Research using Parsortix to isolate CTC clusters from blood identifies drugs which dissociate highly metastatic CTC clusters resulting in a near total elimination of metastasis in animal models
Opportunity for Parsortix liquid biopsy to be routinely used to identify patients who may benefit from the new approach to suppress cancer metastasis
The University of Basel planning to commence clinical trial in breast cancer in 2019
ANGLE plc (AIM:AGL OTCQX:ANPCY), a world-leading liquid biopsy company, is delighted to announce that its ParsortixTM system has been utilised in ground-breaking new cancer research, which may provide a novel way to treat cancer through the suppression of cancer metastasis.
The research, led by Professor Nicola Aceto at the Cancer Metastasis Laboratory, University of Basel (Basel, Switzerland) has been published today as a peer-reviewed publication in the prestigious journal Cell.
The research demonstrated the ability to harvest intact metastatic circulating tumor cell clusters (CTC clusters, a group of cancer and other cells tethered together as a single mass) using Parsortix and highlights the potential to treat cancer patients identified with Parsortix to have CTC clusters with repurposed FDA approved medications, which have been shown in mouse models to break up these CTC clusters and suppress metastasis. Basel’s research indicated that treated animals showed 80x less metastasis compared with untreated animals, with the metastatic spread of cancer virtually eliminated in the treated animals.
The development of metastasis, the spread of cancer to distant sites primarily via the blood, is responsible for more than 90% of all cancer-related deaths. Previous work has shown that CTC clusters in the blood are highly metastatic causing greatly increased spread of the disease. If metastasis could be suppressed by disrupting CTC clusters then patient outcomes could be dramatically improved.
There are a variety of technical challenges to capturing intact CTC clusters from patient blood, which has historically led to problems with other CTC systems and an inability to effectively research CTC clusters. In controlled tests with spiked samples, Basel demonstrated that the Parsortix system used with a specialised protocol performed exceptionally well to overcome these technical challenges and was able to successfully isolate >99% of CTC clusters from a simple blood test.
Using the Parsortix system, Basel was able to investigate CTC clusters both from patient blood and from animal models. The analysis of the CTC clusters led to Basel discovering key, previously unknown, epigenetic changes present in the CTC clusters making them highly effective at spreading the cancer.
Following this discovery, the researchers investigated the potential for 2,486 compounds already approved by the FDA for a number of different indications, to cause the CTC clusters to dissociate (break up into individual cells). They found a small number of drugs with the capability to do this. Once dissociated, they found that CTC clusters (now single cells) lost their high metastatic potential.
The directors believe that the results show exceptional promise for use in human cancer. The mechanism of action of the drugs was to effectively weaken the cell-cell connections in the CTC cluster rather than to kill the cancer cells. Conventional chemotherapy seeks to kill the cancer cell and is consequently inherently toxic, which is why patients can suffer serious side effects from the treatment as non-cancer cells may also be adversely affected. Further, conventional therapies aimed at killing cancer cells are prone to give rise to drug-resistant cell populations, which can ultimately lead to disease relapse. In contrast, the drugs used for the CTC cluster dissociation are already approved by the FDA for different non-cancer indications and do not have the typical side effects of chemotherapy or immunotherapy.
Basel have applied for ethics approval to undertake a clinical trial in 2019 utilising the Parsortix system as a companion diagnostic to identify which patients have CTC clusters and may respond to the identified drugs. The first area of focus is in breast cancer, which complements ANGLE’s ongoing FDA studies in metastatic breast cancer.
Professor Nicola Aceto, Group Leader – Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Switzerland, commented:
“CTC clusters are extraordinarily important mediators of breast cancer metastasis, and discovering the first anti-cluster therapy may provide a new powerful tool to help treat millions of women currently living with this potentially fatal disease. The Parsortix state-of-the-art technology platform has played a key role in enabling us to isolate CTC clusters for investigation. We are now working on proof-of-concept clinical studies using Parsortix as a companion diagnostic.”
ANGLE Founder and Chief Executive, Andrew Newland, commented:
“The ground-breaking CTC cluster work undertaken over the last three years by the University of Basel, one of ANGLE’s leading customers, highlights completely new clinical uses for the Parsortix system with the potential to play a central role in dramatically improving patient outcomes. This is a key potential application for Parsortix liquid biopsy once we receive FDA clearance. Our ultimate aim is for the Parsortix system to be routinely used for all cancer patients in the future.”
The study published in the journal Cell today can be accessed here:
https://www.cell.com/cell/home and is described in the University of Basel’s press release, which is reproduced in full below. An image of CTC clusters in a Parsortix cassette is featured on the front cover of the journal.
Basel researchers identify drug against the formation of metastasis
The most deadly aspect of breast cancer is metastasis. It spreads cancer cells throughout the body. Researchers at the University and the University Hospital of Basel have now discovered a substance that suppresses the formation of metastases. In the journal Cell, the team of molecular biologists, computational biologists, and clinicians reports on their interdisciplinary approach.
The development of metastasis is responsible for more than 90% of cancer-related deaths, and patients with a metastatic disease are considered incurable. The interdisciplinary team led by Prof. Nicola Aceto from the Department of Biomedicine at the University of Basel has identified a drug that suppresses the spread of malignant cancer cells and their metastasis-seeding ability.
Precursors of metastases: Circulating tumor cell clusters
Circulating tumor cells (CTCs) are cancer cells that leave a primary tumor and enter the bloodstream, on their way to seeding distant metastases. These so-called CTCs can be found in the blood of patients as single cells or cell clusters. CTC clusters are the precursors of metastases. The Basel research team has discovered that CTC cluster formation leads to key epigenetic changes that facilitate metastasis seeding. These changes enable CTC clusters to mimic some properties of embryonic stem cells, including their ability to proliferate while retaining tissue-forming capabilities. The scientists have also shown that these epigenetic changes are fully reversible upon the dissociation of CTC clusters.
In their search for a substance that suppresses metastasis development, the research team tested 2486 FDA-approved compounds used for a number of different indications. They found inhibitors with the unexpected ability to dissociate patient-derived CTC clusters. This drug-based dissociation of CTC clusters into individual cells also resulted into epigenetic remodeling and prevented the formation of new metastases.
Preventing metastasis versus killing cancer cells
“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.
In the fight against breast cancer, metastases remain the greatest danger. These new findings on the mechanisms of metastasis formation are the result of a large collaborative effort across various disciplines. “Our ambitious approach would not have been possible without collaboration with outstanding clinicians, molecular and computational biologists, with the support of state-of-the-art technology platforms,” says Aceto and adds: “Our methodology is positioned directly at the interface between these different disciplines. We are already working on the next step, which is to conduct a clinical trial with breast cancer patients.”
Sofia Gkountela, Francesc Castro-Giner, Barbara Maria Szczerba, Marcus Vetter, Julia Landin, Ramona Scherrer, Ilona Krol, Manuel C. Scheidmann, Christian Beisel, Christian U. Stirnimann, Christian Kurzeder, Viola Heinzelmann-Schwarz, Christoph Rochlitz, Walter Paul Weber, Nicola Aceto
Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding
Cell (2018), doi: 10.1016/j.cell.2018.11.046
Research group of Prof. Dr. Nicola Aceto (https://biomedizin.unibas.ch/en/research/research-groups/aceto-lab/)
Additional information on the research group of Prof. Dr. Nicola Aceto (http://www.cancermetastasislab.com/)
Prof. Dr. Nicola Aceto, University of Basel and University Hospital Basel, Department of Biomedicine, phone: +41 61 207 0773, email: Nicola.Aceto@unibas.ch
The accompanying image was chosen as cover story for the current issue of “Cell”. A workshop report on the production of the picture is available under this link once the embargo has expired: https://medium.com/sci-five-university-of-basel
Caption and credit:
The image represents an artistic coloration of a cluster of circulating tumor cells (CTCs), isolated from the blood of a patient with breast cancer, trapped on a microfluidic device.
Image: © M Oeggerli / Micronaut 2018, supported by Pathology-, C-CINA / Biozentrum-, and I Krol, and N Aceto, Faculty of Medicine-, University Hospital and University Basel
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