bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1812: XCE853: A novel PDI inhibitor that inhibits proliferation of human tumor cells in vitro, ex-vivo and in vivo
Authors: Prevost Gregoire P. , Xu Shili , Garrido Marine , Serova Maria , Vewer Olivier D. , Gespach Christian , Briand Jean-François , Tijeras-Raballand Annemilaï , Gutmann Mathieu , Hendrix An , Sabbah Michele , Chachereau Anne , Gramont Armand de , Neamati Nouri , Carniato Denis , Pitty Marc-Henry , Foster Paul 
Published: May 2015

Abstract
XCE853 was originally identified within a family of synthetic compounds displaying a preferential antiproliferative activity on drug resistant human cancer cells (Gutmann et al, AACR annual meeting, 2013). XCE853 induced an irreversible cytolysis of human tumor cells after a short in vitro exposure independently of efflux pumps leading to a tumor cell death by autophagy and particles release (vesicles or protein aggregates).
The interest for XCE853 has been reinforced by three in vitro observations: 1) XCE853 inhibits the recombinant human enzyme PDI recognized as one novel target linked to drug resistance 2) XCE853 has a unique antiproliferative profile compared to the NCI database compounds when using the NCI Compare assay and 3) XCE853 has no activity on human normal prostate cells even at high concentrations whereas XCE shows an IC50 in the nanomolar range on human tumoral cells.
In addition, the ex-vivo approach using fresh human tumor explants cultivated in 3 dimensions with low concentrations of XCE853 has shown a strong decrease of the proliferation (KI-67 labeling) with an apoptosis induction (Caspase-3 labeling) of Head & Neck cancers following 24h of exposure.
Finally, XCE853 which displayed an excellent oral bioavailability in mouse is able to block growth of human ovarian cancer using in vivo xenograft model leading to a complete tumor growth arrest even after the stop of the treatment.
Altogether, these data support further efforts on this drug candidate to initiate the preclinical studies and to define the most relevant human tumor types.
Citation Format: Gregoire P. Prevost, Shili Xu, Marine Garrido, Maria Serova, Olivier DE Vewer, Christian Gespach, Jean-François Briand, Annemilaï Tijeras-Raballand, Mathieu Gutmann, An Hendrix, Michele Sabbah, Anne Chachereau, Armand de Gramont, Nouri Neamati, Denis Carniato, Marc-Henry Pitty, Paul Foster. XCE853: A novel PDI inhibitor that inhibits proliferation of human tumor cells in vitro, ex-vivo and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1812. doi:10.1158/1538-7445.AM2014-1812
Abstract 1813: A novel designed small peptide enhances chemotherapy sensitivity of leukemia cells in stromal microenvironment
Authors: Li Xiaojin , Guo Hua , Yang Yanlian , Meng Jie , Liu Jian , Wang Chen , Xu Haiyan 
Published: May 2015

Abstract
Many types of leukemia cells highly express chemokine receptor (CXCR4) that actively responses to CXCL12, a chemokine constitutively secreted by stromal cells in bone marrow. Activation of CXCR4 induces leukemia cells trafficking and homing to the marrow microenvironment, where CXCL12 retains these cells in close contact with marrow stromal cells that provide growth, self-renewal, and drug resistance signals, which lead to poor prognosis and relapse. We report here a novel designed peptide targeting to CXCR4, named as XW1108-3. The patented sequence is GGQGCRFRNTVDD WISITRAL. We use flow cytometry, cell migration and adhesion assay to study the affinity of XW1108-3 to leukemia cells and the inhibitory effect on CXCL12-induced cell behaviors. The XW1108-3 shows high affinity to different types of leukemia cell highly expressing CXCR4 including HL-60, NB4, THP-1 and U937, the binding was maintained for up to 4 hours. The XW1108-3 treatment significantly inhibited CXCL12- or murine stromal cell MS-5-induced migration of leukemia cells in a concentration dependent manner in the transwell assay and significantly reduced the leukemia cells adhesion to MS-5 cell layer. Mechanistic study with western blot and confocal microscopy assay demonstrates that
XW1108-3 treatment down regulates CXCL12-induced phosphorylation of Erk, Akt and p38 and affects F-actin organization, resulting in the suppression of the cell response to CXCL12 activation. It is notable that XW1108-3 treatment did not induce apoptosis of leukemia cells or human fibroblasts and endothelial cells even at 10 µM, instead enhanced the level of 10-hydroxy camptothecin-induced apoptosis of different leukemia cells co-incubated with the stromal cell MS-5 layer, thereby exhibiting great clinical implications in leukemia chemotherapies and immune therapies.
Citation Format: Xiaojin Li, Hua Guo, Yanlian Yang, Jie Meng, Jian Liu, Chen Wang, Haiyan Xu. A novel designed small peptide enhances chemotherapy sensitivity of leukemia cells in stromal microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1813. doi:10.1158/1538-7445.AM2014-1813
Abstract 1820: Dynamics of HER-2 loss in mammary carcinoma of human HER-2 trangenic mice
Authors: Nanni Patrizia , Palladini Arianna , Landuzzi Lorena , Dall'Ora Massimiliano , Ianzano Marianna , Grosso Valentina , Ranieri Dario , Nicoletti Giordano , Laranga Roberta , Giovanni Carla D. , Iezzi Manuela , Lollini Pier-Luigi 
Published: May 2015

Abstract
Progression of HER-2+ breast cancer can result in the emergence of HER-2-negative tumor variants that activate alternative mitogenic pathways, either spontaneously or after therapy. We found that HER-2 loss occurs even in transgenic mouse models in which the oncogene is driven by viral promoters, thus mammary carcinoma of human HER-2 transgenic mice (huHER-2 mice) can be used to study not only the early phases of HER-2-driven mammary carcinogenesis, but also tumor progression beyond HER-2 addiction. Primary mammary carcinomas of huHER-2 mice express high levels of the oncogene, with a marked intratumoral heterogeneity. Cell lines grown from HER-2+ mammary carcinomas frequently undergo a progressive loss of expression. We have established a model system consisting of cell lines, clones and variants that exhibit one of three phenotypes: a) high and stable HER-2 expression in vitro and in vivo, b) high but labile HER-2 expression which is lost either during in vitro culture, after tumor growth in mice or after in vitro treatment with trastuzumab, and c) complete loss of HER-2 expression After HER-2 loss, most variants displayed a transition to an elongated, motile phenotype (epithelial to mesenchymal transition), an increased ability to generate mammospheres, a reduced expression of CD24 and an increased expression of CD44 (denoting mammary cancer stem cells). Tumorigenic and metastatic ability of HER-2-negative cells was increased in comparison to HER-2+ cells. As expected, HER-2 loss was accompanied by resistance to HER-2 targeted monoclonal antibodies and small molecule inhibitors. The study of therapeutic agents directed against downstream targets showed that HER-2-loss was accompanied by a loss of sensitvity to a Src inhibitor, whereas a PI3K inhibitor was highly effective regardless of HER-2 expression. Our results indicate that human HER-2 transgenic mice are a useful model to study the dynamics of HER-2 loss in advanced HER-2+ mammary carcinoma, and to analyze alternative therapeutic strategies.
Supported by grants from the Italian Association for Cancer Research (AIRC).
Citation Format: Patrizia Nanni, Arianna Palladini, Lorena Landuzzi, Massimiliano Dall'Ora, Marianna Ianzano, Valentina Grosso, Dario Ranieri, Giordano Nicoletti, Roberta Laranga, Carla De Giovanni, Manuela Iezzi, Pier-Luigi Lollini. Dynamics of HER-2 loss in mammary carcinoma of human HER-2 trangenic mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1820. doi:10.1158/1538-7445.AM2014-1820
Abstract 1823: Novel regulation of Jagged1 by ErbB2 in breast cancer: implications for anti-ErbB2 therapy
Authors: Osipo Clodia , Pandya Kinnari , Wyatt Debra 
Published: May 2015

Abstract
We have demonstrated that Notch1 is required for trastuzumab resistance in ErbB2 positive breast cancer. This indicates that ErbB2 suppresses Notch1 in breast cancer and therapeutic intervention targeting ErbB2 might have an unintended consequence which is aberrant up regulation of Notch1 which is a breast oncogene.
However, the mechanism of action by which ErbB2 restricts Notch1 activation is unknown. In this current study, we investigated the role of cis- and trans-activation of Notch signaling by Notch ligands which are developmentally conversed to tightly regulate Notch activation. To address this hypothesis, we performed co-culture studies using fibroblasts expressing no Notch ligands or over-expressing human Jagged1 or Deltalike1 and ErbB2 positive breast cancer cells. We performed flow cytometry to isolate breast cancer cells after co-culture and extracted RNA to measure expression of Notch gene targets as a measure of Notch activity. The results showed that trastuzumab, Lapatinib, or ErbB2 knockdown increased overall Notch activition. Similarly, Co-culture with Jagged1-expressing fibroblasts increased overall Notch activation. However, Knocked down of Jagged1 in the breast cancer cells had little effect on ligand-induced Notch activation relieving the possibility of cis-inhibition. In contrast, Jagged1 knocked down abrogated trastuzumab-induced Notch activation in the breast cancer cells. These results suggest that ErbB2 might restrict Notch activation by preventing Jagged1-mediated trans activation of Notch and not by promoting cis-inhibition. Confocal immunofluorescence showed that Jagged1 is localized with Notch1 when ErbB2 is hyperactive but is trafficked to the cell surface in response to trastuzumab. K44ADynamin abrogated Jagged1 expression on the cell surface as measured by IF and surface biotinylation studies. Furthermore, K44ADynamin expression abrogated trastuzumab-induced Notch1 activation. Importantly, we measured growth consequences of Jagged1-mediated Notch activation in response to trastuzumab and found that Jagged1 is necessary for survival of ErbB2 positive breast cancer cells and trastuzumab resistance as measured by cell cycle analysis and Annexin V staining. These results taken together indicate that ErbB2 restricts Notch by limiting Jagged1-mediated trans-activation.
Citation Format: Clodia Osipo, Kinnari Pandya, Debra Wyatt. Novel regulation of Jagged1 by ErbB2 in breast cancer: implications for anti-ErbB2 therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1823. doi:10.1158/1538-7445.AM2014-1823
Abstract 1825: Jab1/Csn5 a new target in the resistant mechanism to HER2-targeted therapies for breast cancer
Authors: Claret Francois X. , Vu Thuy , Shackleford Terry J. , Allensworth Jennifer , Zhang Qingxiu , Tian Ling , Zhang Ronghua 
Published: May 2015

Abstract
Her2 positive (Her2+) breast cancer (BC) accounts for 20% of all breast cancer subtypes and is associated with high risk of death. Trastuzumab (Ttzm), first FDA-approved targeted therapy for BC, represents a key milestone in the personalized treatment of Her2+ metastatic disease (MBC). However, 75% of Her2+ MBC are or become resistant to Ttzm and experience relapse or disease progression. This suggests that tumors acquire or possess an intrinsic mechanism of resistance that prevents from Her2 inhibition. Therefore, it is important to identify novel pathway to overcome the resistance. Recent studies have proposed various potential mechanisms leading to the resistance, including p27 rapid degradation. Jab1/Csn5 a novel candidate oncogene that we identified contributes to the progression of BC and is correlated with poor prognosis. Our study demonstrated that Jab1/Csn5 degrades p27 in MBC. These findings suggest that Jab1 overexpression contributes to Ttzm-resistance by facilitating p27-degradation. Jab1/Csn5 is overexpressed in 50% of primary and 90% of MBC while its expression is low or absent in normal adult breast tissues. We previously identified that high expression of Jab1 is associated with shorter progression-free survival in MBC patients. In this study, we showed that the knockdown of Jab1 sensitizes to Ttzm-treatment. Mechanistically, we found that Jab1/Csn5 overexpression is significantly correlated with the activation of Akt pathway in Her2+ MBC and xenograft models. Interestingly, activated Akt, due to PTEN-loss or PI3K activating mutation has been widely implicated in the potential mechanism to Ttzm-resistance. Therefore, our results suggest that targeting Jab1/Csn5 overcomes the resistance to Ttzm via interfering with PI3K/Akt pathway. Our study identifies Jab1 as a novel contributor to Ttzm-resistance and elucidates its potential mechanisms of actions. Jab1 could be used as a predictive marker of tumor response to Ttzm, which could assist clinicians in selecting the best treatment modalities for patients with MBC.
Note: This abstract was not presented at the meeting.
Citation Format: Francois X. Claret, Thuy Vu, Terry J. Shackleford, Jennifer Allensworth, Qingxiu Zhang, Ling Tian, Ronghua Zhang. Jab1/Csn5 a new target in the resistant mechanism to HER2-targeted therapies for breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1825. doi:10.1158/1538-7445.AM2014-1825
Abstract 1836: Erlotinib induces NF-kappa B dependence that promotes EGFR tyrosine kinase inhibitor resistance in lung adenocarcinoma
Authors: Blakely Collin M. , Pazarentzos Evangelos , Asthana Saurabh , Olivas Victor , Tan Irena , Fouts Timothy , Meshulam Jeffrey , Bivona Trever G. 
Published: May 2015

Abstract
The vast majority of patients with lung adenocarcinomas harboring activating mutation in EGFR respond to EGFR tyrosine inhibitors (TKI) (i.e. erlotinib). However, the magnitude of tumor regression is variable and responses are short-lived with a median duration of 9-12 months. We recently identified activation of the NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) signaling pathway as a key mediator of de novo resistance to EGFR TKI therapy in cell lines and tumor xenograft models of lung adenocarcinoma. However, the role of NF-κB activation in mediating EGFR TKI acquired resistance in lung adenocarcinoma is not well defined. We have found that erlotinib treatment of EGFR TKI sensitive lung adenocarcinoma cell lines promotes the rapid phosphorylation and degradation of IκB (inhibitor of NF-κB) and subsequent activation of the NF-κB subunit RelA. RelA activation is accompanied by transcriptional activation of downstream NF-κB target genes, including IL6. Prolonged exposure of EGFR TKI sensitive lung adenocarcinoma cell lines to erlotinib leads to EGFR TKI acquired resistance that is accompanied by sustained NF-κB activation and IL6 expression. EGFR TKI acquired resistance can be overcome by treating cells with erlotinib in combination with PBS-1086 (rel∼MD, Inc.), a direct Rel inhibitor. Furthermore, concomitant treatment of EGFR TKI sensitive lung adenocarcinoma cells with erlotinib + PBS-1086 prevents the development of EGFR TKI acquired resistance. Together, these results demonstrate the molecular basis for the synthetic lethality of combined EGFR and NF-κB inhibition and provide mechanism-based rationale for polytherapies against both EGFR and NF-κB to enhance response in lung adenocarcinoma patients. Broadly, our findings provide novel insights into the biological and clinical consequences of the context-specific and dynamic functional interplay between EGFR and NF-κB signaling.
Citation Format: Collin M. Blakely, Evangelos Pazarentzos, Saurabh Asthana, Victor Olivas, Irena Tan, Timothy Fouts, Jeffrey Meshulam, Trever G. Bivona. Erlotinib induces NF-kappa B dependence that promotes EGFR tyrosine kinase inhibitor resistance in lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1836. doi:10.1158/1538-7445.AM2014-1836
Abstract 1837: A HSP90 inhibitor, AUY922, is effective to overcome the MET- and AXL-mediated resistance to EGFR-TKI in lung cancer
Authors: Rho Jin Kyung , Choi Yun Jung , Kime Seon Y. , So Gwang Sup , Choi Se Hoon , Choi Chang-Min , Lee Jae Cheol 
Published: May 2015

Abstract
Activation of bypass signals such as MET and AXL has been identified as one of possible resistant mechanisms to EGFR-TKI. Since various oncoproteins are dependent on HSP90 for its maturation and stability, we investigated the effect of AUY922, a newly developed HSP90 inhibitor of non-geldanamycin class, in lung cancer cells with MET- and AXL-mediated resistance. We established resistant cell lines with HCC827 harboring the deletion mutation on exon 19 of EGFR gene by long-term exposure to increasing concentrations of gefitnib and erlotinib (designated as HCC827/GR and HCC827/ER, respectively). The resistance of HCC827/GR was mediated by MET activation, whereas AXL activation caused resistance in HCC827/ER. AUY-922 treatment effectively suppressed the proliferation and induced cell death in both resistant cell lines. Accordingly, down-regulation of MET and AXL leading to decreased activation of Akt was noted. The inhibitory effect of AUY-922 on AXL and MET was also confirmed in AXL or MET-transfected LK-2 cells. In addition, AUY-922 led to reduced capability of invasion and migration of resistant cells. AUY-922 was effective to control the tumor growth in xenograft mouse models of HCC827/GR and HCC827/ER. Our study showed AUY-922 is one of promising therapeutic options for the MET- and AXL-mediated resistance to EGFR-TKI in lung cancer.
Citation Format: Jin Kyung Rho, Yun Jung Choi, Seon Ye Kime, Gwang Sup So, Se Hoon Choi, Chang-Min Choi, Jae Cheol Lee. A HSP90 inhibitor, AUY922, is effective to overcome the MET- and AXL-mediated resistance to EGFR-TKI in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1837. doi:10.1158/1538-7445.AM2014-1837
Abstract 1840: Contribution of miR-205 in gefitinib-resistant lung cancer cell lines
Authors: Suzuki Toshihiro , Nagasawa Ikuko , Yamaoka Toshimitsu , Ohmori Tohru , Nishio Kazuto , Koyama Kiyotaka , Ogasawara Yuki 
Published: May 2015

Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib is effective therapies for patients with advanced non-small cell lung cancer (NSCLC). Treatment with gefitinib frequently induces drug resistance in NSCLC. Two mechanisms of acquired resistance have been validated in patients. Secondly mutations in EGFR itself, EGFR T790M and amplification of the MET oncogene are observed in resistance case. However, it remains unclear how MET over expression contributes to TKI resistant NSCLC. Recently, micro RNA (miRNA) expression is noted and analyzed because the concern of these molecules in cancer pathogenesis and drug resistance has been elucidated. Circulating tumor cell (CTC) and miRNA are focused as sensitive and non-invasive biomarkers for cancer diagnosis. In this study, we aimed at the miRNA in the gefitinib-resistant cell lines, and evaluated the miRNAs being associated with resistance of gefitinib. We established gefitinib resistant cell lines, in which MET is amplified, PC-9/MET and PC-9/MET-1K by a stepwise escalation of gefitinib concentrations in vitro. Microarray and real time PCR analysis indicated that miR-205 is significantly elevated in both resistant cell lines, and ErbB3 was a significant target. We examine further to reveal that relation between miR-205 and EGFR family, such as ErbB2 and ErbB3. Our results suggest that miR-205 may function as a gefitinib resistance in NSCLC.
Citation Format: Toshihiro Suzuki, Ikuko Nagasawa, Toshimitsu Yamaoka, Tohru Ohmori, Kazuto Nishio, Kiyotaka Koyama, Yuki Ogasawara. Contribution of miR-205 in gefitinib-resistant lung cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1840. doi:10.1158/1538-7445.AM2014-1840
Abstract 1842: Synergistic inhibition of ALK inhibitor-resistant lung cancer cells by dual-targeting EGFR and ALK pathways
Authors: Kim Soyeon , Kim Tae Min , Ahn Yong-Oon , Keam Bhumsuk , Lee Se-Hoon , Heo Dae Seog , Kim Dong-Wan 
Published: May 2015

Abstract
Background: Despite the excellent initial responses of ALK-rearranged lung cancer to the ALK tyrosine kinase inhibitors (TKIs), most patients develop acquired resistance through several mechanisms, including ALK amplification, mutation or activation of alternative signaling pathways. In this study, we investigated the effect of dual-targeting EGFR and ALK pathways in NSCLC cells that are resistant to ALK inhibitors.
Methods: The cell proliferation, apoptosis and cell cycle analysis were measured by spectrophotometry and flow cytometry. The combination effect of EGFR TKI (afatinib or dacomitinib) and ALK TKI (crizotinib or LDK378) was evaluated using a combination index (CI). We analyzed EGFR ligand levels by ELISA and expression of ALK, EGFR and its downstream molecules were detected by Western blot assay after exposure to TKIs.
Results: NCI-H3122CR1 that was resistant to crizotinib and NCI-H3122 cell lines became resistant to LDK378 through the step-wise increase of the drug, resulting in H3122CR1LR1 and H3122LR1 cells, respectively. The resistant cell lines exhibited 10-14-fold higher IC50 values for crizotinib or LDK378 compared with parental cells. The genetic alterations of ALK or EGFR genes were not found in H3122CR1, H3122LR1, and H3122CR1LR1 cells. We analyzed EGFR signaling pathways in these cells to determine their roles in mediating ALK inhibitor resistance. We observed that H3122CR1, H3122LR1 and H3122CR1LR1 cells had higher phospho-EGFR than parental cells. In these cells, mRNA and protein levels of amphiregulin and EGF were up-regulated. Combined treatment with EGFR TKI and LDK378 synergistically inhibited cell growth (CI&lt;1) and induced apoptosis in H3122LR1 and H3122CR1LR1 cells. Similar results were observed in H3122CR1 and SNU-2535 harboring ALK G1269A mutation cells, when exposed to afatinib and crizotinib. The combination of EGFR and ALK TKIs decreased the phosphorylation of several downstream molecules in H3122LR1 and H3122CR1LR1 cells, whereas EGFR or ALK TKI alone did not reduce the phosphorylation levels.
Conclusion: Our results suggest that dual inhibition of ALK and EGFR effectively abrogate ALK and its downstream signals and induce apoptosis in ALK TKIs-resistant, ALK-rearranged NSCLC cells. Therefore, dual-targeting of EGFR and ALK might be a promising strategy for ALK-rearranged NSCLC patients who showed acquired resistance to crizotinib and/or LDK378.
Citation Format: Soyeon Kim, Tae Min Kim, Yong-Oon Ahn, Bhumsuk Keam, Se-Hoon Lee, Dae Seog Heo, Dong-Wan Kim. Synergistic inhibition of ALK inhibitor-resistant lung cancer cells by dual-targeting EGFR and ALK pathways. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1842. doi:10.1158/1538-7445.AM2014-1842