Suppression of Lung Cancer Progression by Extracellular Par-4/SAC Protein

Lung cancer continues to be the leading cause of deaths in the world and there is a critical need for new targeted approaches for primary and metastatic lung cancer. Moreover, as 10% of non-small cell lung cancer (NSCLC) patients have brain metastasis at presentation, and another 25-40% (who may not have metastatic disease initially) eventually develop brain metastasis, strategies that allow suppression of both primary lung tumor growth and brain metastasis are critical for improving patient survival. Ample evidence suggests that lung cancer development and progression results from activation of cell survival pathways and roadblocks in the apoptotic pathways, contributing to uncontrolled tumor growth and metastasis. Based on this concept, we propose studies with the effector domain SAC of the pro-apoptotic gene Par-4 for suppression of primary lung tumors and brain metastasis in mouse models. As Par-4 or the SAC domain effectively kills cancer cells not normal cells in cell culture studies and mouse models, and our recent studies have shown that Par-4 or SAC is secreted and exerts its effects via cell surface receptor interaction, we hypothesize that extracellular (secreted) Par-4 or SAC will induce apoptosis and inhibit the growth and metastasis of lung cancer cells. The Specific Aims are: Specific Aim 1: Determine whether sPar-4 or sSAC produced by stromal cells in transgenic mice inhibits the growth of primary lung tumors. Specific Aim 2: Determine the ability of sPar-4 or sSAC to prevent metastasis of lung cancer, following bone marrow transplantation. The studies will allow us to determine whether extracellular Par-4/SAC have potential for treatment of lung cancer.