Targeting Chemoresistance in Small Cell Lung Cancer
Technical Report,01 Sep 2017,31 Aug 2018
Case Western Reserve University Cleveland United States
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Small cell lung cancer SCLC is the deadliest form of lung cancer and the most strongly associated with smoking history. Unfortunately, chemotherapy remains the main treatment option for patients with SCLC. Although this cancer typically responds extremely well, relapse is fast and largely inevitable. There are no effective therapies for relapsed tumors. The goal of our proposed study is to find new targets for drug therapy against relapsed SCLC tumors and provide continued hope for these patients. In this regard, we have identified a protein called HEPACAM2, which demonstrates unique, high expression in SCLC cell lines and tumors, making it a very attractive target. Knockdown of HEPACAM2 leads to cell cycle arrest, followed by apoptosis. Tankyrase 1 TNKS has been shown to polyADP-ribosylate HEPACAM2 and this modification is necessary for HEPACAM2 spindle localization and mitosis. Specific inhibitors of TNKS have been developed with little activity towards PARP1, a participant in the DNA damage response. We hypothesize that HEPACAM2 represents a novel therapeutic target in SCLC and propose two specific aims 1 to determine the expression and cellular localization of HEPACAM2 in SCLC,and 2 to determine if SCLC cells demonstrate increased sensitivity to TNKS inhibitors. HEPACAM2 expression will be tested at the mRNA and protein levels by qPCR and western blotting, respectively. Subcellular localization will be determined by confocal microscopy. Expression will be determined in multiple lung cancer cell lines, both SCLC and NSCLC, along with non-lung and normal cell lines as additional controls. Tumors will be investigated for expression, which will be correlated with survival. Inhibition of HEPACAM2 function will be tested by siRNA knockdown and small molecule inhibitors of TNKS using cell proliferation,migration and apoptosis assays. Synergism with other PARsylation inhibitors will also be explored.
- Medicine and Medical Research