years ago. We should focus our research on these pathways,” states the cancer expert.

Alternatives for human trials?

And what of the patient? If a tissue sample from her tumour reacts well to one of the drugs being tested, will the drug be used in her treatment?

Not just yet. Using living tissue samples is still at the experimental stage, and it hasn’t been proven with clinical trials. They must first test large patient cohorts to establish that the living tissue really does indicate the efficacy of the drugs.

 “The treating physician is responsible for the life of the patient. They can’t base their treatment decision on just any alternative facts,” Klefström emphasises.

For now, all drugs are tested on patients. If living tissue samples will be approved as credible tools in the future, they can be used to determine which drug works on a particular tumour. This will reduce the need for human trials and speed up the process of finding the right drug.

The physician can administer “experimental” treatment on a patient with a disease that has been unresponsive to traditional treatments. However, this is a divisive issue among physicians and researchers. As a rule, all drugs and treatments must pass clinical trials so that their efficacy and side effects can be reliably documented. On the other hand, an experimental treatment can save a patient’s life.

Klefström believes that it is difficult to draw conclusions about the efficacy of a treatment or the viability of the tissue model if they aren’t backed by controlled clinical trials.

A difficult process

A jungle of regulations stands between the patient and research. The cancer researchers are looking for help to get through it.

 “There is much talk about building bridges between research results and patients. Right now it looks like there is an expanse of a canyon to cross,” says Klefström.

Organising clinical trials is a difficult, expensive process, with a great deal of paperwork and logistics involved. Hospital physicians exhausted by patient work and researchers toiling away in laboratories may not have the wherewithal to start the process.

They would need mediators who could take charge of the arrangements. Such a mediator could be a service centre, or even a company. There have been fewer clinical trials in Finland lately, even though the need for them is increasing. One reason for this is the budget cut to the special state subsidy that allowed physicians to take research leave. Now, any physician interested in research may have to find the time in the evening after a full workday.

Aiming for a cure

Basic research is evaluated on the number of publications and doctoral dissertations produced. Time spent to move project forward to clinical research is taken away from the core work that is the research group’s livelihood, Klefström points out.

 “I wish the evaluation of research groups would consider how well the research results could benefit actual patients.”

While on a researcher exchange at the Dana-Farber/Harvard Cancer Center, Heidi Haikala saw how quickly research ideas can be brought to clinical trials, if the motivation is there.

 “The D-F/HCC’s mission is explicitly to cure cancer.”

Finnish researchers are trying to do the same. This January, the Helsinki University Central Hospital Cancer Centre established the Early Phase Trial Unit, which promotes clinical trials of new drugs and treatments.

Research meets patient

Klefström’s nightmare is physicians becoming too exhausted or unwilling to participate in research at all. If doctors burn out in clinical work, they lose their passion. That would leave researchers helpless, as without the participation of physicians, research results cannot be used to treat patients.

For this reason, Klefström applied for and received Tekes funding to develop a new model for clinical research. Its goal is to achieve statistically significant results with smaller patient cohorts. When patients are selected for trials through molecular biology and genetics, a sample of a few dozen or hundred patients can be sufficient – instead of the more typical three thousand or so.

 “We could select the patients who would benefit from the treatment. This way we would no longer waste energy or resources repeating failed trials, but could instead focus on confirming the results of successful ones,” Klefström explains.

The Tekes-funded TEHO project will be launched this spring with animal trials. If everything goes according to plan, Heidi Haikala’s research results on the combinations of existing drugs could also come to clinical trials. The border is being crossed – research and patient can meet.

This article was published in Finnish in the Y/04/17 issue of Yliopisto magazine.

Data mining and personalised medicine

Researchers at the Institute for Molecular Medicine Finland are testing the efficacy of leukaemia medication on blood samples, not patients. This is enabling them to seek the most suitable drug without burdening the patient.

Researcher Jing Tang intends to combine extensive biomedical resources and use data mining to find personalised drug alternatives to treat leukaemia, and in the future, other cancer types. The most effective combination of drugs will be determined for each patient through extensive drug testing and genome profile databases.

 “We could provide treatment recommendations based on the patient’s genetic background,” Tang suggests.

Jing Tang’s team iCombine is taking part in the Helsinki Challenge science competition. The team includes researchers in medicine, biology and information science from the University of Helsinki and University of Turku.

 “We are developing a series of computational models to predict, model and analyse the efficacy of drug combinations,” says Tang.

This method is not routinely used in clinical work, but through research cooperation it is already being tested in the treatment of patients whose disease has been unresponsive to normal medication. The doctor decides whether an experimental treatment can be recommended for the patient. The treatment involves cancer drugs which have already been approved, but of which some are intended for treating another form of cancer.

According to professor of clinical haematology Kimmo Porkka (@kporkka), the goal is to bring the treatment to clinical trials. However, the research would have to be conducted in cooperation with several pharmaceutical companies.

 “Each patient is a bit different, which should be taken into account when selecting medication. The practical application of this under the current pharmaceutical legislation is a major challenge,” says Porkka.

Elisa Lautala & Reetta Vairimaa