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GrB TWEAK: A Potential Novel Biologic for NSCLC Therapy


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My laboratory studies the cytokine named TWEAK and its cell surface receptor named Fn14 and their role in cancer biology. We reported previously that Fn14 is expressed at low levels in normal lung tissue but highly expressed in many non-small cell lung cancers (NSCLCs). Additionally, in collaboration with Dr. Rosenblum's research group we have successfully developed several Fn14-targeted fusion proteins that exhibit cytotoxic activity on cancer cells in vitro and in vivo. In this Lung Cancer Idea Award application we proposed to test the effects of these fusion proteins, and in particular the GrB-Fc-IT4 construct, on NSCLC cell growth in vitro (Aim 1) and in vivo (Aim 2). During year 1, we were able to demonstrate that two different Fn14-targeted proteins that use granzyme B (GrB) as the cell killing agent (TWEAK-GrB, GrB-Fc-IT4) exhibit pro-apoptotic activity when added to numerous Fn14-positive NSCLC cell lines. During year 2, we conducted additional work to inform the design of the in vivo studies. During our no-cost extension, we worked with Dr. Berens group to test whether the GrB-Fc-IT4 construct could inhibit lung cancer PDX growth in vivo. This data is described in this FINAL REPORT ADDENDUM.



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