bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4090: Preclinical pharmacokinetics of CASC-578, a novel, selective, potent, and orally bioavailable small molecule checkpoint kinase 1 inhibitor
Authors: Leviten Dina , Sierra Teresa , Dozier Ashley , Boyce Richard , Boyle Bob , Peterson Scott , Vo Alex C. 
Published: July 2017

Abstract
Introduction: Checkpoint kinase 1 (Chk1) is a serine/threonine protein kinase that regulates cell division in response to genotoxic stress by arresting cell cycle progression in the S & G2 phases. Pharmacological inhibition of Chk1 is proposed to selectively uncouple the completion of DNA replication from G2/M phase transition in tumor cells that have impaired DNA damage response networks, resulting in mitotic catastrophe and cell death. CASC-578 is a novel small molecule inhibitor of Chk1 that is selective, highly potent and orally bioavailable in multiple preclinical species.
Methods: The in vitro ADME properties of CASC-578 were evaluated, including in vitro intrinsic microsomal clearance, Caco2 permeability, plasma protein binding and stability, blood to plasma partitioning, cytochrome P450 inhibition and induction, and transporter inhibition. Pharmacokinetic studies of CASC-578 were conducted in mice, rats, and cynomolgus monkeys as either single dose (IV and/or PO) or repeat dose (PO only). Multiple oral dose pharmacokinetic studies were conducted in mice, rats and cynomolgus monkeys for 5-7 days.
Results: CASC-578 is highly bound in plasma protein across all species. The apparent permeability is high in Caco2 bi-directional transport study and correlated well with a rapid absorption profile observed in vivo. CASC-578 is not a substrate of P-glycoporotein (efflux =1). There was no direct nor time dependent inhibition on human CYP450 enzymes, and only a slight induction of CYP3A4 was seen at 10 uM drug concentration in a transporter cell-based induction assay. In all animal species, CASC-578 exhibited species-dependent systemic clearance resulting from both phase I and phase II metabolism, and a moderate to high volume of distribution. The elimination kinetics appeared to be monophasic. Oral bioavailability was high in all species studied (&gt;60% F). There was no significant difference in the pharmacokinetics of the drug between genders. Maximal plasma concentration and total drug exposure (AUC) appeared to be proportional from repeat dose studies. Overall, CASC-578 has very desirable drug-like properties and ideal pharmacokinetics for an oral once daily drug, and represents a suitable candidate for clinical development as a novel potential therapeutic approach for the treatment of solid and hematological malignancies
Citation Format: Dina Leviten, Teresa Sierra, Ashley Dozier, Richard Boyce, Bob Boyle, Scott Peterson, Alex C. Vo. Preclinical pharmacokinetics of CASC-578, a novel, selective, potent, and orally bioavailable small molecule checkpoint kinase 1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4090. doi:10.1158/1538-7445.AM2017-4090
Abstract 4092: Targeting compensatory mechanisms of resistance to phosphatidylinositol 3-kinase inhibitors in head and neck squamous cell carcinoma
Authors: Michmerhuizen Nicole L. , Leonard Elizabeth , Foltin Susan K. , Kulkarni Aditi , Carey Thomas E. , Bradford Carol R. , Jiang Hui , Brenner Chad 
Published: July 2017

Abstract
Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated, oncogenic pathway in this cancer type. Despite the frequency of activating mutations or amplification in PIK3CA (the gene encoding the catalytic subunit of PI3K), targeted inhibitors of PI3K have not shown clinical efficacy as monotherapies. We tested a panel of more than 20 patient-derived oral cavity squamous cell carcinoma (OCSCC) cell lines, which were profiled by Nimblegen V3 exome sequencing, and observed resistance to PI3K inhibitors despite PIK3CA copy number amplification and/or mutation. Of six inhibitors tested, only alpha-isoform selective and pan-PI3K agents were somewhat effective; these inhibitors, despite on-target and downstream activity, did not cause an appreciable reduction in cell viability when administered at submicromolar concentrations. We hypothesized that other oncogenic pathways might still be functional in the presence of PI3K inhibitors and might serve as mediators of this resistance. For example, our group and others have evaluated co-dependence on the Ras-MEK-ERK pathway in OCSCC, showing that this serves as a compensatory mechanism in some models. In order to more fully characterize other novel mechanisms of resistance, we have also developed a high-throughput screening approach that utilizes a resazurin cell viability assay. This screen serves as an unbiased means of testing ~1400 inhibitors as monotherapies and in combination with alpha-isoform selective PI3K inhibitor HS-173 and pan-PI3K inhibitor BKM120 in several OCSCC models. Further validation of “hits” from this screen, which are drugs that are effective in combination but not as monotherapies, may identify additional resistance mechanisms and lead to combination therapies to improve HNSCC patient prognosis.
Citation Format: Nicole L. Michmerhuizen, Elizabeth Leonard, Susan K. Foltin, Aditi Kulkarni, Thomas E. Carey, Carol R. Bradford, Hui Jiang, Chad Brenner. Targeting compensatory mechanisms of resistance to phosphatidylinositol 3-kinase inhibitors in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4092. doi:10.1158/1538-7445.AM2017-4092
Abstract 4103: IL-6 dynamics regulate neuroendocrine transformation in gefitinib acquired resistance EGFR mutant lung cancer cells
Authors: Wu Shang-Yin , Yeh Hsuan-Heng , Hung Chun-Hua , Lin Chien-Chung , Su Wen-Pin , Su Wu-Chou 
Published: July 2017

Abstract
Transformation to small-cell lung cancer (SCLC, one of aggressive neuroendocrine [NE] tumor) is reported when activating epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer acquired resistance to tyrosine kinase inhibitors (TKI, such as gefitinib). IL-6 activation confers to acquire TKI resistance and associates with p53 and RB inactivation those are SCLC hallmark changes. Whether NE transformation could phenocopy in isogenic acquired resistance cell line and the role of IL-6 in this process remain unknown. We established 827GRs (including 827GR, 827GR+ and 827GR.M6) acquired resistance to gefitinib from HCC827 cells by long term stepwise treated with gefitinib and they still had EGFR exon 19 deletion without acquired T790M. 827GR was parental resistance line with unstable gefitinib resistance in drug-free medium by passage. We maintained 827GR in medium with or without 1μM gefitinib over 6 months to generate stable clones: 827GR+ and 827GR.M6. 827GRs had SCLC hallmark changes, i.e., inactivation of p53, RB and Notch by western blot and gene set enrichment analysis. Compared to HCC827, 827GRs were more sensitive to cisplatin and etoposide but not paclitaxel. IL-6 level was positive correlated with gefitinib resistance among 827GRs by cytokine array and ELISA. Interestingly, among 827GRs, 827GR.M6 harbored low IL-6 secretion had obviously NOTCH-ASCL1-DLL3 alteration, high NE marker expression and significant inter-rater agreement with selected Byers’ SCLC gene signature than high IL-6 secretion 827GR+, suggesting IL-6 dynamics might regulate NE marker expression. IL-6 genetic manipulation in HCC827 and 827GR+ also demonstrated this phenomenon. Moreover, IL-6 dynamics correlate with NE expression also showed in patient derived lung cancer cell line in published microarray dataset (GSE64322). In conclusion, our work demonstrated activating EGFR mutant lung cancer acquired resistance to TKI with NE transformation could phenocopy in isogenic cell line model and IL-6 dynamics might regulate this process.
Citation Format: Shang-Yin Wu, Hsuan-Heng Yeh, Chun-Hua Hung, Chien-Chung Lin, Wen-Pin Su, Wu-Chou Su. IL-6 dynamics regulate neuroendocrine transformation in gefitinib acquired resistance EGFR mutant lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4103. doi:10.1158/1538-7445.AM2017-4103
Abstract 4104: Intrinsic and acquired resistance to cetuximab in colorectal cancer patients
Authors: Bray Steven M. , Lee Jeeyun , Kim Seung Tae , Ebert Philip J. , Calley John N. , Wulur Isabella H. , Gopalappa Thejaswini , Wong Swee Seong , Qian Hui-Rong , Ting Jason C. , Liu Jiangang , Willard Melinda D. , Aggarwal Amit , Novosiadly Ruslan D. , Kim Hee-Cheol , Reinhard Christoph 
Published: July 2017

Abstract
Anti-EGFR antibodies, such as cetuximab, are effective therapies for many late-stage colorectal cancer (CRC) patients; unfortunately, many tumors are initially unresponsive while others show initial efficacy but eventually develop acquired resistance. Genomic studies of patient tumors, cell lines, and xenograft models have identified putative anti-EGFR resistance markers, including mutations in KRAS, NRAS, BRAF, PIK3CA, and the EGFR extracellular domain, as well as amplifications in ERBB2 and MET. In order to further confirm and identify new resistance mechanisms to anti-EGFR treatment in CRC, we performed retrospective genomic profiling of 25 CRC patients treated at Samsung Medical Center from 2006-2015. Patients received cetuximab containing chemo regimens with varying duration of responses, including acquired resistance cases. Our analysis identifies mutations in receptor tyrosine kinases, such as EGFR, NTRK1, and PDGFRA, as well as RAS/MAPK pathway genes that affect cetuximab response. We also uncover genomic alterations in ERBB2 and c-KIT as potential novel mechanisms regulating sensitivity to anti-EGFR antibodies. Additional genomic analyses of acquired resistance tumors and in vitro studies of a patient-derived cell line provide added insights into clonal selection and signaling pathways that bypass the EGFR blockade. Overall, our study elucidates important new facets in the landscape of anti-EGFR resistance mechanisms.
Note: This abstract was not presented at the meeting.
Citation Format: Steven M. Bray, Jeeyun Lee, Seung Tae Kim, Philip J. Ebert, John N. Calley, Isabella H. Wulur, Thejaswini Gopalappa, Swee Seong Wong, Hui-Rong Qian, Jason C. Ting, Jiangang Liu, Melinda D. Willard, Amit Aggarwal, Ruslan D. Novosiadly, Hee-Cheol Kim, Christoph Reinhard. Intrinsic and acquired resistance to cetuximab in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4104. doi:10.1158/1538-7445.AM2017-4104
Abstract 411: In vivo pooled shRNA library identifies KPNB1 as a new drug target for epithelial ovarian cancer
Authors: Kodama Michiko , Kodama Takahiro , Yoshihara Kosuke , Hashimoto Kae , Mabuchi Seiji , Sawada Kenjiro , Kimura Tadashi , Copeland Neal , Jenkins Nancy 
Published: July 2017

Abstract
Objective
Epithelial ovarian cancer (EOC) is a most lethal cancer in gynecology, of which cure rate is 30%. To seek its new therapeutic targets, we performed in vivo loss of function screen.
Method
Human EOC cell line, SKOV3, was transduced with pooled druggable shRNA library containing 42450 shRNAs targeting 7490 genes. Transduced cells were intraperitoneally injected into 12 female nude mice and monitored for PC tumor formation. Genomic DNA of 12 biggest PC tumors were sequenced to identify shRNAs depleted in these tumors.
Results
Ten potential drug targets were identified, including 2 known oncogenes, ERBB2 and RAF1. Second highest ranked gene, KPNB1, is known as a nuclear transporter. KPNB1 inhibition significantly decreased and overexpression increased in vitro cell proliferation in multiple EOC cell lines. KPNB1 inhibition caused multi-phase cell cycle delay at both of G1/S and G2/M transition via elevation of p21 and p27 and induced apoptosis. KPNB1 inhibition significantly decreased in vivo tumor formation through the same mechanism as in vitro, because more cleaved PARP and less Ki67 positive cells were found in KPNB1 knockdown tumors via immunochemical staining. We found a positive correlation between KPNB1 mRNA levels and poor survival of EOC patients, suggesting the oncogenic role of KPNB1 in human EOC. Comprehensive mass spectrometric study identified that KPNB1 positively regulated several members of anaphase promoting complex/cyclosome. Lastly, we found that ivermectin, a well-known anti-parasitic drug, exerted an anti-proliferative effect on EOC cell lines via KPNB1 inhibition, and its combination with paclitaxel synergistically suppressed cell proliferation in vitro and inhibited tumor formation in vivo.
Conclusion
In vivo pooled shRNA library screen identified KPNB1 as a new drug target for EOC. Ivermectin can be a new therapeutics for EOC especially combined with paclitaxel.
Citation Format: Michiko Kodama, Takahiro Kodama, Kosuke Yoshihara, Kae Hashimoto, Seiji Mabuchi, Kenjiro Sawada, Tadashi Kimura, Neal Copeland, Nancy Jenkins. In vivo pooled shRNA library identifies KPNB1 as a new drug target for epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 411. doi:10.1158/1538-7445.AM2017-411
Abstract 4110: Combinatory approaches targeting EGFR, HER2 and c-MET in recurrent SCCHN
Authors: Wang Dongsheng , Magliocca Kelly R. , Nannapaneni Sreenivas , Steuer Coner , Patel Mihir R. , El-Deiry Mark W. , Wang Xu , Chen Zhengjia , Shin Dong M. , Saba Nabil F. , Chen Zhuo G. 
Published: July 2017

Abstract
Squamous cell carcinoma of the head and neck (SCCHN) cells that escape cetuximab inhibition exhibit HER2, HER3, and/or c-Met activation. Simultaneous inhibition of EGFR, HER2, HER3 and c-Met presents an attractive clinical strategy for treating SCCHN that has progresses despite EGFR-targeted therapy. In an effort to develop new combination drug therapy options for recurrent SCCHN, we evaluated three different c-Met inhibitors in combination with a pan-HER inhibitor (afatinib/crizotinib, afatinib/tivantinib, afatinib/cabozantinib) and investigated their anti-tumoral effects. SCCHN cell lines (JHU022 highly expresses c-Met, and SCC1-C is cetuximab resistant) as well as patient derived xenograft (PDX) animal models from patients with recurrent SCCHN were investigated. In our cell line study, western-blot assay indicated that activation of EGFR, HER2, and c-Met was blocked in all three combinations. In addition the downstream PI3K/AKT and ERK signaling pathways were inhibited. Sulforhodamin B colorimetric assay (SRB) revealed SCCHN cell growth was more effectively inhibited by the combinations compared to any of the single inhibitors in vitro. Furthermore, the combination was more potent in inducing apoptosis when compared to each of the single treatments. Finally in the PDX study, all treatment groups had significantly greater efficacy compared to the non-treated control group (p&lt;0.005) and all combination treatments exhibited better efficacy in tumor growth inhibition than their respective single inhibitors (p&lt;0.0l). In conclusion, our study demonstrates that targeting EGFR, HER2, and c-Met with combination of their inhibitors is more effective than each of the single inhibitors alone both in vitro and in SCCHN PDX models. This study paves the way for further clinical investigation of this combination in patients with SCCHN who have progressed after cetuximab-based therapy. (This study is supported by NIH/NCI R21 CA182662-01A1 to NFS and ZGC)
Citation Format: Dongsheng Wang, Kelly R. Magliocca, Sreenivas Nannapaneni, Coner Steuer, Mihir R. Patel, Mark W. El-Deiry, Xu Wang, Zhengjia Chen, Dong M. Shin, Nabil F. Saba, Zhuo G. Chen. Combinatory approaches targeting EGFR, HER2 and c-MET in recurrent SCCHN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4110. doi:10.1158/1538-7445.AM2017-4110
Abstract 4116: Acquired lapatinib resistant induces EMT-phenotype in breast cancer cells via Src and RUNX3
Authors: Kim So Hyeon , Min Ahrum , Kim Seongyeong , Ha Dong Hyeon , Jang Hyemin , Kim Yu Jin , Lee Kyung-Hun , Kim Tae-Yong , Im Seock-Ah 
Published: July 2017

Abstract
Background: Lapatinib is an effective EGFR and HER2 targeting small molecular tyrosine kinase inhibitor which is widely used for HER2 positive breast cancer patients. However, patients eventually acquire resistance, limiting its long-term use. Overexpression of heregulin, a HER3 ligand, acquired stemness were mechanism that confers resistance to the anti-HER2 lapatinib. However, still, unknown mechanisms of developing lapatinib resistant remain as a question to solve. Thus, we tried to find out there is a novel mechanism which related to lapatinib resistant, and any specified molecules were involved in this process.
Methods: Acquired resistant SK-BR-3 cells were established by chronic exposure to lapatinib or trastuzumab. Lapatinib or trastuzumab sensitivity were confirmed by MTT assay. Western blotting was used to determine signal transduction molecule changes. Wound healing assay and Boyden chamber assay were conducted for verifying invasive ability. Whole exome sequencing (WES) and siRNA knock-down system were used for further analysis.
Results: Lapatinib resistant (LR) cell lines showed down-regulation of p-HER2, p-Akt, and p-Erk. The activity of Src family kinase was increased in LR cells. Vimentin, famous EMT marker, is also increased in LR cells. Migration and invasion were significantly increased in LR cells. Correlated with a missense mutation of RUNX3, which identified by WES, expression of RUNX3 was decreased in LR cells. Moreover, siRNA knock-down parental cells showed more resistance to lapatinib.
Conclusion: The increase of Src activation, cell migration, and invasion was observed in LR cells. RUNX3, which identified by WES, affected to lapatinib sensitivity in SK-BR-3 cells. Therefore, RUNX3 might be a specified molecule, which partially contributes resistance to lapatinib.
Citation Format: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Dong Hyeon Ha, Hyemin Jang, Yu Jin Kim, Kyung-Hun Lee, Tae-Yong Kim, Seock-Ah Im. Acquired lapatinib resistant induces EMT-phenotype in breast cancer cells via Src and RUNX3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4116. doi:10.1158/1538-7445.AM2017-4116
Abstract 4126: Validation of hypoglycosylated MUC1-CIN85 protein-protein interaction as a new therapeutic target for prevention of cancer invasion and metastasis
Authors: Cascio Sandra , Faylo Jacque , Sriram Raahul , Vlad Anda , Camacho Carlos , Finn Olivera J. 
Published: July 2017

Abstract
Overexpression and abnormal glycosylation of the epithelial glycoprotein MUC1 in cancer cells promotes metastasis. We have identified CIN85 (Cbl-interacting protein 85 KDa), as a binding partner of MUC1 in tumors. MUC1/CIN85 complex is found in early as well as advanced clinical stages of breast, ovarian, colon and prostate cancers among others. Co-localization of MUC1 and CIN85 on invadopodia structures enhances invasion and migration of cancer cells. Our hypothesis is that preventing the formation or dissociating existing CIN85/MUC1 complexes may result in a less aggressive tumor by decreasing local invasion and preventing distant metastases. To test this hypothesis, we have already identified and tested two novel compounds that significantly reduce the association between hypoglycosylated form of MUC1 and CIN85, and at 10μM concentration drastically reduce the migratory activity of mouse and human epithelial cancer cells. Our preliminary data also suggest that dissociation of the MUC1 and CIN85 complex decreases expression of hypoglycosylated MUC1, restoring the expression of its normal, fully glycosylated form. We are currently investigating the MUC1/CIN85-dependent signaling pathway with a particular focus on the ability of CIN85 to modulate MUC1 glycosylation by controlling its plasma membrane-Golgi trafficking. Ongoing experiments in an in vivo mouse model will confirm the ability of these drug compounds to decrease tumor growth and metastasis and validate CIN85/MUC1 complex as a viable therapeutic target and support development and testing of more potent antagonists.
Citation Format: Sandra Cascio, Jacque Faylo, Raahul Sriram, Anda Vlad, Carlos Camacho, Olivera J. Finn. Validation of hypoglycosylated MUC1-CIN85 protein-protein interaction as a new therapeutic target for prevention of cancer invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4126. doi:10.1158/1538-7445.AM2017-4126
Abstract 4130: Characterization of URST1 as a prognostic biomarker and therapeutic target for lung cancer
Authors: Takano Atsushi , Miyagi Yohei , Daigo Yataro 
Published: July 2017

Abstract
Lung cancer is the most frequent cause of cancer deaths worldwide and its overall prognosis remains poor. Therefore, next generation of biomarkers and therapeutic strategies for lung cancer are eagerly awaited. We selected genes that were overexpressed in the majority of lung cancer using our gene expression profile database. During this process, we identified URST1 (Up-regulated in solid tumor 1) as a candidate. Immunohistochemical staining showed that URST1 expression was observed in the majority of non-small cell lung cancer (NSCLC) patients (P = 0.0013 by log rank test). Multivariate analysis revealed high level of URST1 expression was an independent prognostic factor for NSCLC patients. Moreover, reduction of URST1 by siRNA or treatment with URST1 inhibitor significantly suppressed lung cancer cell growth probably through cell cycle arrest at G2/M. Exposure of cancer cells to URST1 inhibitor significantly suppressed These data suggest that URST1 is a possible prognostic biomarker and therapeutic target for lung cancer.
Citation Format: Atsushi Takano, Yohei Miyagi, Yataro Daigo. Characterization of URST1 as a prognostic biomarker and therapeutic target for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4130. doi:10.1158/1538-7445.AM2017-4130