Abstract 1776: Investigation into the enhancement of 20S proteasome-mediated proteolysis as a therapeutic for HPV-associated cervical cancer

Abstract Human papillomaviruses (HPVs) are one of the most common sexually transmitted infections (STIs) in the world. HPVs can be divided into two main categories, low-risk and high-risk. Low-risk HPVs do not cause cancer and can often be cleared by the infected person’s immune system. However, high-risk HPVs are responsible for approximately 5% of cancers worldwide - most commonly cervical cancer, and there is currently no cure once infection occurs. While prophylactic vaccines exist that can successfully prevent the infection of many high-risk HPVs, vaccination rates worldwide are low. After infection, the virus incorporates its genome into the host cell genome, and the cell begins to produce HPV proteins. In high-risk HPVs, two of these proteins, HPV E6 and E7, are oncoproteins with partially disordered structures. E6 and E7 proteins have many functions impacting cancer development, including inducing the degradation of tumor suppressor proteins p52 and pRB, respectively, through the ubiquitin-26S proteasome system (UPS). The removal of these cell cycle progression checkpoints allows for uncontrolled cell growth, which can promote cancer. The Tepe lab works on the development of small molecules which can increase the protein degradation capacity of the 20S proteasome, a protease that specifically degrades disordered proteins in a ubiquitin-independent manner. This project works to establish if the 20S proteasome can degrade HPV E6 and E7 proteins, and if the use of 20S proteasome enhancing small molecules can deplete levels in HPV+ cervical cancer cells. We have discovered that treatment with two of these compounds decreases E6 and E7 levels in a HPV18+ cervical cancer cell line and work is ongoing to determine if this impact is through 20S proteasome activation. Additionally, we are investigating if this decrease is enough to inhibit the out-of-control cell growth caused by E6 and E7. The goal of this project is to understand if 20S proteasome activators can be used as a therapy for HPV-mediated cervical cancer. Citation Format: Shannon M. Cartwright, Linh Le, Kate Hartnett, Jetze J. Tepe. Investigation into the enhancement of 20S proteasome-mediated proteolysis as a therapeutic for HPV-associated cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1776.