Cancer cells that migrate and attempt to metastasize a new organ do not receive a warm welcome. Instead, they must adapt to new conditions that often require changing their metabolism and reorganizing their DNA. The majority of them die.
Those that survive create a new tumor, separate from the original, that must be eradicated through treatment as well. But some scientists are taking a different approach. “Why not, instead of treating established metastasis, try to prevent metastasis?” Manuel Valiente, a neuroscientist and brain cancer researcher at the Spanish National Cancer Research Centre, said to DDN.
In a new paper published in Cancer Cell, Valiente’s team showed for the first time that there is a uniquely vulnerable time where prevention might be possible. “Unexpectedly, we have found that very aggressive cancer cells, metastatic cells that make it all the way to the brain, when they get in, they have to stop their aggressive nature for some time,” explained Valiente.
Their team named this time the “proliferative pause” to describe how the cancer cells temporarily stop dividing. By targeting these cells during this crucial window using a combination of drugs in mouse models and human brain tissue samples, his team demonstrated how a new prevention strategy could be applied to cancer metastasis in the brain — and potentially anywhere else in the body.
Testing current drugs to prevent metastasis
In the new work, Valiente’s team identified that the proliferative pause is driven by the MXD4 (MAX dimerization protein 4) gene, which regulates cell proliferation. To test out a new prevention strategy, Valiente said they realized that they could apply the new discovery to the post-surgical relapse phase, which leads to metastasis in the brain in up to 60 percent of patients after removal of the brain tumor.
Why not, instead of treating established metastasis, try to prevent metastasis?
—Manuel Valiente, Spanish National Cancer Research Centre
Without any MXD4 inhibitors available to test out metastasis prevention, the researchers used three different drugs in a variety of ex vivo and in vivo preparations including post-surgical mouse model and human brain tissue samples — which the lab received after neurosurgery and made into organotypic cultures to test drugs. The drugs they used were obatoclax or venetoclax, a BCL-2 (B-cell lymphoma 2) inhibitor; ceralasertib, an ATR (ataxia telangiectasia and rad3-related protein kinase) inhibitor; and ATS-033, a blood-brain barrier-permable HSP90 (heat shock protein 90) inhibitor given to the researchers from AtmosR.
While the drugs worked to delay relapse, they did not yet fully prevent it.
“We are now open to bringing these drugs or any other drugs targeting any of these three pillars, which are crucial in the proliferative pause, into a potential clinical trial,” said Valiente.
A window of opportunity
To bring this novel prevention strategy to the clinic, Valiente said his team is now focused on testing combinations of the drugs that they tested in isolation to improve outcomes and ultimately reach prevention of metastasis. They also want to use multiple drugs at once to better combat the heterogeneity they saw across the early metastatic colonization phase. “We don't know where this heterogeneity is coming from, but it makes it plausible that if you give just one therapeutic pressure, the cancer cells will find their way to survive,” noted Valiente.
The researchers are also pursuing a search for biomarkers using proteomics in liquid biopsies to find an early way to find disseminated cancer cells before they become symptomatic and can be treated to prevent metastasis. In addition, the team will continue to investigate the underlying biology of the proliferative pause, and particularly the importance of crosstalk and collaboration with nearby endothelial cells.
“We think that we have found a very clear window of opportunity in which there is no clear standard of care,” said Valiente, referring to the time period after brain tumor removal surgery. “I think that this is the proof of concept to keep working on preventive strategies."
