This project is based on the hypothesis that histone deacetylation is a crucial step in the loss of specifichomeostatic molecular signals in the transition from normal lung epithelium to in situ carcinoma, and finally toinvasive and metastatic lung cancer. Loss of TGF-G-induced tumor suppressor function in tumors is one suchsignal, and resistance to TGF-& in lung cancers occurs mostly through the loss of TISRII expression. Ourexperiments suggest that activation of the MAPK/ERK pathway causes down-regulation of TURN throughhistone deacetylation and further that DNA hypermethylation has no effect. In addition, we have observedthat TGF-li-induced tumor suppressor function is restored in TGF-li resistant lung cancer cells via exogenousTBRII expression or with the treatment of histone deacetylase (HDAC) inhibitors (HDI). The expression ofother tumor suppressor genes including PGDH, E-cadherin and p21cl' is also reduced in lung cancer cell linesdue to histone deacetylation. HDAC inhibitors are exciting new anticancer agents that inhibit proliferation, andinduce apoptosis and differentiation of tumor cells. Clinical trials of the HDI SAHA show that this inhibitor iswell tolerated at the doses required to hyperacetylate histones and show clinical potential for the treatment ofleukemias and solid tumors. We will study the clinical and molecular effects of SAHA in Phase II clinical trialsin patients with advanced or resectable non-small cell lung cancer. We have hypothesized that since themajority of lung tumors are resistant to TGF-S due to loss of TBRII, restoration of TGF-IJ signaling by SAHA (inaddition to its other antitumor effects) may be an effective therapeutic intervention alone or in combinationwith other agents in lung cancer. The overall goals of this project are 1) to determine the mechanism bywhich lung tumors become resistant to TGF-B tumor suppressor function, 2) to determine a molecular profilethat can identify candidate patients who are more likely to respond to SAHA, and 3) to identify novelsurrogate clinical markers of drug-induced inhibition of HDAC activity that will give insights into themechanisms of SAHA antitumor activity or resistance. The following Specific Aims are proposed: (1) Todetermine the mechanism for the loss of TGF-6-induced tumor suppressor function. (2) To determine theintracellular signaling pathways involved in the down-regulation of TIJRII and PGDH in primary lung cancer.(3) To determine whether restoration of TGF-IJ signaling by the HDI, SAHA can be a potential mechanism forits antitumor activity. (4) To determine if SAHA inhibits HDAC activity in patients and to test candidatemolecular profiles predictive of clinical benefit from SAHA.
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