High-risk human papillomaviruses (HPVs) are etiological agents of cervical cancer, the second most common cause of cancer death in women worldwide. In addition, high-risk HPVs are also associated with a number of other anogenital tract carcinomas, including, anal, vulvar and penile cancers as well as approximately 20% of oral cancers. Despite the recent introduction of a prophylactic vaccine that is to protect from infection with some high-risk HPV types, it will be several decades before this will affect cervical cancer incidence and death rates. Currently 10 women succumb to cervical cancer every day in the US, alone. HPV-associated carcinogenesis is driven by HPV E6/E7 oncoprotein expression;these proteins not only contribute to induction of premalignant lesions, but also mechanistically contribute to malignant progression, a relatively rare event that generally occurs several years to decades after the initial infection. Progression is frequently associated with HPV genome integration into a host cellular chromosome, a terminal event for the viral life cycle. As a consequence, E6 and E7 are the only viral proteins that are consistently expressed in cervical cancers. This project is focused on investigating biological activities of high-risk HPV oncoproteins and to determine whether they could be harnessed as a novel therapeutic modality for high-risk HPV-associated lesions and cancers.
In aim 1, it is proposed to determine the mechanistic basis of HPV16 E7-induced trophic sentinel signaling in human keratinocytes, a cellular tumor suppressor pathway that thwarts the proliferation of cells that have suffered oncogenic alterations, which lead to aberrant cell proliferation.
Aim 2 is to determine the mechanistic basis of HPV16 E7-induced autophagy in human keratinocytes and if/how this is connected to trophic sentinel signaling. Since autophagy is an evolutionary ancient and conserved response to metabolic stress we will determine how HPV16 E7 expression causes increased metabolic requirements.
Aim 3 is to investigate the mechanism by which HPV16 E6 abrogates HPV16 E7 induced trophic sentinel signaling. In this aim we will test whether small molecule inhibitors of the pathways that E6 and E7 may be targeting and that are currently in the clinic may be harnessed as a novel therapeutic modality for HPV-associated lesions and cancers. Since the cellular pathways that are targeted by the E6 and E7 oncoproteins are frequently rendered dysfunctional by mutation in non-HPV associated human solid tumors, these studies may also be applicable for therapy of other human cancers.

Public Health Relevance

Infections with high-risk human papillomaviruses (HPVs) have been associated with a variety human cancers, including cervical carcinoma, the second most common cause of cancer death in women worldwide. Despite the recent introduction of a prophylactic HPV vaccine, it will be decades before such vaccination will decrease incidence and mortality of cervical cancer and more than 10 women will succumb to HPV-associated cervical cancer in the US every day for the next several decades. The focus of this proposal is to determine the molecular mechanisms by which HPV16 E7 oncoprotein expression predisposes cells to commit cellular suicide, to delineate the mechanism by which the E6 oncoprotein holds this E7 activity in check and to perform proof of principle experiments with small molecule inhibitors that are already in the clinic to determine whether this dormant cell death response may be harnessed as a therapeutic modality for HPV-associated lesions and cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA081135-14
Application #
8208218
Study Section
Special Emphasis Panel (ZRG1-IDM-P (02))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2000-02-15
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
14
Fiscal Year
2012
Total Cost
$293,049
Indirect Cost
$128,876
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Meyers, Jordan M; Munger, Karl (2014) The viral etiology of skin cancer. J Invest Dermatol 134:E29-32
Mesri, Enrique A; Feitelson, Mark A; Munger, Karl (2014) Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe 15:266-82
Mack, Hildegard I D; Munger, Karl (2013) The LKB1 tumor suppressor differentially affects anchorage independent growth of HPV positive cervical cancer cell lines. Virology 446:9-16
Yu, Yueyang; Munger, Karl (2013) Human papillomavirus type 16 E7 oncoprotein inhibits the anaphase promoting complex/cyclosome activity by dysregulating EMI1 expression in mitosis. Virology 446:251-9
Spangle, Jennifer M; Munger, Karl (2013) The HPV16 E6 oncoprotein causes prolonged receptor protein tyrosine kinase signaling and enhances internalization of phosphorylated receptor species. PLoS Pathog 9:e1003237
Meyers, Jordan M; Spangle, Jennifer M; Munger, Karl (2013) The human papillomavirus type 8 E6 protein interferes with NOTCH activation during keratinocyte differentiation. J Virol 87:4762-7
Spangle, Jennifer M; Ghosh-Choudhury, Nayana; Munger, Karl (2012) Activation of cap-dependent translation by mucosal human papillomavirus E6 proteins is dependent on the integrity of the LXXLL binding motif. J Virol 86:7466-72
Hellner, Karin; Munger, Karl (2011) Human papillomaviruses as therapeutic targets in human cancer. J Clin Oncol 29:1785-94
Zhou, Xiaobo; Munger, Karl (2010) Clld7, a candidate tumor suppressor on chromosome 13q14, regulates pathways of DNA damage/repair and apoptosis. Cancer Res 70:9434-43
Spangle, Jennifer M; Munger, Karl (2010) The human papillomavirus type 16 E6 oncoprotein activates mTORC1 signaling and increases protein synthesis. J Virol 84:9398-407

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