Inhibition of tumor growth using A conjugated nanobody that specifically targets c-MYC

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• The MYC oncogene is frequently activated in human cancers, correlating with poor prognosis.
• Targeting MYC is challenging due to its lack of enzyme-binding sites, limiting small-molecule therapies.
• Current MYC-targeting treatments are limited, necessitating novel therapeutic strategies.

Purpose of the Study:

• To develop a novel therapeutic agent targeting the MYC oncogene.
• To evaluate the efficacy of a cell-permeable MYC-targeting nanobody (CPMycNB) in preclinical cancer models.

Main Methods:

• Development of a conjugated nanobody (CPMycNB) using sortase-mediated protein ligation.
• Assessment of CPMycNB's nuclear entry, binding to c-MYC, and disruption of c-MYC-MAX interaction.
• Evaluation of CPMycNB's effects on gene expression, apoptosis, cell proliferation, and tumor growth in xenograft models.
• Utilized hydrogen-deuterium exchange mass spectrometry to identify CPMycNB's binding domain on c-MYC.

Main Results:

• CPMycNB successfully entered the nucleus and bound to c-MYC, disrupting the c-MYC-MAX interaction.
• Disruption led to downregulation of MYC targets, apoptosis activation, and inhibited tumor cell growth.
• Hydrogen-deuterium exchange mass spectrometry confirmed CPMycNB interaction with c-MYC's leucine zipper domain.
• Xenograft studies demonstrated significant reduction in tumor size and weight with CPMycNB treatment.

Conclusions:

• CPMycNB is an effective therapeutic agent for targeting MYC in cancer.
• The nanobody disrupts crucial MYC interactions, leading to anti-tumor effects.
• CPMycNB shows significant therapeutic potential for treating MYC-associated malignancies.