Detection of circulating tumor cells (CTCs) as a next-generation liquid biopsy for neuroendocrine tumors (NETs) by taking advantage of existing theranostic probes

When neuroendocrine cells become cancerous, the resulting Neuroendocrine Tumours (NETs) can be challenging to detect. NETs are often asymptomatic, because they often lead to hormonal imbalances, which are associated with other diseases. In terms of biomarkers, NETs often overexpress Somatostatin Receptor 2 (SSTR2). This biomarker is the primary method of detecting and treating NETs and a specific molecule called DOTATATE is used for clinical PET scans and therapies to detect and combat this cancer in NET patients. DOTATATE compounds consist of two active components. The DOTA component is a metal chelator that carries the component detected by PET scan. The TATE component is a modified octreotate compound which binds to the Somatostatin Receptor 2 (SSTR2).Here, we offer the TATE-Cy5 probe, which takes advantage of the clinical use of DOTATATE for use in a blood test. Similar to DOTATATE, TATE-Cy5 also contains tyrosine-3-octreotate, meaning that it can to bind to SSTRs with equal effectiveness. However, instead of the DOTA chelator, TATE-Cy5 has a fluorescent Cy5 probe, which can be used to detect the presence of NETs because we hypothesize we can detect circulating tumor cells (CTCs) in patient blood samples. We predict that there are high numbers of CTCs that bind the TATE-Cy5 probe in patient whole blood samples according to disease severity.Results show that TATE-Cy5 binds to cell lines overexpressing SSTR2. Moving onto clinical samples, we also observe the presence of CTCs that bind TATE-Cy5 in whole blood samples from NET patients. We further subclassified CTCs as based on a combination of co-expressing biomarkers, CTCS that are positive for SSTR2, and tumours positive for both SSTR2 and EpCAM. With further testing, we will be able to use TATE-Cy5 to monitor patient treatment response over time.In summary, we have developed a novel and cancer specific CTC liquid biopsy that takes advantage of existing imaging probes in the form of DOTATATE. This technology has significant clinical implications because it can be used as a companion liquid biopsy for existing and emerging therapies.