Prevention of HPV-Associated Anogenital Cancers Using HIV Protease Inhibitors

At a Glance

Human papillomavirus (HPV) is the most common sexually transmitted disease in the United States and the number one risk factor for developing anogenital cancers, such as squamous cell carcinoma of the anus (SCCA). Once HPV-driven anal pre-cancers are diagnosed, there are few treatment options that are effective or well-tolerated. This project further explored recent findings that show select FDA-approved protease inhibitors, previously used orally to treat HIV infection, can also be used topically to prevent HPV-associated cancers, in particular SCCA. This team of interdisciplinary researchers worked to determine the molecular mechanisms supporting these effects and repurpose these drugs as an approach for anal cancer prevention in Wisconsin.

The Challenge

Human papillomavirus (HPV) is the most common sexually transmitted disease in the United States – an estimated 79 million Americans are currently infected— and the number one risk factor for developing anogenital cancers, such as squamous cell carcinoma of the anus (SCCA). In Wisconsin, HPV-positive SCCA disproportionately affects underserved populations, particularly those living with HIV. Once HPV-driven anal pre-cancers are diagnosed, there are few treatment options that are effective or well-tolerated.

Project Goals

The long-term goal of this research is to develop a new strategy to prevent HPV-associated cancers, particularly SCCA, especially in high-risk patients such as people living with HIV. The project’s primary goal was to determine if the anti-HPV effects of HIV-1 protease inhibitors can be used to prevent HPV-associated SCCA, especially in the high-risk, underserved HIV positive population in Wisconsin.

Results

The research team discovered that HIV protease inhibitors are operating through induction of a cellular signaling pathway known as the integrated stress response (ISR), suggesting the ISR as a target for anti-HPV interventions. They found that PI-mediated activation of the ISR correlated strongly with downregulation of HPV16 E6 and E7 oncoprotein expression, whereas alternative ISR agonists caused depletion of E6 and E7 proteins.

The team conducted experiments using mouse models of SCCA as tools to define the effects, dosing, and timing of treatment for protease inhibitors to prevent anogenital cancers. The researchers specifically used saquinavir (SQV), a protease inhibitor medication used to treat HIV. The findings suggest that topical SQV decreases histological progression of anal disease in HPV transgenic mice regardless of DMBA (topical carcinogen) treatment without leading to local side effects or significant systemic absorption.

The research team performed a phase 1 clinical trial of protease inhibitors in patients living with HIV with high-grade anal intraepithelial neoplasia to establish safety and provide preliminary data on protease inhibitor efficacy. Four patients successfully completed the clinical trial with no side effects and no systemic absorption of the drug. The UW Carbone Cancer Center will continue to support this clinical trial until completion.