LONDON – Swiss researchers have uncovered a potential new route to preventing metastasis, after succeeding in harvesting intact circulating tumor cell (CTC) clusters that are the precursors of metastases, from the blood of breast cancer patients.
The clusters were screened against 2,486 drugs, approved by the U.S. FDA for a number of indications, throwing up several compounds that caused clusters to dissociate. Mice with xenograft human tumors had an 80 times lower metastatic burden when treated with the most effective of those drugs.
CTC clusters, consisting of tumor and other cells tethered together as a single mass, have been known for some time to be key drivers of metastasis. But the difficulty of isolating intact clusters has made it hard to study them.
Using Angle plc's Parsortix liquid biopsy system, the researchers developed a specialized protocol, which, rather than picking out single circulating cancer cells, is able to isolate more than 99 percent of clusters from a blood sample.
The scientists, at the Cancer Metastasis Laboratory at University of Basel, are applying for ethical approval for a clinical trial in which they will use Parsortix as a companion diagnostic to identify patients who have CTC clusters and are likely to respond to drugs identified in the screen.
"CTC clusters are extraordinarily important mediators of breast cancer metastasis," said researcher Nicola Aceto. "Discovering the first anticluster therapy may provide a powerful new tool to help treat millions of women."
The ability to isolate intact clusters has, for the first time, allowed them to be studied in detail, leading to the discovery of key epigenetic changes that promote metastasis seeding.
A profile of the DNA methylation landscape of CTC clusters from breast cancer patients found binding sites for both stemness- and proliferation-associated transcription factors were hypomethylated. Those included binding sites for OCT4, NANOG, SOX2 and SIN3A, which are required for the self-renewal of stem cells.
Writing in the current issue of Cell, the researchers said those epigenetic changes enable CTC clusters to mimic the ability of stem cells to proliferate, while retaining tissue-forming capabilities.
The researchers also discovered that the DNA methylation profile of CTC clusters can be found in the primary tumor in a subset of breast cancers that have a poor prognosis.
The epigenetic changes are fully reversed when cells in the clusters are induced to separate. "We thought of acting differently from standard approaches, and sought to identify drugs that do not kill cancer cells, but simply dissociate them," Aceto said.
The discovery would not have been possible without the ability to isolate CTC clusters using Parsortix, Aceto said.
The drugs emerging from the screen are sodium-positive/potassium-positive-ATPase (Na+/K+-ATPase) inhibitors traditionally used to treat heart failure, but which also have been studied in cancer.
That research was prompted by epidemiological evidence of an antitumor effect in patients with heart disease who also had cancer. Na+/K+-ATPase is up-regulated in some solid tumors, and there is preclinical evidence that inhibition of the enzyme promotes cancer cell death. In addition, Na+/K+-ATPase inhibitors have been shown to break tumor resistance to other chemotherapies.
Parsortix relies on cancer cells having two essential physical differences from blood cells, being both bigger and rigid. That means blood cells can get through filters that cancer cells cannot. To date, the technology has been used to isolate single circulating tumor cells for DNA and RNA screening.
Andrew Newland, founder and CEO of Guildford, U.K.-based Angle, said the company had worked in collaboration with the Basel researchers in making the adjustments required to enable CTC clusters to be isolated.
"We own the protocol and have the ability to use it in different areas. It's a new application of the existing product," Newland told BioWorld MedTech.
Screening for CTC clusters could become a standard test for assessing the metastatic potential of a tumor and response to therapy. It could also become a regular part of follow-up of patients who have been treated for cancer. "You could deploy it at various stages, as a test that is complementary to existing treatments," said Newland.
The protocol would be applicable to isolating intact CTC clusters arising from any solid tumor, Newland said.
During the first quarter of 2019, Angle is expecting results of a U.S. study of the use of Parsortix to harvest single CTCs from patients with metastatic breast cancer. It hopes that will lead to the company being first to have FDA approval for a liquid biopsy that isolates whole cancer cells from blood.
Newland said the ability to isolate CTC clusters would be complementary and will further differentiate Parsortix from FDA-approved liquid biopsies that enumerate CTCs to assess prognosis, or which identify cancer genes from fragments of circulating tumor DNA.