AKT AND TUMOR SUPPRESSOR PATHWAYS IN MESOTHELIOMA

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Recent work suggests that asbestos and SV40 can act as co-carcinogens in the etiology of malignant mesothelioma (MM) and that AKT, a critical mediator of cell survival signals, is frequently activated in this disease. Human MMs often exhibit mutation of the NF2 tumor suppressor gene (TSG). Furthermore, homozygous deletion of the INK4a/ARF locus, which encodes the TSG products p16(INK4a) and p14(ARF), is frequently observed, although the relative contribution of p16(INK4a) versus p14(ARF) in MM pathogenesis has not been elucidated. Our hypothesis is that alterations of these three TSGs and expression of SV40 and AKT oncoproteins represent key disturbances in mesothelial cell physiology that collectively contribute to the development of MM. Understanding the molecular pathogenesis of MM and signaling pathways perturbed in this malignancy may elucidate invaluable molecular targets for therapeutic/preventive intervention, which is the broad, long-term objective of this project. The specific aims are: 1) Using in vitro and in vivo assays, we will determine whether restoration of NF2 expression can inhibit the growth and invasiveness of NF2-deficient MM cells. We will also conduct experiments to evaluate the therapeutic potential of adenovirus-mediated expression of NF2 and selective PAK inhibitors, as well as experiments to further elucidate merlin's function. 2) Using various murine knockout models, evaluate the relative contribution of Nf2, p19(Arf), and p16(lnk4a) inactivation to induction of MM by asbestos. Molecular genetic characterization of tumors derived from these mice will be conducted to establish the requirement for biallelic inactivation of the predisposing TSG and/or cooperation of oncogenes or other TSGs. We will compare susceptibility to asbestos-induced MM in p16(lnk4a)+/-, p14(Arf)+/- and doubly heterozygous Ink4a/Arf+/- mice in the same genetic background. In addition, determine if a SV40 Tag/tag mouse model is predisposed to MM spontaneously and/or following treatment with asbestos. 3) Further characterize the involvement of AKT in MM and determine whether pharmacologic inhibition of the AKT signaling pathway can repress MM cell growth and if combining an AKT pathway inhibitor with chemotherapeutic agents having a different mode of action results in increased efficacy. This Project will provide important insights regarding the involvement of key oncoproteins and TSG products in the pathogenesis of MM and will benefit from the availability of human and hamster MM samples through Project 1 and Cores B and C as well as from co-carcinogenesis and signaling work conducted in Project 2.