Targeting Synaptic Vesicle 2 Proteins for Treating Medullary Thyroid Cancer

Objective: Discovery of alternative biomarkers and therapeutic targets for the control of persistent, recurrent medullary thyroid cancer (MTC) and the treatment of metastatic disease.Methods: The expression of SV2... [ view full abstract ]

Objective: Discovery of alternative biomarkers and therapeutic targets for the control of persistent, recurrent medullary thyroid cancer (MTC) and the treatment of metastatic disease.

Methods: The expression of SV2 proteins in MTC cell lines (TT and MZ-CRC-1) was detected by Western blot. The heavy-chain receptor binding domain (HCR/A) of botulinum neurotoxin type A was produced and purified to treat MTC cell lines and non NE thyroid cell lines (FTC-236, HTh7, and TPC-1) for 24 hrs. The effect of the HCR/A targeting ligand on the cellular uptake was measured with anti-HCR/A antibody. The cell proliferation and the expression of NE markers (ASCL1 and CgA) after treatment with HCR/A were assessed by MTT assay and Western blot, respectively.

Results: We confirmed expression of SV2 proteins in MTC cell lines. Furthermore, we showed that botulinum neurotoxin type A cleaved SNAP25 expressed in MTC cells indicating that HCR/A can be internalized into MTC cells. Moreover, treating MTC cells with HCR/A reduced the expression of NE tumor markers CgA and ASCL1 suggesting alteration of neuroendocrine phenotype, and existence of unforeseen signaling pathways downstream of the SV2 receptor.

Conclusion: SV2 proteins can serve as novel and alternative targets for MTC. HCR/A has therapeutic potential and utility as a drug delivery ligand in the treatment of MTC.