The human papillomaviruses (HPVs) are causally linked to a number of human cancers. Over 140 different HPVs have been identified and a subset of them, referred to as the high-risk HPVs, is associated with cancer. Virtually all cases of cervical cancer are attributable to infection by HPV. These high-risk HPVs are also associated with other anogenital cancers and with approximately 20% of oropharyngeal cancers. The current VLP-based vaccines prevent infection by only 2 of the 14 high-risk HPV types and vaccination rates in young women vary greatly among countries; in the United States the rate of vaccination among young women is presently only about 30%. Despite the availability of VLP-based preventive vaccines against HPV16 and HPV18 (that account for roughly 70% of cervical cancers), there is a need for therapeutic options to target HPV-associated cancers and the persistent infections that give rise to these cancers. With 500,000 new cases of cervical cancer diagnosed worldwide annually and since current vaccines having no therapeutic benefit for the millions of already infected women, there is an unmet need for the therapeutic options. Two viral oncogenes, E6 and E7, drive HPV-associated carcinogenesis. Perturbing the functions of E6 and E7 (or their expression) in HPV-associated malignancies provides the potential for therapeutic development. Research in my laboratory has been focused on the papillomaviruses for nearly 40 years and has contributed significantly to critical aspects of our current understanding of the molecular mechanisms underlying the oncogenicity of these papillomavirus-host cell interactions. This OIA application is based on my vision to translate what we know and continue to learn about these interactions to identify therapeutic targets for treating HPV-positive cancers and precancers. I propose to continue using unbiased approaches to learn more about the cellular interactions of the viral E6 and E7 oncoproteins, as well as of the E2 regulatory protein that controls viral oncogene expression, with the goal of identifying cellular targets and pathways that could serve as therapeutic targets. Major transforming activities of E6 and E7 that were discovered in my laboratory nearly 25 years ago are the inactivation of p53 and the retinoblastoma family proteins. E6 targets p53 inactivation through ubiquitin-mediated proteolysis by hijacking the cellular ubiquitin ligase E6-associated protein (E6AP). Inhibition of E6 or E6AP in HPV-positive cells leads to p53 stabilization resulting in apoptosis or senescence due to E7-induced oncogenic stress. Therefore my highest priority is targeting E6/E6AP mediated proteolysis of p53. Despite the discovery of E6AP and this ubiquitylation pathway in my laboratory over 20 years, surprisingly little has been learned about its regulation or the identity of other genes that are involved in its regulation. Ongoing research in my laboratory is focused on (1) identifying genes and pathways involved in E6-mediated ubiquitylation of p53 and (2) identifying small molecules that stabilize p53 in HPV-positive cancers.

Public Health Relevance

Specific high-risk human papillomaviruses are associated with cancer. Despite the availability of VLP-based preventive vaccines against HPV16 and HPV18, there is an unmet need for therapeutic options for HPV associated cancers and precancers. The goal of this proposal is to extend our knowledge of the mechanisms by which these papillomavirus function, with an eye towards identifying potential therapeutic targets for the development of specific therapies for HPV-associated cancers and precancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA197262-05
Application #
9843492
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2016-01-01
Project End
2022-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Bentley, Peris; Tan, Min Jie Alvin; McBride, Alison A et al. (2018) The SMC5/6 complex interacts with the papillomavirus E2 protein and influences maintenance of viral episomal DNA. J Virol :
Kühnle, Simone; Martínez-Noël, Gustavo; Leclere, Flavien et al. (2018) Angelman syndrome-associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome. J Biol Chem 293:18387-18399
Chiang, Cindy; Pauli, Eva-Katharina; Biryukov, Jennifer et al. (2018) The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling. J Virol 92:
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White, Elizabeth A; Münger, Karl; Howley, Peter M (2016) High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation. MBio 7: