Seeking a partner

Okayama University research opens potential for non-invasive ‘liquid biopsy’ method to capture circulating tumor cells

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OKAYAMA, Japan—July 10 saw Okayama University medical researchers announce that they were seeking partners to commercialize their “clinically proven” non-invasive fluorescence virus-guided capture system of human colorectal circulating tumor cells (CTCs) from blood samples for genetic testing.
The researchers note that this kind of non-invasive companion diagnostic is important for personalized and targeted cancer therapy, and they wrote: “This ‘liquid biopsy’ via a simple blood test could be carried out in real time and enables optimized and timely decisions for therapeutic intervention.”
The research was led by Prof. Toshiyoshi Fujiwara of the Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and was published in the May 2014 issue of Gut under the title “Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non- invasive companion diagnostics.”
According to the researchers, the key factor in capturing extremely low quantities of live CTCs from millions of background blood leukocytes is targeting the high telomerase activity of malignant tumor cells with green fluorescent protein (GFP)-expressing telomerase-specific replication adenovirus (using OBP-401 and TelomeScan in their case). Further, they note that combining an OBP-401-based CTC capture system and genetic testing enabled the detection of KRAS and BRAF mutations in blood samples taken from patients with colorectal cancer and, notably, these mutations were determined to be identical to the ones seen in the primary tumors of the patients. However, they also admit that this use of the technology still requires large-scale testing.
Fujiwara and colleagues have previously reported on clinical tests on OBP-401-based GFP labeling to detect live CTCs in gastrointestinal and ovarian cancers. In the current research, Fujiwara’s team reportedly showed that their OBP-401-based CTC capture system enables the monitoring of genetic mutations in both epithelial and mesenchymal types of CTCs, thereby opening up the possibility of a new non-invasive companion diagnostic method for genetic testing and personalized medicine.
The team goes back to the 1800s in describing their work, noting that in 1869, Thomas Ashworth first reported the presence of CTCs in patients with advanced cancer in his paper entitled “A case of cancer in which cells similar to those in the tumors were seen in the blood after death.”
However, it is challenging to detect CTCs because there are very small quantities of CTCs in the bloodstream, Fujiwara notes. The CellSearch system is widely used to detect CTCs, he adds, noting that with it, antibodies are used to target the major epithelial cell surface marker known as the epithelial cell adhesion molecule.
Recent research has shown the existence of heterogeneous CTCs that have both epithelial and mesenchymal characteristics, Fujiwara adds. This discovery has led to demand for the development of CTC capture systems that are able to detect CTCs irrespective of the epithelial cell marker for cancer treatment with molecularly targeted drugs.
Another important fact noted by the researchers is that currently, targeted cancer treatment for individual patients is carried out by analysis of primary tumors. The difficulties with this approach are that the primary tumors contain very few cells that cause metastasis or reoccurrence, and samples for analysis are obtained by needle core biopsies or surgical removal of tumor tissue—procedures that are not only invasive but which preclude the extraction of tissue from locations inaccessible by surgery. As such, they note, there is a need for non-invasive methods capable of detecting CTCs independent of the epithelial cell marker.
Okayama University is one of the largest comprehensive universities in Japan, with roots going back to the Medical Training Place sponsored by the Lord of Okayama and established in 1870. Now with 1,300 faculty and 14,000 students, the university offers courses in specialties ranging from medicine and pharmacy to humanities and physical sciences. Okayama University is located in the heart of Japan, approximately three hours west of Tokyo by Shinkansen.

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