Nigel McMillan

Novel therapeutic strategies for targeting E6 and E7 oncoproteins in cervical cancer

Cervical cancer is the fourth most common cause of cancer-related mortality among women worldwide. The main aetiological factor for developing cervical cancer is the persistent infection of Human papillomavirus (HPV). The E6 and E7 oncoproteins produced by HPV mainly contribute to the carcinogenic process by inhibiting the function of tumour suppressor genes. The E6 protein causes degradation of p53 leading to impaired cellular stress response. In contrast, the E7 protein impairs the activity of retinoblastoma protein (pRb) resulting in continuous cell cycle propagation. Even though screening programmes and prophylactic vaccination have reduced the incidence of cervical cancer, the disease burden is still high, especially in low socioeconomic countries. Treatment of cervical cancer involves a multimodal strategy incorporating surgery, chemotherapy, and radiotherapy. Most of these management approaches use invasive techniques and are associated with adverse effects. Drug resistance is observed over time with chemotherapeutic agents. Hence there is a crucial need for developing novel targeted treatment strategies for cervical cancer. The E6 and E7 viral oncoproteins are continuously expressed in HPV infected cells making them ideal targets for developing therapies. Therapeutic DNA vaccines, gene therapy involving RNA interference technology, and CRISPR are currently under intensive study. These technologies represent a productive and promising approach for the future treatment of cervical cancer. Moreover, several new compounds demonstrate significant anti-cancer effects against cervical cancer. This review provides an updated account of therapeutic strategies currently under research targeting the E6 and E7 viral oncoproteins.

RNA-based gene targeting therapies for human papillomavirus driven cancers

While platinum-based chemotherapy, radiation therapy and or surgery are effective in reducing human papillomavirus (HPV) driven cancer tumours, they have some significant drawbacks, including low specificity for tumour, toxicity, and severe adverse effects. Though current therapies for HPV-driven cancers are effective, severe late toxicity associated with current treatments contributes to the deterioration of patient quality of life. This warrants the need for novel therapies for HPV derived cancers. In this short review, we examined RNA-based therapies targeting the major HPV oncogenes, including short-interfering RNAs (siRNAs) and clustered regularly interspaced short palindromic repeats (CRISPR) as putative treatment modalities. We also explore other potential RNA-based targeting approaches such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and mRNA vaccines as future treatment modalities for HPV cancers. Some of these technologies have already been approved for clinical use for a range of other human diseases but not for HPV cancers. Here we explore the emerging evidence supporting the effectiveness of some of these gene-based therapies for HPV malignancies. In short, the evidence sheds promising light on the feasibility of translating these technologies into a clinically relevant treatment modality for HPV derived cancers and potentially other virally driven human cancers.

What If Trojan Horse Nanoparticles Could Change the Game for HPV Gene‐Targeted Therapies?

ABSTRACT Human papillomavirus (HPV) is a common sexually transmitted infection linked to various cancers, particularly cervical cancer, primarily driven by high‐risk strains like HPV16 and HPV18. While vaccines are effective in preventing new infections, they do not address existing cases, highlighting the need for innovative therapies. Gene‐targeted approaches, such as CRISPR/Cas and siRNA, show promise in inhibiting HPV oncogenes. Recent advancements in Trojan horse nanoparticles (NPs) offer a strategy for delivering these therapies directly to HPV‐infected cells. These NPs improve stability and targeted delivery, enhancing the biodistribution of CRISPR/Cas systems and siRNAs while protecting them from degradation. However, challenges like immune responses and regulatory hurdles persist. Therefore, this review emphasizes the potential of Trojan horse NPs in treating HPV‐related cancers, identifies critical areas for future research, and provides updates on gene‐targeted therapy encapsulated NPs in preclinical and clinical trials.