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Non-toxic fragment of botulinum neurotoxin type A and monomethyl auristatin E conjugate for targeted therapy for neuroendocrine tumors. | LitMetric

AI Article Synopsis

  • * A new treatment using a recombinant heavy-chain receptor binding domain (rHCR) of botulinum neurotoxin type A can target specific receptors in NET cells, showing reduced tumor markers and cell proliferation.
  • * When combined with an antimitotic agent, rHCR significantly decreased tumor size in mouse models without harmful effects, highlighting its potential as a safe treatment targeting neuroendocrine tumors.

Article Abstract

Surgical resection is the only cure for neuroendocrine tumors (NETs). However, widespread metastases have already occured by the time of initial diagnosis in many cases making complete surgical removal impossible. We developed a recombinant heavy-chain receptor binding domain (rHCR) of botulinum neurotoxin type A that can specifically target synaptic vesicle 2 (SV2), a surface receptor abundantly expressed in multiple neuroendocrine tumors. Expression of neuroendocrine differentiation markers chromogranin A (CgA) and achaete-scute complex 1 (ASCL1) were signficantly reduced when treated with rHCR. rHCR conjugated to the antimitotic agent monomethyl auristatin E (MMAE) significantly suppressed proliferation of pancreatic carcinoid (BON) and medullary thyroid cancer cells (MZ) at concentrations of 500 and 300 nM respectively, while no growth suppression was observed in pulmonary fibroblasts and cortical neuron control cell lines. In vivo, rHCR-MMAE significantly reduced tumor volume in mouse xenografts with no observed adverse effects. These data suggest recombinant HCR (rHCR) of BoNT/A preferentially targets neuroendocrine cancer without the neurotoxicity of the full BoNT/A and that SV2 is a specific and promising target for delivering drugs to neuroendocrine tumors.

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Source
http://dx.doi.org/10.1038/s41417-020-0167-xDOI Listing

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