title: Targeted Molecular Therapies for HPV-driven Cervical Cancers
Creators: name: Fallaha, Sora
Publisher: name: Griffith University
Year: 2017
Subjects: subject: Molecular therapies
subject: HPV-driven cervical cancers
subject: Genomic properties

description: The report by zur Hausen in 1980 linking Human papilloma virus (HPV) infections to major cancers was a key turning point in the HPV-driven cancer discovery era. HPV are doublestranded DNA viruses that belong to the Papillomaviridae family. Most HPV infections resolve spontaneously, or may cause indications (such as warts, anogenital, oro-laryngeal and -pharyngeal papillomas) that are easy to treat. Persistent and untreated infections with certain types of high risk (HR) HPV, particularly types 16 and 18, increase the risk for the development of cancer, such as cervical cancer (CC). In fact, high risk HPV are now reported as causative agents for &gt;95% of cervical, anogenital, and head and neck cancers. Indeed, malignancies derived from HPV account for &gt; 610,000 deaths annually and represent ~5% of the total cancer burden worldwide. The World Health Organisation (WHO) in 2012 declared that cervical cancer was the second most common cancer in women globally, with a high mortality rate of 52%. More than 85% of the deaths occur in low and middle income (less developed) countries where access to effective screening, early detection, and vaccination strategies is poor. The implementation of the HPV vaccine, co-developed by Professor Ian Frazer, was a milestone discovery in the fight against HPV-mediated CC, providing highly efficient protection against most common HR HPV infections. However, this vaccine does not cure women currently diagnosed with HPV-driven cancers as the immunogens are no longer present. Therefore, the actual benefits of implementing this vaccine may not be revealed until 30 years, which is the time required for cervical cancers to develop following infection. Current interventions to treat cervical cancer include surgery followed by radioand chemotherapy, e.g. cisplatin, but these exhibit numerous cytotoxic side effects. Consequently, we need alternative therapeutic strategies. The evolution of molecular targeted therapies against cancers is providing a better understanding of the dynamics of cellular transformation caused by infection with certain viruses. In this research, multiple targeted therapeutic strategies against HPV-driven cervical cancers were explored at early and advanced stages of the disease in mice. The first strategy involved the use of PEGylated lipoplex-entrapped alginate scaffold (PLAS) system loaded with small interfering ribonucleic acids (siRNAs) which target type 16 E6/E7 proteins. Our results showed that intravaginally delivered siS10-PLAS targeting HPV16 E6/E7 in CIN/VIN II- K14-E7 models significantly reduced the level of E6/E7 mRNA in the cervico-vaginal regions compared to control siRNA however, no change in disease outcome was observed. Nevertheless, the ability of the treatment to induce apoptotic cell death evidenced by apoptotic bodies observed in the cervico-vaginal epithelia suggested promising potential to treat early stage CIN/VIN. The second strategy involved the use of Alisertib, an anti-mitotic inhibitor that is known to target Aurora A kinase for the treatment of late stage HPV-driven cervical cancer. Our results showed that Alisertib have a dual inhibition activity to Aurora A and B as it can inhibit Aurora B kinase at relatively higher concentrations (~1μM). Indeed, it was the loss of Aurora A and B kinases that induced a selective and lethal assault to HPV transformed cervical cancer cell (Hela and CaSki) in vivo. Moreover, this lethal effect appeared to be due to cell death by apoptosis evidenced by cleaved caspase-3 by means of a p53-independent pathway. Lastly, we demonstrated that HPV-tumour (TC-1) cell death induced by Alisertib treatment was unable to promote sterilising anti-tumour immunogenic response. This suggested that an immune combination could improve the anti-tumour potential of the drug that could generate a stronger immunogenic signal which would protect mice from subsequent tumour challenge. It is hoped that the outcomes revealed from this research may provide potential interventional approaches against HPV-cervical cancers that could be translated into clinical trials in the near future.