Lung cancer is the leading cause of cancer-related mortality and most patients with lung cancer have poor prognosis due to chemoresistance. Development of more effective, new drugs that act through basic molecular mechanisms, including apoptosis, to overcome chemoresistance is critical to improve the prognosis of patients with lung cancer. Bcl2, a major antiapoptotic molecule, is extensively expressed in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells. One major factor implicated in the resistance to chemotherapy is the overexpression of Bcl2, suggesting that Bcl2 should be an attractive therapeutic target in human lung cancer. The BH4 domain of Bcl2, which encompasses an amphipathic a1-helix, has been demonstrated to be a required domain for Bcl2's antiapoptotic function. Therefore, we chose the BH4 domain as a docking site for screening of small molecules that may inactivate Bcl2 using the computerized DOCK program and a database from the National Cancer Institute (NCI). Two hundred of the compounds determined to have the highest affinity were obtained from the NCI and tested for their effects on cell death. Four of the two hundred compounds have been found to potently induce apoptosis of various human lung cancer cells. We named these compounds as small molecule Bcl2 inhibitors (i.e. SMBI-1~4). Intriguingly, SMBI-1~4 represent significantly less apoptotic effect on normal small airway epithelial cells as compared to lung cancer cells, indicating a selectivity of these compounds for tumor cells. The lead SMBI potently represses tumor growth in association with increased apoptosis in tumor tissues in NSCLC animal models. These preliminary findings suggest that SMBI(s) may have great potential to be developed as a new class of anti-lung cancer drugs. Modulation of the mTOR pathway is being clinically developed as an advanced strategy for lung cancer treatment. However, expression of Bcl2 is associated with resistance of lung cancer cells to mTOR inhibitor(s). Thus, an effective way to enhance the sensitivity of lung cancer cells to mTOR inhibition is to combine a mTOR inhibitor with a Bcl2 inhibitor (i.e. SMBI). Our preliminary data reveal that treatment of lung cancer cells with a combination of SMBI and rapamycin not only synergistically induces apoptosis but also augments growth inhibition, suggesting that the combined mTOR and Bcl2 inhibition may additively suppress lung tumor growth, leading to sustained regression in vivo. To critically test these hypotheses, we have identified two specific aims: (1) To determine the mechanism(s) by which SMBI(s) induces apoptosis in human lung cancer cells;(2) To determine whether SMBI(s) represses tumor growth in both SCLC and NSCLC xenografts. Studies will evaluate whether co-targeting Bcl2 and mTOR by a combination of SMBI and a mTOR inhibitor synergistically improves the anti-lung cancer efficacy in vivo. From the results, it is expected that a new class of anti-cancer drugs and a more effective approach for cancer treatment will be developed by co-targeting Bcl2 and mTOR.
Project Narrative Most patients with lung cancer have a poor prognosis due to chemoresistance. Development of more effective new drugs that act through basic molecular mechanisms to overcome chemoresistance is critical to improve the prognosis of patients with lung cancer. Studies in this proposal are designed to develop small molecules as novel anti-lung cancer drugs that inhibit the antiapoptotic function of Bcl2 in lung cancer cells.
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