Research focus 1: Characterize novel interactions between HPV and host cells to identify druggable biomarkers for therapy of HPV-positive tumors.

The molecular mechanism by which HPV proteins reprogram host cells to control viral replication and promote tumorigenesis is not yet fully understood. The E6 and E7 are the main oncoproteins of HPV. We aim to better characterize their oncogenic properties with the goal of using these results for development and improvement of therapeutic approaches for HPV-induced carcinomas.  Our research aims are:

• Analysis of how HPV mediates inhibition of DNA damage repair.
• Study changes in energy and phospholipid metabolism in HPV-positive keratinocytes.
• Characterization of epigenetic and genetic alterations in HPV-positive stationary and migratory stem cells.

Research focus 2: Development of a therapeutic approach for treatment of high-risk alphaHPV-associated tumors in preclinical animal models.

The molecular mechanism of HR-HPV-induced tumorigenesis is based on inactivation of key cellular factors by viral oncoproteins. Mechanistic investigations have revealed that the viral E6 protein binds to the cellular E3 ligase E6AP and to the DNA binding domain (DBD) of p53. The recruitment of E6AP to the vicinity of p53 results in the ubiquitination and degradation of p53. We developed a Designed Ankyrin Repeat Protein (DARPin) that binds to the p53 DBD. We have shown that our novel p53-DARPin can block the interaction of E6 with p53, stabilize p53, and drive HPV-positive cells to undergo apoptosis. The advantage of this p53 specific DARPin is that it most probably blocks the binding of all HR-HPV E6 proteins to p53. Our aim is to characterize the potential of the p53-DARPin as a therapeutic strategy for either mono- or combinational therapy with cisplatin on orthotopically xenotransplanted HPV-positive cancer cell lines in immunologically humanized mice.

Research focus 3: Development of a therapeutic vaccination approach for the treatment of betaHPV-associated skin tumors in preclinical animal models.

Persistent betaHPV infections of the skin are well-controlled by the immune system in immunocompetent individuals and are largely asymptomatic. However, weakened immune control, for example, as a result of iatrogenic immunosuppression in organ transplant recipients, leads to high levels of betaHPV in the skin and, consequently, a significantly increased risk of skin cancer. Unlike mucosal HPV types, a prophylactic vaccine for the induction of neutralizing antibodies to protect against betaHPV infection as skin cancer prophylaxis is not available because of the ubiquitous nature of betaHPV infections and the plurality of betaHPV without defined high-risk types. Our aim is to develop vaccination approaches for therapeutic immune activation against betaHPV through "in situ autovaccination" as a treatment for skin cancer.