Anticancer Drugs Aimed at E6 and E7 Activity in HPV-Positive Cervical Cancer

S.      Tan; E.      G.E. de Vries; A.      G.J. van der Zee; S.      de Jong

doi:10.2174/156800912799095135

Abstract

Standard treatment of locally advanced cervical cancer currently consists of concurrent chemoradiation, leading to a 5-year disease-free survival of 66-79%, indicating that there is still ample room for improvement. Characteristic of cervical cancer is the presence of high risk (HR) human papillomavirus (HPV) DNA in more than 99% of these tumors. When the HR HPV genome integrates into the host genome, oncogenic E6 and E7 proteins become constitutively expressed. These oncogenes are also active earlier in the infection cycle and hence are available as therapeutic targets at the preneoplastic stages as well. E7 plays an important role in the early stage of carcinogenesis by stimulating proliferation. HR HPV E6-induced proteasomal degradation of p53 hampers p53 functionality in cell cycle arrest and apoptosis. As p53 plays a key role in the intrinsic apoptotic pathway, current chemoradiation cannot optimally activate this pathway. In this review, we focus on targeted anticancer drugs to eliminate the consequences of HR HPV E6 and E7 activity. Strategies for direct and indirect targeting of HR HPV E6 and E7, including RNA interference, small molecules, proteasome inhibitors, and histone deacetylase inhibitors, are described. In addition, the extrinsic apoptotic pathway as possible alternative therapeutic target for apoptosis induction is reviewed. The rational for implementing recombinant human TRAIL and death receptor agonists and the latest developments on combining these drugs with standard treatment in preclinical settings as well as clinical trials are discussed.

Keywords: Apoptosis, cervical cancer, death receptors, E6, E7, HR HPV, TRAIL, ataxia telangiectasia mutated, Bcl-2, –, associated X protein, B-cell lymphoma-2, CREB binding protein, cervical intraepithelial neoplasia, death inducing signalling complex, extracellular signal-regulated kinase, FLICE-inhibitory protein