TARGETING HISTONE DEACETYLASES IN NSCLC

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This project is based on the hypothesis that histone deacetylation is a crucial step in the loss of specific homeostatic molecular signals in the transition from normal lung epithelium to in situ carcinoma, and finally to invasive and metastatic lung cancer. Loss of TGF-G-induced tumor suppressor function in tumors is one such signal, and resistance to TGF-& in lung cancers occurs mostly through the loss of TISRII expression. Our experiments suggest that activation of the MAPK/ERK pathway causes down-regulation of TURN through histone deacetylation and further that DNA hypermethylation has no effect. In addition, we have observed that TGF-li-induced tumor suppressor function is restored in TGF-li resistant lung cancer cells via exogenous TBRII expression or with the treatment of histone deacetylase (HDAC) inhibitors (HDI). The expression of other tumor suppressor genes including PGDH, E-cadherin and p21cl" is also reduced in lung cancer cell lines due to histone deacetylation. HDAC inhibitors are exciting new anticancer agents that inhibit proliferation, and induce apoptosis and differentiation of tumor cells. Clinical trials of the HDI SAHA show that this inhibitor is well tolerated at the doses required to hyperacetylate histones and show clinical potential for the treatment of leukemias and solid tumors. We will study the clinical and molecular effects of SAHA in Phase II clinical trials in patients with advanced or resectable non-small cell lung cancer. We have hypothesized that since the majority of lung tumors are resistant to TGF-S due to loss of TBRII, restoration of TGF-IJ signaling by SAHA (in addition to its other antitumor effects) may be an effective therapeutic intervention alone or in combination with other agents in lung cancer. The overall goals of this project are 1) to determine the mechanism by which lung tumors become resistant to TGF-B tumor suppressor function, 2) to determine a molecular profile that can identify candidate patients who are more likely to respond to SAHA, and 3) to identify novel surrogate clinical markers of drug-induced inhibition of HDAC activity that will give insights into the mechanisms of SAHA antitumor activity or resistance. The following Specific Aims are proposed: (1) To determine the mechanism for the loss of TGF-6-induced tumor suppressor function. (2) To determine the intracellular 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 for its antitumor activity. (4) To determine if SAHA inhibits HDAC activity in patients and to test candidate molecular profiles predictive of clinical benefit from SAHA.