Acute Promyelocytic Leukemia (APL) has become a paradigm for the study of cancer pathogenesis and cancer therapy for its distinctive features: i) a distinct block of differentiation at the promyelocytic stage of myeloid hemopoiesis; ii) the invariable association with specific translocations which always involve a prototypical transcription factor such as the Retinoic Acid Receptor alpha (RARalpha); iii) the exquisite sensitivity of APL blasts to the differentiating action of Retinoic Acid (RA) and Arsenicals. Furthermore, our more recent analysis of the aberrant transcriptional mechanisms underlying APL pathogenesis has led us to investigate the efficacy, in this leukemia and other cancers, of chromatin remodeling drugs such as Histone Deacetylase Inhibitors (HDACIs). Here we propose to define genetically, in vivo, through the use, generation and validation of several mouse models of APL, how aberrant transcriptional activity and inappropriate chromatin remodeling can lead to cancer and resistance to therapy. We will test whether the pharmacological interference with these altered transcriptional processes can be exploited for cancer treatment and prevention by testing in these mouse models of APL the clinical efficacy of HDACIs also in combination with other anti-neoplastic agents. Furthermore, we will generate and validate additional murine models of leukemia and lymphoma caused by aberrant chromatin remodeling and transcription, and test the efficacy of this new category of anti-tumoral agents in these new cancer models. HDACIs and/or anti-neoplastic drug combinations will also be tested as broad anti-neoplastic and/or chemopreventive agents in solid tumor mouse models such as our recently generated Pten+/- mice and p53-/- mice. We also propose to synthesize new HDACIs, which we will design through a crystal structure/function analysis of the various mammalian HDACs and HDAC complexes. The clinical relevance of these new and more specific HDACIs will subsequently be tested in our mouse models of cancer. Furthermore, we propose to identify the pre-programmed set of genes whose transcriptional modulation induces cell-cycle arrest, apoptosis and cellular differentiation in response to HDACIs and/or RA using two methods: 1) immunoselection of target genes by chromatin immunoprecipitation (ChIP assay) of a) acetylated histones and b) RARalpha and X-RARalpha oncoproteins; and 2) differential expression of RNA using DNA arrays. These genes might constitute new """"""""markers of response"""""""" to HDACIs/RA treatment, new target genes for further therapeutic intervention, and will define the mechanisms underlying the anti-tumoral action of these drugs.
Showing the most recent 10 out of 25 publications
