New cancer research goal is to eradicate metastasis before it appears

Héctor Peinado, Manuel Valiente and Eva González, three of the organizers of the 'CNIO Frontiers Meeting-Metástasis' congress / Esther Sánchez. CNIO

The results of the basic research conducted over the last few decades on how metastasis originates are starting to reach clinical practice. Several trials presented at the CNIO Frontiers Meeting ‘Metastasis’, which runs until 8 November, are testing out strategies to eradicate this process before it manifests, because treating metastasis once it has developed remains very complex today.

“Today we are still treating too late; cancer is one step ahead. Understanding the biology [of how metastasis begins] allows us to act when it is still dormant,” explained Julio Aguirre-Ghiso, from the Albert Einstein College of Medicine (USA), who discovered ‘dormant’ metastasis: there may be dormant cancer cells around the body, which don’t spread for years, but even after the primary tumour is removed, they can reactivate and form metastasis.

Metastasis, the process by which a tumour reproduces in other organs, is the leading cause of cancer-related mortality. One of the recent paradigm shifts is that “it is a disease in itself,” explains Eva González-Suárez, head of the Transformation and Metastasis Group at CNIO. Fighting it involves different strategies from those used to treat the primary tumour.

First challenge: identify metastatic cells

A key concept is that only “a very small part of all the cells that make up a tumour have the ability to metastasise,” says Héctor Peinado, head of the CNIO Microenvironment and Metastasis Group. “The first challenge is to identify these cells.”

Today this has only been achieved in some tumour types and for some cells, but “there is still no universal marker of metastasis,” he adds. “We only know a few markers of spread; it is crucial to keep moving forward in identifying biomarkers.”

The next step, once metastatic cells are identified, is to target therapy against them. Cyrus Ghajar, from the Fred Hutchinson Cancer Center (USA), is testing a strategy based on the activation of immune system cells (T lymphocytes).

Increase specific defensive cells

Ghajar begins with an idea that is both simple and innovative, as he explained at the congress: metastasis progresses because both the metastatic cells spread by the body and the defensive cells that must fight them are very few and far between, and they are not being found. It’s “a matter of numbers,” he said. His strategy is to swell the defensive cell population, to increase the probability of interaction.

“Metastatic cells leave the tumour and make their way to organs, and it can take them many years to wake up and metastasise,” Ghajar explains. “We initially investigated several mechanisms by which these dormant cells evade the body’s defences. But we are left with the most obvious solution, which is that they are rare, one metastatic cell in a million, and tumour-specific T cells are also very scarce. To encourage their interaction, we must increase the number of T cells.”

This is the strategy that this researcher has tested on experimental breast cancer models, and “now we’re going to test it in people,” he says.

Chemical signals that prevent excessive proliferation

But Aguirre-Ghiso believes that metastatic cells also have active mechanisms to escape defences. His group has discovered several of the chemical signals that control cell proliferation. They have just finished “a clinical trial where we reprogramme tumour cells [their epigenetics] to make them activate those mechanisms [that prevent excessive growth].”

They have also studied how metastatic cells survive whilst they are dormant, and how to “try to move them directly from sleep to death.”

These are some of the “really fascinating results we are seeing”, says Manuel Valiente, head of the Brain Metastasis Group at CNIO and one of the organisers of this congress, which has the support of Fundación “la Caixa”.

The CNIO-Caixa Research Frontiers Meeting ‘Metastasis’, which runs until 8 November, brings together some twenty international experts to offer “the most up-to-date perspective on metastasis, including the best ways to simulate it computationally, encompass its heterogeneity and prevent it from occurring, among other key issues,” the organisers say.

Seven sessions are addressing the topics on which metastasis research today is concentrating. These include: the influence of the microorganisms (bacteria) present in the tumour on the probability of metastasis; the importance of the cells and factors surrounding the tumour (the tumour microenvironment); the latest techniques to detect tumour markers as soon as possible in fluids such as blood ; and the most promising therapeutic approaches .

By investigating the multiple phases of metastasis, researchers are identifying new weak points, targets on which to act in order to curb metastasis.

The organisers are:

EVA González-Suárez, head of the Transformation and Metastasis Group at CNIO. She is researching breast cancer. She has found that an already approved drug, denosumab, which blocks the RANK pathway, could be used in the prevention and treatment of breast cancer and even in the context of resistance in metastatic cancer, when conventional drugs stop working. She is leading clinical trials to select biomarkers that allow personalised oncological treatments.

Héctor Peinado, head of CNIO’s Microenvironment and Metastasis Group. He participates in the European PANCAID project , which has almost 10 million euros in funding, to look for detectable biomarkers in the blood that flag the presence of pancreatic cancer, as products derived from tumour cells.

Manuel Valiente, head of the Brain Metastasis Group at CNIO. He is one of the creators of the RENACER network of live samples of brain metastasis, and co-author of a pioneering study that has revealed how brain tumours ‘hack’ communication between neurons.

Julio Aguirre-Ghiso, from the Albert Einstein College of Medicine, USA. He is one of the discoverers of ‘dormant’ metastasis: the patient can be a carrier of latent disseminated cancer cells, which do not multiply for years, but even after the primary tumour is eliminated they can reactivate and form metastasis.

Caroline Dive, from the Cancer Research UK Manchester Institute. She works mainly in lung cancer, particularly in the development of liquid biopsies to detect cancer cells that have detached from tumours and circulate in the bloodstream.

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