Targeted degradation of the HPV oncoprotein E6 reduces tumor burden in cervical cancer

Area of Science:

• Oncology
• Virology
• Immunology

Background:

• Human Papilloma Virus (HPV)-related cancers pose a significant global health challenge.
• Currently, no targeted therapies exist for patients with chronic HPV infections.
• The HPV E6 protein is crucial for tumor development and immune evasion, making it a key therapeutic target.

Purpose of the Study:

• To develop a novel Proteolysis Targeting Chimera (PROTAC) targeting the HPV E6 protein.
• To investigate the efficacy of the E6-targeting PROTAC in inhibiting HPV(+) tumor growth.
• To elucidate the mechanism underlying the PROTAC's antitumor effects, including its impact on the host immune response.

Main Methods:

• Generation of nanobodies targeting oncogenic HPV16 E6 protein.
• Construction of an E6-degrading PROTAC (PROTAC^E6) by fusing an E6 nanobody to the Von Hippel Lindau (VHL) E6 ligase.
• Validation of E6 degradation via the CRL2^VHL E3 ligase.
• Assessment of PROTAC^E6 efficacy in an immunocompetent mouse model of HPV(+) cancer via intralesional administration using a DNA vaccine.
• Evaluation of the role of CD4+ and CD8+ T-cells in the PROTAC^E6-mediated antitumor response.

Main Results:

• A high-affinity E6 nanobody (A5) was identified and used to create PROTAC^E6.
• PROTAC^E6 specifically degraded the HPV E6 protein through the CRL2^VHL E3 ligase.
• Intralesional PROTAC^E6 administration significantly reduced tumor burden in a mouse model.
• The antitumor effects were dependent on CD4+ and CD8+ T-cells, indicating an immune-mediated mechanism.

Conclusions:

• Targeted degradation of HPV E6 protein inhibits its oncogenic functions.
• PROTAC^E6 therapy stimulates a potent immune response against HPV(+) tumors.
• This approach offers a promising new avenue for virus-specific therapies against HPV-related cancers.