Drug dissociates metastasis precursors in blood

In Cell, the team headed by Nicola Aceto from University Hospital Basel, Switzerland, reported that a screening of 2,486 FDA-approved compounds identified Na⁺/K⁺-ATPase inhibitors that triggered dissociation of clusters of  circulating tumour cells (CTCs) in patient blood in into single cells. The ability of CTCs to form clusters has been previously linked to increased metastatic potential and epithelial-mesenchymal transition. The drugs initiatied remodelling of DNA methylation in CTC genes of transcription factors responsible for stemness and proliferation of the pre-metastatic cells and metastasis suppression. CTC cluster hypomethylation in the binding sites for OCT4, SOX2, NANOG, and SIN3A correlates with a poor prognosis in breast cancer.

The development of metastasis is responsible for more than 90% of cancer-related deaths, and patients with metastatic disease are considered incurable. Until recently, it was not possible to isolate and analyse the rare CTCs. However, advances in microfluidic technologies driven forward in projects like Cancer-ID etc are allowing the isolation and characterization of human circulating tumor cells (CTCs) that escaped a primary tumor mass and are in the process of seeding a distant metastasis ”We thought of acting differently from standard approaches, and sought to identify drugs that do not kill cancer cells, but simply dissociate them,” states Nicola Aceto, holder of an ERC starting grant and SNSF professorship. Aceto's team found CTC cluster formation to be accompanied by hypomethylation of stemness- and proliferation-associated transcription factors that facilitate metastasis seeding. In fact, hypomethylated CTC clusters mimic some properties of embryonic stem cells, including their ability to proliferate while retaining tissue-forming capabilities. The good news, however, from genome-wide DNA methylation analyses of CTC clusters from mice and women with breast cancer was that these epigenetic changes are fully reversible upon the dissociation of the tumours cell clusters in the blood.

According to Aceto, the next goal is now to start clinical trails with the optimised drug candidate. In 2003, the US company Bionaut Pharmaceuticals filed a patent for Na⁺/K⁺-ATPase inhibitors to treat pancreatic cancer. The last record of the company on the Internet dating back to 2005 is about a collaboration with the National Cancer Institute to assess if the patented drug can prevent metastases.