High-risk human papillomaviruses (HPVs) are etiological agents of cervical cancer, the second most commoncause of cancer death in women worldwide. In addition, high-risk HPVs are also associated with a number ofother anogenital tract carcinomas, including, anal, vulvar and penile cancers as well as approximately 20% oforal cancers. Despite the recent introduction of a prophylactic vaccine that is to protect from infection withsome high-risk HPV types, it will be several decades before this will affect cervical cancer incidence and deathrates. Currently 10 women succumb to cervical cancer every day in the US, alone. HPV-associatedcarcinogenesis is driven by HPV E6/E7 oncoprotein expression; these proteins not only contribute to inductionof premalignant lesions, but also mechanistically contribute to malignant progression, a relatively rare eventthat generally occurs several years to decades after the initial infection. Progression is frequently associatedwith HPV genome integration into a host cellular chromosome, a terminal event for the viral life cycle. As aconsequence, E6 and E7 are the only viral proteins that are consistently expressed in cervical cancers. Thisproject is focused on investigating biological activities of high-risk HPV oncoproteins and to determine whetherthey 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 inhuman keratinocytes, a cellular tumor suppressor pathway that thwarts the proliferation of cells that havesuffered oncogenic alterations, which lead to aberrant cell proliferation.
Aim 2 is to determine the mechanisticbasis of HPV16 E7-induced autophagy in human keratinocytes and if/how this is connected to trophic sentinelsignaling. Since autophagy is an evolutionary ancient and conserved response to metabolic stress we willdetermine how HPV16 E7 expression causes increased metabolic requirements.
Aim 3 is to investigate themechanism by which HPV16 E6 abrogates HPV16 E7 induced trophic sentinel signaling. In this aim we willtest whether small molecule inhibitors of the pathways that E6 and E7 may be targeting and that are currentlyin the clinic may be harnessed as a novel therapeutic modality for HPV-associated lesions and cancers. Sincethe cellular pathways that are targeted by the E6 and E7 oncoproteins are frequently rendered dysfunctional bymutation in non-HPV associated human solid tumors, these studies may also be applicable for therapy of otherhuman cancers.
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. Despitethe recent introduction of a prophylactic HPV vaccine; it will be decades before such vaccination will decreaseincidence and mortality of cervical cancer and more than 10 women will succumb to HPV-associated cervicalcancer in the US every day for the next several decades. The focus of this proposal is to determine themolecular mechanisms by which HPV16 E7 oncoprotein expression predisposes cells to commit cellularsuicide; to delineate the mechanism by which the E6 oncoprotein holds this E7 activity in check and to performproof of principle experiments with small molecule inhibitors that are already in the clinic to determine whetherthis dormant cell death response may be harnessed as a therapeutic modality for HPV-associated lesions andcancers.
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