Epigenetic control of HPV oncogene expression and therapeutic implications

Background

A major research aspect in the field on HPV-associated cancer is the observation that these tumors occur with a prominent host cell specificty. For example, HPV-positive cancers predominantly arise within the epithelium of the squamous columnar junction zone of the uterine cervix or the linea dentata in the anus. The are also restricted to the Waldeyer epithelium of the oropharynx, whereas they rarely occur in cells outside these very specific epithelial sites.

This observation suggests that for the activation of the viral oncogenes E6 and E7 presumably epigenetic conditions within these cells are required that allow to modify the epigenetic imprint of the viral genome and thus also its expression activity.

What we do

Our research revealed that distinct methylation marks of CpG dinucleotides within the HPV-upstream regulatory region (HPV-URR) of the HPV genomes contributes to the activation of the E6-E7 oncogenes. Specific drugs that interfere with the essential methylation steps appear to block the HPV-triggered transformation and reverse the malignant growth.

We are currently developing therapeutics to treat HPV-induced lesions and cancers of the skin and mucosa. One core project is supported by the EXIST program of the Federal Ministry for Economic Affairs and Energy (BMWi) and the European Social Fond (ESF) of the European Union. The program aims at developing a novel therapeutic for subsequent testing in a clinical trial accompanied by a profound business development plan to prepare founding of a spin-off.

In frame of the Heidelberg NCT 3.0 Proof of Concept Program we have been initiating a phase I study exploring the safety of radiotherapy in combination with an epigenetically active substance in patients with cancers of the anogenital and head and neck region.

Key publications

• Stich M, Ganss L, Puschhof J, Prigge ES, Reuschenbach M, Gutierrez A, Vinokurova S, von Knebel Doeberitz M. 5-aza-2'-deoxycytidine (DAC) treatment downregulates the HPV E6 and E7 oncogene expression and blocks neoplastic growth of HPV-associated cancer cells. Oncotarget. 2016 Jul 16. doi: 10.18632/oncotarget.10631.
• Reuschenbach M, Huebbers CU, Prigge ES, Bermejo JL, Lateis, MS, Preuss SF, Seuthe IM, Kolligs J, Spee EJ, Oltholf N, Kremer B, Wagner S, Klussmann JP, Vinokurova S, von Knebel Doeberitz M. Methylation staus of HPV16 E2-binding sites classifies subtypes of HPV-associated oropharyngeal cancers. Cancer 2015 Jun 121 (12) 1966-76.

• Chaiwongkot A, Vinokurova S, Pientong C, Ekalaksananan T, Kongyingyoes B, Kleebkaow P, Chumworathayi B, Patarapadungkit N, Reuschenbach M, von Knebel Doeberitz M. Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions. Int J Cancer 2013 May 1;132(9):2087-9

• Vinokurova S, von Knebel Doeberitz M. Differential methylation of the HPV 16 upstream regulatory region during epithelial differentiation and neoplastic transformation. PLoS One. 2011;6(9):e24451.