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To: zeta1961 who wrote (498)	3/5/2006 9:23:41 PM
From: zeta1961	Respond to of 802

Abstract Number: 3011 Presentation Title: Adenovirus- mediated FRNK gene transfer cooperates with Ad-p53 to augment drug-induced death of a transformed epithelial cell line Presentation Start/End Time: Monday, Apr 03, 2006, 1:00 PM - 5:00 PM Location: Exhibit Hall, Washington Convention Center Poster Section: 14 Poster Board Number: 4 Author Block: Lori J. Kornberg. University of Florida College of Medicine, Gainesville, FL Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed in many tumors of epithelial origin. Studies performed in several laboratories demonstrate that FAK, in part, regulates the cell cycle, survival, migration, and invasion in vitro and the initiation of metastasis in vivo. Hence, there is considerable interest in using FAK inhibitors as anti-cancer agents. I previously constructed a recombinant adenovirus (Ad-FRNK) which expresses FAK-Related Non-Kinase (FRNK), an inhibitor of FAK activity. Because FAK regulates cell survival through p53-dependent and p53- independent pathways, I postulated that Ad-FRNK and Ad-p53 would cooperate to increase drug-induced cytotoxicity. Transformed cells derived from the head and neck region were transfected with Ad-p53, Ad-FRNK, or both in the presence or absence of cytotoxic drugs. In the absence of drugs, co-transfection of RPMI 2650 cells, which contain functional p53, with Ad-FRNK and Ad-p53 induced more cytotoxicity and apoptosis than transfection with either virus alone. Likewise, co-transfection of RPMI 2650 cells with Ad-FRNK and Ad-p53 appeared to synergistically increase the cytotoxicity of paclitaxel, 5-fluorouracil, and etoposide, but not cisplatin. Surprisingly, Ad-FRNK and Ad-p53 did not cooperate to increase drug-induced cytotoxicity in SCC25 and FaDu cells which lack functional p53. The mechanism of the Ad-FRNK and Ad-p53 mediated enhancement of drug-induced cytotoxicity is currently being examined in RPMI 2650 cells. Comparisons of responsive and non-responsive cell lines may lend insight into the mechanisms of drug resistance. This work was funded by the Flight Attendant Medical Research Institute.

To: zeta1961 who wrote (498)	3/5/2006 9:34:23 PM
From: zeta1961	Respond to of 802

p53/pten/mtor pathway in GBB<NY Medical College> Abstract Number: 2201 Presentation Title: Coordination of tumor suppressor p53 and PI3K/PTEN-Akt-mTOR signaling pathways in glioblastoma multiforme pathogenesis Presentation Start/End Time: Monday, Apr 03, 2006, 8:00 AM -12:00 PM Location: Exhibit Hall, Washington Convention Center Poster Section: 18 Poster Board Number: 12 Author Block: Amrith Jamoona, Vahe M. Zohrabian, Alex Braun, Raj Murali, Meena Jhanwar-Uniyal. New York Medical College, Valhalla, NY Glioblastoma multiforme (GBM), the most common primary brain tumor in humans, comprises 12-15% of all intracranial neoplasm and 50-60% of astrocytic tumors. GBM has been characterized further as primary or secondary, with primary GBM denoting no antecedent neoplasm, and secondary GBM referring to that subset in which a less aggressive astrocytoma temporally precedes GBM. GBM results in mortality within one year of diagnosis despite aggressive treatment with current modalities. Mutation of the p53 tumor suppressor gene is the most frequent genetic alteration encountered in both subsets of GBM. Also, studies have linked increased angiogenic activity, most especially noted with increased transcription of the mitogen vascular endothelial growth factor (VEGF), to loss of wild-type p53. While elucidating altered signaling pathways in GBM, such as K-Ras and PI3K/PTEN-Akt-mTOR, has been of particular interest for the development of novel therapeutic interventions, the role of mutant p53 in signaling pathways associated with GBM pathogenesis remains elusive. The expression of p53 in primary and secondary GBM was assessed by immunohistochemistry. The GBM cell line LN-18, with intact PTEN and mutant p53 at codon 238, was used to investigate the involvement of PI3K/PTEN-Akt-mTOR and MAPK pathways in GBM progression. Quiescent cells were treated with Rapamycin, a specific inhibitor of protein kinase mTOR, or LY 294002 (LY), a PI3K signaling inhibitor. Platelet-derived growth factor (PDGF-BB) or extracellular matrix protein fibronectin (FN) was given to cells with or without pre-treatment with either Rapamycin or LY. Immunoblotting analysis was performed for levels of activated p70S6k, Akt, Stat3, and ERK1/2. The results of our study demonstrated that the expression of mutant p53 in primary GBM was confined to the cytoplasm of cells localized around the vasculature of the tumors. In contrast, samples of secondary GBM revealed nuclear mutant p53 expression with a diffuse pattern within tumors. In a separate study, we observed that aggressive tumors with the loss of wild-type p53 exhibited higher levels of VEGF. In accordance with the cooperation of p53 and PI3K/PTEN-Akt-mTOR, treatment with Rapamycin or LY significantly suppressed PDGF-BB or FN-induced phosphorylation of p70S6k at Thr389, a downstream substrate of mTOR. Furthermore, LY pre-treatment abolished PDGF-BB or FN-induced activation of Akt. Rapamycin and LY blocked the PDGF-BB or FN-induced phosphorylation of Stat3 at Ser727, an mTOR sensitive site, without influencing activation of ERK1/2. However, pre-treatment with LY inhibited PDGF-BB or FN-induced phosphorylation of ERK1/2. The results of this study shows that p53-associated cell survival pathways of GBM may contribute to drug resistance, and provides a mechanistic basis for enhancing mTOR-targeted GBM therapy by possibly combining mTOR and Ras/MAPK inhibitors.