Patrick R. Menden, MS
Position title: Lambert Laboratory 2010-2013
Research Title: Inhibition of the mTOR and MEK/ERK Pathways Arrests Growth of Human Anal Caner Tumorgrafts and Causes Regression of Recurrent Cancer
Research Summary: Patrick’s project investigated the capability of the Human Papilloma Virus (HPV) to dysregulate cell signaling pathways which contribute to viral amplification and tumorigenesis. HPV is known to infect squamous epithelial cells. The viral activity and amplification is closely tied to the development of these cells. As the cells divide a subset of the daughter cells advance to the super basal cell layer and HPV is activated. Here HPV expresses its proteins and commandeers the cellular replication machinery to amplify its own genome. Patrick’s research specifically looked at the ability of the HPV oncogenes E6 and E7 to activate the Phosphoinositide 3-kinase (PI3K) and its downstream effectors namely the AKT/mTOR and MEKIERK pathways. There are endogenous inhibitors for the key components of these pathways to prevent their over activity namely DEPTOR and N HERF-1 which are two potential targets for E6/E7. Degradation NH ERF-1 and DEPTOR could result in over activity of PI3K and mTOR respectively resulting in a cascade effect that activates eiF48, ERK, and AKT resulting in a global increase of translation, transcription, and advancement of the cell cycle. 1 am using cell lysates derived from cells that express E6 and or E7 and attempting to observe E6/DEPTOR, E7/DEPTOR interaction by making immunoprecipitation assays with recombinant DEPTOR followed by western blotting. Furthermore, Patrick transfected cells with DEPTOR to perform the reciprocal assay by attempting to IP DEPTOR with E6 or E7. He looked to influence of constitutively active PI3K signaling on the onset and development of HPV associated cancers (cervical, anal, head and neck) using the HPV transgenic mouse model for cancer. Patrick generated mice that express either E6 or E7 and a conditional! Y constitutively active P13K mutant directed to the squamous epithelial. He prepared to activate the PI3K mutant so that he was able to determine if there is any synergy between PI3K activity and the HPV.