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Item Doses of radiation to the pericardium, instead of heart, are significant for survival in patients with non-small cell lung cancer(Elsevier, 2019-04) Xue, Jianxin; Han, Chengbo; Jackson, Andrew; Hu, Chen; Yao, Huan; Wang, Weili; Hayman, James; Chen, Weijun; Jin, Jianyue; Kalemkerian, Gregory P.; Matuzsak, Martha; Jolly, Struti; Kong, Feng-Ming (Spring); Radiation Oncology, School of MedicineBackground and purpose: Higher cardiac dose was associated with worse overall survival in the RTOG0617 study. Pericardial effusion (PCE) is a common cardiac complication of thoracic radiation therapy (RT). We investigated whether doses of radiation to the heart and pericardium are associated with PCE and overall survival in patients treated with thoracic radiation for non-small cell lung cancer (NSCLC). Materials and Methods: A total of 94 patients with medically inoperable/unresectable NSCLC treated with definitive RT in prospective studies were reviewed for this secondary analysis. Heart and pericardium were contoured consistently according to the RTOG1106 Atlas, with the great vessels and thymus of the upper mediastinal structures included in the upper part of pericardium, only heart chambers included in the heart structure. Clinical factors and dose-volume parameters associated with PCE or survival were identified via Cox proportional hazards modeling. The risk of PCE and death were mapped using DVH atlases. Results: Median follow-up for surviving patients was 58 months. The overall rate of PCE was 40.4%. On multivariable analysis, dosimetric factors of heart and pericardium were significantly associated with the risk of PCE. Pericardial V30 and V55 were significantly correlated with overall survival, but presence of PCE and heart dosimetric factors were not. Conclusion: PCE was associated with both heart and pericardial doses. The significance of pericardial dosimetric parameters, but not heart chamber parameters, on survival suggests the potential significance of radiation damage to the cranial region of pericardium.Item The effects of verteporfin on non-small cell lung cancer(2016-08) Ackerman, Todd R., Jr; Quilliam, Lawrence A.; Wells, Clark D.; Goebl, Mark G.Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers and is the leading cause of cancer death in the Unites States. Better treatments must be devised in order to improve the prognosis of this disease. Verteporfin, an FDA approved drug, has recently been reported to downregulate a potential core pathway of NSCLC, the Hippo pathway. The pathway consists of a kinase cascade to control the transcriptional coactivators YAP and TAZ. When these transcriptional coactivators lack phosphorylation of key residues, they are able to translocate into the nucleus and bind to the TEAD member of transcription factors. This augments transcription for genes responsible for proliferation, survival, and stem maintenance. In this study, we report that verteporfin limits proliferation and survival of NSCLC and may potentially be a viable treatment option. Inhibition of cell survival dose-dependently correlated with inhibition of YAP-TEAD transcription target CTGF. We also report the covalent homo-oligomerization of p62, a prominent protein involved with autophagy, with the introduction of verteporfin into NSCLC cells.Item Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone(Elsevier, 2020-02) Torrente, Laura; Prieto-Farigua, Nicolas; Falzone, Aimee; Elkins, Cody M.; Boothman, David A.; Haura, Eric B.; DeNicola, Gina M.; Biochemistry and Molecular Biology, School of MedicineAlterations in the NRF2/KEAP1 pathway result in the constitutive activation of NRF2, leading to the aberrant induction of antioxidant and detoxification enzymes, including NQO1. The NQO1 bioactivatable agent β-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species (ROS), which are actively scavenged in cells with NRF2/KEAP1 mutations. However, whether NRF2/KEAP1 mutations influence the response to β-lapachone treatment remains unknown. To address this question, we assessed the cytotoxicity of β-lapachone in a panel of NSCLC cell lines bearing either wild-type or mutant KEAP1. We found that, despite overexpression of NQO1, KEAP1 mutant cells were resistant to β-lapachone due to enhanced detoxification of ROS, which prevented DNA damage and cell death. To evaluate whether specific inhibition of the NRF2-regulated antioxidant enzymes could abrogate resistance to β-lapachone, we systematically inhibited the four major antioxidant cellular systems using genetic and/or pharmacologic approaches. We demonstrated that inhibition of the thioredoxin-dependent system or copper-zinc superoxide dismutase (SOD1) could abrogate NRF2-mediated resistance to β-lapachone, while depletion of catalase or glutathione was ineffective. Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to β-lapachone exposure. Our results suggest that NRF2/KEAP1 mutational status might serve as a predictive biomarker for response to NQO1-bioactivatable quinones in patients. Further, our results suggest SOD1 inhibition may have potential utility in combination with other ROS inducers in patients with KEAP1/NRF2 mutations.Item Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor–related Pneumonitis. An Official American Thoracic Society Research Statement(American Thoracic Society - AJRCCM, 2019-09-15) Sears, Catherine R.; Peikert, Tobias; Possick, Jennifer D.; Naidoo, Jarushka; Nishino, Mizuki; Patel, Sandip P.; Camus, Philippe; Gaga, Mina; Garon, Edward B.; Gould, Michael K.; Limper, Andrew H.; Montgrain, Philippe R.; Travis, William D.; Rivera, M. Patricia; Medicine, School of MedicineRationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined. Objectives: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis. Methods: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis. Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis. Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.Item A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor(Elsevier, 2015-07-15) Ishida, Naomasa; Fukazawa, Takuya; Maeda, Yutaka; Yamatsuji, Tomoki; Takaoka, Munenori; Haisa, Minoru; Yokota, Etsuko; Shigemitsu, Kaori; Morita, Ichiro; Kato, Katsuya; Matsumoto, Kenichi; Shimo, Tsuyoshi; Okui, Tatsuo; Bao, Xiao-Hong; Hao, Huifang; Grant, Shawn N.; Takigawa, Nagio; Whitsett, Jeffrey A.; Naomoto, Yoshio; Department of Medicine, Division of Hematology and Oncology, IU School of MedicineThe PI3K–AKT pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment. We previously reported that a novel PI3K inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC.