bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4781: Changes in intracellular signaling following chronic FGFR inhibition in urothelial bladder cancer models
Authors: Jerchel Isabel S. , Kamburov Atanas , Lesche Ralf , Zitzmann-Kolbe Sabine , Walter Alexander , Ellinghaus Peter , Mumberg Dominik , Politz Oliver , Gruenewald Sylvia 
Published: August 2018

Abstract
Preclinical and clinical studies have validated the therapeutic potential of FGFR inhibition in urothelial bladder cancer (UBC) patients with FGFR genetic aberrations. Rogaratinib is a potent small-molecule pan-FGFR inhibitor being studied in phase I trials in UBC. Here, we studied the effects of chronic exposure of bladder cancer cells in vitro to FGFR inhibition by rogaratinib to identify changes in signaling and gene expression patterns that may identify possible drug combinations that may enhance efficacy of rogaratinib and help overcome inherent and/or acquired treatment resistance. Cell proliferation in response to rogaratinib was evaluated using crystal violet staining in a panel of 13 UBC cell lines. Continuous culture of two cell lines–JMSU1 and RT112–with either constant or increasing concentrations of rogaratinib in several independent approaches generated the resistant sublines, JMSU1-R1 to -R4 and RT112-R1 to -R4. In both cellular models rogaratinib resistance (defined as &gt;30-fold [JMSU1] or &gt;100-fold [RT112] difference in absolute IC50 of sublines vs. parental lines) arose reproducibly and with various treatment schedules. Morphologic changes were also observed. Transcriptomic (RNAseq) and proteomic (R&D Systems proteome profiler arrays) analyses of these cell lines or rogaratinib-treated versus untreated parental cells, respectively, revealed changes that co-occur with the development of resistance. Analysis of the phospho-proteome showed increased phosphorylation of several receptor tyrosine kinases compared to the parental cell lines. Phosphorylation levels varied among the 4 resistant sublines that were derived from the same parental line. This resulted in alteration of downstream signaling pathways in rogaratinib-treated sublines compared to parental cell lines. In conclusion, exposure of selected bladder cancer cell lines to rogaratinib resulted in development of resistance and changes in FGFR signaling and gene expression pathways that may identify strategies to optimize treatment with FGFR inhibitors.
Citation Format: Isabel S. Jerchel, Atanas Kamburov, Ralf Lesche, Sabine Zitzmann-Kolbe, Alexander Walter, Peter Ellinghaus, Dominik Mumberg, Oliver Politz, Sylvia Gruenewald. Changes in intracellular signaling following chronic FGFR inhibition in urothelial bladder cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4781.
Abstract 4788: Preclinical evaluation of E-191, a highly selective EGFR T790M inhibitor
Authors: Xile Liu , Hu Lihong , Ding Charles Z , Mao Weifeng , Wang Liqing , Shi Xiaohe , Long Chaofeng , Chen Xiaoxin , Li Haijun , Liu Xing , Liu Zhuowei 
Published: August 2018

Abstract
Objective: Patients of non-small cell lung cancer (NSCLC) with activating EGFR mutations initially respond to the first generation reversible EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib. However, most of the patients acquire resistance within 10~16 months. The most common mechanism of resistance is the EGFR T790M mutation. In addition, selectivity of the EGFR inhibitors is important, as inhibition of EGFR wild type can lead to dose limiting toxicities, including rash and diarrhea. This may be the reason why the second generation irreversible EGFR inhibitors, such as afatinib, which also inhibit EGFRWT, is not widely used. Here, we disclose our clinical candidate compound E-191 as a novel irreversible inhibitor that potently inhibits the resistance mutant forms of EGFR with a good selectivity sparing EGFRWT.
Method: The anti-proliferative activity of E-191 was evaluated in NCI-H1975 (EGFRT790M/L58R), HCC827 (EGFRd746-750), and A431 (EGFRWT) cell lines. Daily oral administration of E-191 at 3 doses was used to evaluate the in vivo anti-tumor activity in three cell-derived tumor xenograft (CDX) models, NCI-H1975, HCC827, and Ba/F3 (EGFRT790M /d746-750). The in vivo selectivity was evaluated in the A431 (EGFRWT) CDX model. Effects on EGFR signaling pathway were assessed by western blot analysis of the downstream effector proteins p-EGFR (Y1068), p-AKT (Ser473) and p-ERK (Thr202/Tyr204).
Result: E-191 displayed potent anti-proliferative activity in the EGFR mutant cell lines NCI-H1975 (IC50 = 22 nM) and HCC827 (IC50=1.9 nM), and a much less potent activity in the EGFRWT A431 cell line (IC50 = 531 nM). E-191 has about 24 fold selectivity for EGFRT790M over EGFRWT. E-191 potently inhibited tumor growth at all doses tested (P&lt;0.001) in the NCI-H1975, HCC827 and Ba/F3 (EGFRT790M /d746-750) models, while significantly less so in the A431 model. Western blot analysis of the tumor samples in the NCI-H1975 model study showed that E-191 inhibited p-EGFR (Y1068), p-AKT (Ser473), and p-ERK (Thr202/Tyr204), indicating that the tumor growth inhibition was through inhibition of the resistant mutant EGFR.
Conclusion: We have demonstrated with in vitro and in vivo preclinical models that E-191 is a selective inhibitor of the resistance mutant forms of EGFR, potently inhibiting EGFRT790M but not EGFRWT. These results make us believe that E-191 has a good potential in the clinic for the treatment of resistant EGFR driven NSCLC.
Citation Format: Liu Xile, Lihong Hu, Charles Z Ding, Weifeng Mao, Liqing Wang, Xiaohe Shi, Chaofeng Long, Xiaoxin Chen, Haijun Li, Xing Liu, Zhuowei Liu. Preclinical evaluation of E-191, a highly selective EGFR T790M inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4788.
Abstract 4792: Preclinical evaluation of GST-HG161, a potent and highly selective c-MET inhibitor
Authors: Xu Xiongbin , Li Gang , Hu Lihong , Hao Junguo , Ding Charles Z. , Chen Shuhui 
Published: August 2018

Abstract
Objective: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Studies indicate that aberrant activation of mesenchymal-epithelial transition factor (c-MET) is associated with HCC development. Blocking c-MET signaling shows antitumor efficacy in patients with HCC. Thus, c-MET has been an attractive therapeutic target for HCC. We disclose here for the first time a potent and selective c-MET inhibitor GST-HG161 and show the antitumor efficacy data in preclinical models of HCC.
Method: MHCC97H HCC cell line with c-MET overexpression was used to evaluate the anti-proliferative activity of GST-HG161 in a 120-hour viability assay. Selectivity was evaluated with a panel of cell lines without overexpression of c-MET. Daily oral administration of GST-HG161 doses of 1, 3, 10 and 30mg/kg was used to evaluate its in vivo antitumor efficacy in two animal models of HCC with c-MET overexpression, MHCC97H xenograft (CDX) model and LI-03-0317 xenograft (PDX) model. The c-MET protein levels and gene copy number in LI-03-0317 PDX were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. High c-MET expression in LI-03-0317 PDX was determined by the presence of tumor cells with membrane staining of 3+ intensity. Effect of GST-HG161 on c-MET signaling inhibition was assessed by western blot analysis of downstream effector proteins including p-MET, p-AKT and p-ERK.
Result: GST-HG161 displayed potent anti-proliferative activity in MHCC97H HCC cell line (IC50 = 5 nM) while showed little activity in the cell lines without c-MET overexpression. It significantly inhibited tumor growth at tested doses (3, 10 and 30mg/kg) (P&lt;0.05) in both MHCC97H CDX model and LI-03-0317 PDX model. In MHCC97H CDX model, western blot analysis showed that GST-HG161 potently inhibited p-MET and downstream effector proteins p-AKT and p-ERK in the tumor tissue, indicating that the tumor growth inhibition in this model was mediated through inhibition of c-MET.
Conclusion: GST-HG161 is a potent and highly selective c-MET inhibitor. Its excellent antitumor efficacy as shown in
the HCC mouse models provide us with confidence that GST-HG161 has high potential in the clinic for treating patients of HCC with high c-MET activity.
Citation Format: Xiongbin Xu, Gang Li, Lihong Hu, Junguo Hao, Charles Z. Ding, Shuhui Chen. Preclinical evaluation of GST-HG161, a potent and highly selective c-MET inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4792.
Abstract 4794: Preclinical evaluation of WX-0593, a potent orally active ALK inhibitor
Authors: Xile Liu , Ding Charles Z , Mao Weifeng , Qin Yuxin , Zheng Shansong , Yang Yingying , Zheng Qingmei , Zhang Long , Zhao Shuyong 
Published: August 2018

Abstract
Objective: ALK is a tyrosine kinase belonging to the insulin receptor super-family. The constitutively active ALK fusions are oncogenic and linked with multiple types of human cancer. The EML4-ALK fusion has been proven to be the driver of approximately 5% of NSCLC patients. We disclose here for the first time a novel ALK inhibitor WX-0593 and its preclinical evaluation data in preclinical models of ALK driven NSCLC.
Method: The enzyme activities of WX-0593 for ALKWT, ALKL1196M, ALKC1156Y and EGFRL858R/T790M were measured with corresponding kinase assays. The anti-proliferative activity was evaluated in Karpas-299, Ba/F3, Ba/F3 (EML4-ALK-WT), Ba/F3 (EML4-ALK-L1196M), Ba/F3 (EML4-ALK-C1156Y), and NCI-H1975 cell lines. The specific effect (PD) of WX-0593 on ALK signaling was analyzed in NCI-H3122 cells. Antitumor activity of WX-0593 was evaluated in three patient-derived xenograft (PDX) models of NSCLC (LU-01-0015, LU-01-0319, and crizotinib resistant LU-01-0319R) and one cell-derived xenograft (CDX) model of NSCLC (NCI-H3122). PKPD was assessed by western blot analysis of the treated tumor tissues for p-ALK (Tyr1604), p-STAT3 (Tyr705), p-STAT5 (Tyr694), p-AKT, and p-ERK.
Result: WX-0593 displayed potent enzymatic activities for ALKWT, ALKL1196M, ALKC1156Y and EGFRL858R/T790M with IC50 of 5.38, 9.26, 9.28, and 16.74 nM respectively. It also showed expected anti-proliferative activity in six cell lines, Karpas-299, Ba/F3, Ba/F3 (EML4-ALK-WT), Ba/F3 (EML4- ALK-L1196M), Ba/F3 (EML4-ALK-C1156Y), and NCI-H1975, with IC50 of 4.5, 2208, 4, 9.5, 9, and 508 nM, respectively. Western blot study in NCI-H3122 cells showed that WX-0593 could fully inhibit p-ALK, p-ERK,p-STAT5 at 11.1 nM and p-AKT at 100 nM. WX-0593 significantly inhibited tumor growth at all doses tested (P&lt;0.001) in the LU-01-0015 (HIP1-ALK), LU-01-0319 (EML4-ALK), and LU-01-0319R NSCLC PDX models as well as in the NCI-H3122 CDX model. Western blot analysis of the tumor samples showed that WX-0593 inhibited p-ALK (Tyr1604), p-STAT3 (Tyr705), p-STAT5 (Tyr694), p-AKT, and p-ERK, indicating that the tumor growth inhibition was mediated by inhibition of ALK signaling.
Conclusion: We have identified a potent orally active second generation ALK inhibitor, WX-0593. It can inhibit the activity of both wide type and crizotinib resistant ALK and showed strong antitumor activity in in vitro and in vivo preclinical models. These results are considered highly promising and warrant moving the compound forward to clinical investigation.
Citation Format: Liu Xile, Charles Z Ding, Weifeng Mao, Yuxin Qin, Shansong Zheng, Yingying Yang, Qingmei Zheng, Long Zhang, Shuyong Zhao. Preclinical evaluation of WX-0593, a potent orally active ALK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4794.
Abstract 4795: Potency of a new ALK/ROS1 inhibitor TPX-0005 to ALK G1202R mutation and ROS1 G2032R mutation
Authors: Yoda Satoshi , Dardaei Leila , Prutisto-Chang Kylie , Cui Jean , Shaw Alice T. , Hata Aaron N. 
Published: August 2018

Abstract
ALK rearrangements and ROS1 rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC). ALK-positive NSCLC is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib, and ROS1-positve NSCLC is currently treated with crizotinib. Even though these drugs produce responses in most patients, drug resistance eventually develops. Notable mechanisms of resistance are kinase domain solvent front mutations, such as ALK G1202R and ROS1 G2032R. Genomic analysis of relapsed cases show ALK G1202R in 21%, 29%, or 43% of ceritinib-, alectinib-, or brigarinib-resistant cases, and ROS1 G2032R in 41% of crizotinib-resistant cases.
The novel ALK/ROS1 inhibitor TPX-0005 was designed to overcome clinical resistance mutations, especially solvent front mutations, and is currently being evaluated in a phase 1/2 study. Engineered preclinical models have demonstrated the potency of TPX-0005 against ALK G1202R and ROS1 G2032R. For example, Ba/F3 cells expressing EML4-ALK G1202R or CD74-ROS1 G2032R resistant to second-generation ALK inhibitors or crizotinib, respectively, but were sensitive to TPX-0005. Here we investigate the potency of TPX-0005 to overcome solvent front mutations in resistant patient-derived models. We generated cell lines and patient-derived xenograft mouse models from ALK G1202R and ROS1 G2032R tumors at the time of relapse on second-generation ALK inhibitors or crizotinib, respectively. As expected, these models were resistant to second-generation ALK inhibitors or crizotinib. In contrast, TPX-0005 suppressed ALK or ROS1 phosphorylation, and led to decreased cell viability and tumor regression in vivo. These data demonstrate that TPX-0005 overcomes solvent front mutations in clinically relevant models and provides rationale for the clinical development of TPX-0005 for patients harboring ALK G1202R or ROS1 G2032R resistance mutations.
Citation Format: Satoshi Yoda, Leila Dardaei, Kylie Prutisto-Chang, Jean Cui, Alice T. Shaw, Aaron N. Hata. Potency of a new ALK/ROS1 inhibitor TPX-0005 to ALK G1202R mutation and ROS1 G2032R mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4795.
Abstract 480: Regulation of crosstalk between AR and Wnt/Beta-catenin pathways by miR-644a in prostate cancer
Authors: Plaga Alexis R. , Shukla Girish C. 
Published: August 2018

Abstract
Prostate Cancer (PCa) is the most commonly diagnosed cancer in males with 161,360 people diagnosed in the United States and is predicted to cause 26,730 deaths in 2017. The current treatment of androgen deprivation therapy (ADT) initially depletes circulating androgens; however, intratumoral androgens rescue androgen receptor (AR) signaling and promotes the development of castration-resistant prostate cancer (CRPC). The dysregulation of the Wnt/B-catenin signaling pathway has been implicated in the development of many cancers including PCa. The disruption of this signaling leads to the stabilization of B-catenin which upregulates many genes involved in tumorigenesis. Additionally, B-catenin acts as AR cofactor. Our previous studies show that AR is a direct target of miR-644a. We hypothesized that targeting the expression of both the B-catenin pathway and AR by conventional drugs and/or tumor suppressor miR-644a would have synergistic therapeutic benefits. In this study, we are investigating miR-644a mediated posttranscriptional downregulation of GSK3-B and B-catenin in the wnt/B-catenin signaling pathway. The effect of miR-644a in combination with inhibitors (B-catenin or GSK3-B) was also assessed using viability assays and a significant downregulation was observed. We will further study the posttranscriptional effects of tumor suppressor miR-644a on the wnt/B-catenin pathway as well as assess if miR-644a can inhibit the cross-talk of these pathways.
Citation Format: Alexis R. Plaga, Girish C. Shukla. Regulation of crosstalk between AR and Wnt/Beta-catenin pathways by miR-644a in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 480.
Abstract 481: QKI, a direct target of miRNA-200, inhibits epithelial-to-mesenchymal transition
Authors: KIM Eun Ju , Sun Der Sheng , Won Hye Sung , Ko Yoon Ho , Ahn Young-Ho 
Published: August 2018

Abstract
MicroRNA (miR)-200 family members are well-known regulators of epithelial-to-mesenchymal transition (EMT) in epithelial tumors. To identify novel miR-200 targets, we analyzed TargetScan and TCGA data sets. Among 20 candidate genes, we selected QKI gene and studied its role during EMT process in human head and neck squamous cell carcinoma (HNSCC) and non-small cell lung carcinoma (NSCLC) cells. The expression of QKI was proved to negatively correlate with those of miR-200 members in TCGA data sets. miR-200 suppressed QKI expression directly, which was confirmed by 3'-UTR reporter assays. Interestingly, shRNA-mediated knockdown of QKI promoted migration, invasion, and EMT in cancer cells and increased tumor growth in a xenograft mouse model. These results indicate that QKI inhibits EMT and tumorigenesis in HNSCC and NSCLC cells. Even though further studies are necessary to elucidate the underlying mechanism, we suggest that QKI and miR-200 form a feedback loop to maintain homeostatic responses to EMT-inducing signals.
Citation Format: Eun Ju KIM, Der Sheng Sun, Hye Sung Won, Yoon Ho Ko, Young-Ho Ahn. QKI, a direct target of miRNA-200, inhibits epithelial-to-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 481.
Abstract 4814: Adaptation of uveal melanoma cells to MEK inhibition can be overcome through HDAC inhibition
Authors: Faião-Flores Fernanda , Maria-Engler Silvya S. , Eroglu Zeynep , Smalley Keiran S. 
Published: August 2018

Abstract
Uveal melanoma is the most common adult cancer of the eye. Although uveal melanoma has a low incidence, it has a high capability to develop metastases, mainly to the liver. Mortality rates are high and new therapeutic strategies are urgently needed. 85-90% of all uveal melanomas harbor driver mutations in GNAQ or GNA11 leading to constitutive activation of many signaling pathways, including the MAPK pathway. Although MEK inhibitors have been evaluated clinically for metastatic uveal melanoma, responses are short-lived, and the mechanisms of adaptation are not well delineated. In the current study we performed mass spectrometry-based proteomics to define the adaptive response of uveal melanoma cells to MEK inhibition at a systems level with the hope of identifying the key escape pathways. These analyses identified MEK inhibition to lead to increased histone phosphorylation and histone deacetylase (HDAC) activity, as well as reorganization of the cytoskeleton associated with cortactin phosphorylation. MEK inhibition also increased receptor tyrosine kinase (RTK) signaling (through ROR1 and IGFIR) and enhanced AKT phosphorylation. Use of pan-HDAC inhibitors sensitized the uveal melanoma cells to MEK inhibition leading to enhanced apoptosis and decreased cell invasion. Mechanistic studies showed the MEK+HDAC inhibitor combination inhibited MAPK, PI3K/AKT and the Hippo signaling, an effect associated with increased cell death inhibition of cell invasion. Chronic MEK inhibitor treatment led to acquired resistance that was associated with increased RTK signaling and the adoption of an invasive phenotype. Studies are ongoing to identify the key HDAC isoform required for the adaptation to MEK inhibitor therapy as well as the anti-invasive potential of the cortactin knockdown with the goal of developing novel combination therapies that can be evaluated clinically.
Citation Format: Fernanda Faião-Flores, Silvya S. Maria-Engler, Zeynep Eroglu, Keiran S. Smalley. Adaptation of uveal melanoma cells to MEK inhibition can be overcome through HDAC inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4814.
Abstract 4841: Prostate cancer cell death triggered by a small molecule interacting with the hTERT G-quadruplex
Authors: Song Jin H. , Luevano Libia A. , Kang Hyunjin , Gokhale Vijay , Hurley Laurence H. , Kraft Andrew S. 
Published: August 2018

Abstract
Human telomerase reverse transcriptase (hTERT), a catalytic subunit of telomerase, is widely overexpressed in human cancers including prostate cancer. Along with its regulation of the telomere, hTERT was also shown to regulate various signal transduction mechanisms involving DNA damage response, cell cycle checkpoint, and apoptosis. The majority of human solid tumors display telomerase activity, which was found to be well correlated with hTERT expression, and hTERT inhibition led to reduced telomerase activity and telomere length. However, approaches that directly inhibit the action of telomerase have not produced a therapeutically useful response because of long lag times for subsequent cell division to produce telomere shortening. Alternatively, recent studies demonstrated that this delay problem can be solved through downregulation of hTERT transcription. It was shown that telomeric DNA is capable of folding into four-stranded guanine quadruplex (G4) structures, which then lock the hTERT promoter activity that leads to robust telomere shortening. Our new approach has focused on the discovery of small molecules that could stabilize G-quadruplexes by interacting with the telomeric G-rich overhang stem loop, producing a lead candidate compound that enhances the kinetic folding rate of the G4 silencer element. Our in vitro studies demonstrate that this singular mechanism of action permitted reduced telomerase production and telomere shortening. Significantly, hTERT downregulation with the identified molecule caused prostate cancer cell death, which was characterized by activation of the caspase cascade and increased Annexin V- positive cells. In contrast, this compound did not harm normal prostate epithelial cells. Similarly, mouse prostate cancer cells that do not contain a G-quadruplex were not killed, demonstrating that the unique mechanism of action is mediated through the hTERT promoter G-quadruplex element. Our in vivo study demonstrated that administration of this significantly delayed tumor growth on xenografted mice. The rapid onset of cell death by G4 stands in contrast to the delayed action of classic telomerase inhibition. Therefore, our current study provides important data to support developing inhibitors of hTERT as a cancer drug target.
Citation Format: Jin H. Song, Libia A. Luevano, Hyunjin Kang, Vijay Gokhale, Laurence H. Hurley, Andrew S. Kraft. Prostate cancer cell death triggered by a small molecule interacting with the hTERT G-quadruplex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4841.