bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2073: A systematic investigation of the effect of scheduling of targeted combination therapies on response and dynamics of relapse in triple negative breast cancer cells
Authors: Patwardhan Gauri A. , Wali Vikram B. , Pusztai Lajos , Hatzis Christos 
Published: July 2017

Abstract
Cancer treatment typically involves administration of combination of targeted therapies, but initial response is often followed by disease relapse. The efficacy of a treatment regimen depends on the complex interplay between cancer growth dynamics, drug specificity and kinetics, treatment dose and its scheduling. In standard high-throughput drug screening assays, cells are treated with a single drug cocktail bolus and cell viability is assessed after 2-3 days, thus not considering treatment interactions and long-term effects. Recently we have reported a promising synergistic combination of crizotinib (ALK/MET inhibitor) and ABT-263 (BCL2/BCL-XL inhibitor) against triple negative breast cancer cells. To understand the effect of the sequence and combination doses of crizotnib and ABT-263, we designed a comprehensive experimental plan that involved a total of 567 treatment regimens by varying treatment duration with the first drug (1, 2, or 3 days), followed by drug withdrawal and recovery period (2, 5 or 10 days) and then by a second cycle of treatment and recovery periods over a 26-day period. Cell viability was assessed by the CellTiter-Glo luminescence assay. Interestingly, ABT-263 alone induced higher cytotoxicity than an equivalent dose of crizotinib, but the remaining viable cells recovered much faster after ABT-263 withdrawal than cells after crizotinib withdrawal. Furthermore, cells exposed to higher doses of ABT-263 eventually become less sensitive to crizotinib. Among sequential regimens, crizotinib followed by ABT-263 was significantly more effective than ABT-263 followed by crizotinib, and combinations that included lower doses of ABT-263 were most effective. Taken together, our results show a significant interaction between the two targeted therapies, and suggest that it may be possible to select treatment scheduling that can delay drug resistance and tumor relapse in vivo.
Note: This abstract was not presented at the meeting.
Citation Format: Gauri A. Patwardhan, Vikram B. Wali, Lajos Pusztai, Christos Hatzis. A systematic investigation of the effect of scheduling of targeted combination therapies on response and dynamics of relapse in triple negative breast 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 2073. doi:10.1158/1538-7445.AM2017-2073
Abstract 2078: CK-101 (RX518), a mutant-selective inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC
Authors: Qian Xiangping , Zhu Yong-Liang , Cullen Edward , Niecestro Robert M. , Oliviero James F. 
Published: July 2017

Abstract
Patients with non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations initially respond to small molecule inhibitors of the EGFR tyrosine kinase such as gefitinib and erlotinib. However, secondary mutations in the kinase domain lead to acquired resistance to these inhibitors and limited clinical efficacy, with the EGFR T790M mutation being the most common mechanism of acquired resistance in more than half the patients that experience disease progression. CK-101 (also known as RX518) is a novel, irreversible, orally administered EGFR kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) EGFR. WT EGFR inhibition is believed to drive the commonly observed side effects of skin rash and diarrhea. The 50% inhibitory concentrations (IC50s) of CK-101 and 2 reference compounds, afatinib and AZD-9291, were determined in cell proliferation assays in human cancer cell lines in vitro after incubation for 72 hours. Xenograft studies were conducted in BALB/c nude mice or SCID/Beige mice using once daily oral administration of CK-101 or afatinib for 14 or 21 days. CK-101 selectively inhibited cell proliferation of cell lines expressing both the activating (e.g. HCC827, IC50 &lt;0.015 µM) and resistance mutations (NCI-H1975, IC50 &lt;0.005 µM), but was much less potent at inhibiting proliferation of cell lines expressing the WT form of the receptor (e.g. A431, IC50 &gt;0.5 µM; i.e., CK-101 was over 100 fold less potent against A431 than against NCI-H1975). Single agent CK-101 significantly inhibited tumor growth in EGFR-mutated NSCLC tumor xenograft models, with no activity in a WT EGFR tumor xenograft model. In a xenograft study of PC-9 cells (exon 19 deletion) in SCID/Beige mice, CK-101 inhibited tumor growth by up to 90% (p &lt;0.001). In a xenograft study of NCI-H1975 cells (L858R/T790M double mutant) in BALB/c nude mice, CK-101 inhibited tumor growth by up to 95% (p &lt;0.001). The pre-clinical findings from this work strongly supported the clinical development of CK-101, and a first-in-human study of CK-101 was initiated in September 2016.
Citation Format: Xiangping Qian, Yong-Liang Zhu, Edward Cullen, Robert M. Niecestro, James F. Oliviero. CK-101 (RX518), a mutant-selective inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC [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 2078. doi:10.1158/1538-7445.AM2017-2078
Abstract 208: Proteomic measurements of protein abundance and phosphorylation identify novel kinase-substrate relationships in ovarian cancer
Authors: McDermott Jason E. , Liu Tao , Payne Samuel , Petyuk Vladislav , Zhang Hui , Zhang Zhen , Chan Daniel , Smith Richard , Rodland Karin ,   Clinical Proteomic Tumor Analysis Consortium
Published: July 2017

Abstract
As part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we have recently published the first large-scale proteomic and phosphoproteomic analysis of high-grade serous ovarian tumors. We observed that phosphorylation status was an excellent indicator of pathway activity and could discriminate between patient survival times. This dataset covers tumor samples from 69 patients with deep phosphoproteomic depth (&gt;20,000 phosphopeptides confidently identified). Our continuing analysis of this dataset, reported here, has revealed that the correlation between kinase protein abundance and abundance of phosphorylated target peptides is very low, indicating that kinase abundance is not a good proxy for phosphorylation status overall. However, highly correlated kinase-substrate pairs are significantly more likely to be true relationships (from existing knowledge), demonstrating that this method could be used to predict novel kinase targets in some cases. Using this approach we predicted novel kinase-target relationships and constructed a kinase activity network of ovarian cancer. To better analyze cancer-relevant pathway activity we developed a novel approach that characterizes correlation, differential abundance, and statistical interactions between components to analyze multiple omics types in the context of signaling and functional pathways. We used this approach, called the Layered Enrichment Analysis of Pathways (LEAP), to identify active pathways in molecular subtypes of ovarian cancer, contrasting observations in patients stratified for short versus long overall survival. This analysis resulted in a pre-treatment protein-based signature that is significantly predictive of overall survival. Our results show that integration of multiple omics types has the ability to inform our understanding of novel kinase-substrate interactions, and potentially identify novel interactions associated with patient survival.
Note: This abstract was not presented at the meeting.
Citation Format: Jason E. McDermott, Tao Liu, Samuel Payne, Vladislav Petyuk, Hui Zhang, Zhen Zhang, Daniel Chan, Richard Smith, Karin Rodland, Clinical Proteomic Tumor Analysis Consortium. Proteomic measurements of protein abundance and phosphorylation identify novel kinase-substrate relationships in 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 208. doi:10.1158/1538-7445.AM2017-208
Abstract 2080: Polycomb-mediated disruption of an AR-feedback loop drives castration-resistant prostate cancer
Authors: Fong Ka-Wing , Zhao Jonathan , Kim Jung , Li Shangze , Yang Angela , Song Bing , Rittié Laure , Hu Ming , Yang Ximing , Perbal Bernard , Yu Jindan 
Published: July 2017

Abstract
Androgen receptor (AR) is an androgen-stimulated transcription factor that critically promotes prostate cancer development and progression. In addition to its conventional role in transcriptional activation, AR also acts as a transcriptional repressor to directly inhibit target gene expression. Through meta-analysis of androgen-regulated expression microarray data, we nominated CCN3/NOV, a CCN family protein, as one of the top AR-repressed genes in prostate cancer, implicating that CCN3 may play a tumor suppressive role in prostate cancer development. Therefore, we sought to investigate the molecular functions of CCN3 and its roles in prostate cancer progression especially in castration-resistant prostate cancer (CRPC). We first showed that CCN3 protein physically interacts with AR. The CCN3 interaction domain was mapped in the N-terminal domain of AR which is also present in constitutively active AR variants. Using immunofluorescence microscopy as well as subcellular fractionation technique, we demonstrated that CCN3 sequesters AR or AR variants into the cytoplasm to inhibit AR nuclear translocation, which in turn suppresses AR chromatin targeting and transcriptional activation. However, this negative feedback loop between AR and AR-repressed gene CCN3is disrupted in CRPC through CCN3 persistent epigenetic silencing by the Polycomb group protein EZH2, rendering AR transcriptional activation and CRPC progression. Taking advantage of this repressive mechanism, we restored CCN3 in CRPC cell model, either through ectopic overexpression or treatment with EZH2 inhibitor, which results in strong suppression of CRPC cell proliferation and anchorage-independent cell growth. Consistently, application of EZH2 inhibitor remarkably reduced tumor size in a castrated mice model. Taken together, our data highlight CCN3 as a novel regulator of AR signaling and support the promise of EZH2-targeting agents in treating CRPC.
Citation Format: Ka-Wing Fong, Jonathan Zhao, Jung Kim, Shangze Li, Angela Yang, Bing Song, Laure Rittié, Ming Hu, Ximing Yang, Bernard Perbal, Jindan Yu. Polycomb-mediated disruption of an AR-feedback loop drives castration-resistant prostate 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 2080. doi:10.1158/1538-7445.AM2017-2080
Abstract 2090: Targeting estrogen receptor negative breast cancer cells using diarylthiourea analogs of SHetA2
Authors: Zou Hongye , Ginn Emily , Francis Sabah M. , Liu Shengquan , Louie Maggie 
Published: July 2017

Abstract
Breast cancer is one of the most common cancers that occur in women in the United States. Depending on the expression of estrogen receptor α (ERα), breast cancer can be classified as ER-positive or negative. ER-negative (ER-) breast cancers are often more aggressive and have poorer prognosis compared with the ER-positive (ER+) subtype. Consequently, there is a great need to develop more targeted therapeutic options for ER- breast cancer. One such compound is SHetA2, a flexible heteroarotinoid (flex-hets) that has been shown to inhibit growth of multiple cancer types including breast cancer. However, the clinical utility of SHetA2 is limited by its high lipophilicity (LogP). The goal of this study is to screen eleven 2nd generation analogs of SHetA2 with lower LogP values— SL1-22, 24, 27, 29, 30, 32, 36, 37, 38, 39, and 40— on different breast cancer cell lines to identify potential lead compounds that show the highest anti-growth activities against ER- breast cancer cells and further delineate the mechanism by which these compounds affect breast cancer cell growth. Results from this study demonstrate that SL1-38 [1-(3-chloro-4-methylphenyl)-3-(4-nitrophenyl)thiourea] and SL1-39 [1-(4-chloro-3-methylphenyl)-3-(4-nitrophenyl)thiourea], inhibit ER-negative breast cancer cells (MDA-MB-231, MDA-MB-453 and MDA-MB-468) effectively at micromolar concentrations. In order to understand the mechanisms of action, we evaluated the effects of SL1-38 and 39 on the expression of key cell cycle regulators. Our results show that these two analogs down-regulate the expression of cyclin A, cyclin B, cyclin D1, cyclin E and cdk2 and block S-phase progression. Taken together, these preliminary results suggest that SL1-38 and 39 may be further developed as anti-cancer agents for treating ER-negative breast cancer.
Citation Format: Hongye Zou, Emily Ginn, Sabah M. Francis, Shengquan Liu, Maggie Louie. Targeting estrogen receptor negative breast cancer cells using diarylthiourea analogs of SHetA2 [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 2090. doi:10.1158/1538-7445.AM2017-2090
Abstract 2095: E7090, a novel and selective FGFR inhibitor, for the treatment of cholangiocarcinoma cells harboring FGFR2-fusion genes
Authors: Miyano Saori W. , Arai Yasuhito , Matsui Junji , Shibata Tatsuhiro 
Published: July 2017

Abstract
Genetic abnormalities (gene fusion, mutation and amplification) of fibroblast growth factor receptor (FGFR) family members are known to cause constitutive activation of their signaling pathways, which play an important role in proliferation, survival and migration of cancer cells, as well as tumor angiogenesis. Several recent studies have identified that FGFR2 gene fusions were found in about 10% of intrahepatic cholangiocarcinoma and acted as oncogenes. E7090, an orally available FGFR1, 2 and 3 inhibitor, whose chemical-structure and basic kinase inhibitory profile have been disclosed at AACR2015, is currently under a first-in-human study (NCT02275910). The antitumor activity of E7090 against NIH3T3 and human cholangiocarcinoma cells harboring FGFR2-fusion genes was investigated. NIH3T3 cells stably infected of five FGFR2-fusion genes (FGFR2-AHCYL1, FGFR2-BICC1 type1, FGFR2-BICC1 type2, FGFR2-TXLNA, or FGFR2-KCTD1), all of which were discovered in human intrahepatic cholangiocarcinoma patients, were successfully established and exhibited anchorage-independent cell growth in soft agar assay. E7090 revealed an inhibitory activity on soft agar colony formation of these cells with IC50 values of 0.9 to 17.3 nmol/L in a dose dependent manner. E7090 also reduced activation of downstream pathways of FGFR signaling (MAPK and STAT3) in these cells. Subcutaneous transplantation of FGFR2-BICC1 type2, FGFR2-TXLNA, or FGFR2-KCTD1 expressing cells into immune-deficient mice produced tumor growth, and then oral administration of E7090 at 12.5, 25 and 50 mg/kg showed significant tumor growth inhibition. Finally, antitumor activity of E7090 was examined in a patient derived xenograft (PDX) model of human cholangiocarcinoma harboring FGFR2-BICC1 fusion gene. E7090 also showed dose-dependent antitumor activity and more than 50% of tumor regression was achieved at a dose of 50 mg/kg. In conclusion, E7090 showed potent antitumor activity against FGFR2-fusion genes found in intrahepatic cholangiocarcinoma both in vitro and in vivo models, suggesting that E7090 may provide therapeutic opportunities for cholangiocarcinoma harboring FGFR2-fusion genes.
Citation Format: Saori W. Miyano, Yasuhito Arai, Junji Matsui, Tatsuhiro Shibata. E7090, a novel and selective FGFR inhibitor, for the treatment of cholangiocarcinoma cells harboring FGFR2-fusion genes [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 2095. doi:10.1158/1538-7445.AM2017-2095
Abstract 21: Regulation of proliferation and invasion through the inhibition of IGF signaling pathway on Epstein-Barr virus associated gastric cancer
Authors: Jeong Inhye , Lee Hoi Young , Roh Jae Kyung , Kim Tae Soo , Lee Suk Kyeong , Jang Woo-Ick , Chung Hyun Cheol , Rha Sun Young 
Published: July 2017

Abstract
Epstein-Barr virus associated gastric cancer (EBVaGC) is one subtype of four molecular classifications by TCGA group. Specifically, EBV related viral RNAs, microRNAs and proteins regulate cancer progression phenomena like aggressiveness, motility, invasion and metastasis. Nonetheless, understanding the mechanisms of viral growth dependency beyond malignant EBV transformation are still deficient. Finding the EBV dependent pathway with significant biological role and the clinically appropriated drug is needed for EBVaGC in this regard. We investigated new therapeutic target and its role of regulating in proliferation and invasion using EBVaGC cell line model. First, we determined proliferation both of AGS and EBV infected AGS (AGS-EBV) cell lines during 7 days by proliferation assay. For the test of BI836845 (IGF ligand neutralizing antibody, Boehringer Ingelheim, German) efficacy, CCK-8 assay was performed. mRNA expression levels of IGF-1R, IGF-1, IGFBP-3 and IGFBP-6 which is the key regulator of IGF-signaling were measured by RT-PCR. Also, protein expression levels of IGF associated and downstream factors were confirmed by Western blotting. Lastly, invasiveness of cells was detected by invasion assay. As a result, AGS-EBV showed the slower proliferation rate compared to AGS, but the sensitivity to BI836845 was significantly increased in a dose-dependent manner (p&lt;0.001). Interestingly, baseline IGFBP-3 mRNA expression of was enhanced in AGS-EBV compared with AGS. In addition, BI836845 treated group showed up-regulated IGFBP-3 mRNA level in AGS and down-regulated IGFBP-3 mRNA level in AGS-EBV. When BI836845 treated to AGS-EBV, phospho-Akt level was highly inhibited. Moreover, invasiveness of AGS-EBV was elevated about 2 fold more than AGS. Treatment of BI836845 in AGS-EBV represented significant decrease the invasiveness (p=0.08). In conclusion, AGS-EBV seems to modulate their proliferation and invasion through the IGF signaling pathway. Inhibition of IGF signaling pathway would be the potential therapeutic strategy for EBV associated gastric cancer.
Citation Format: Inhye Jeong, Hoi Young Lee, Jae Kyung Roh, Tae Soo Kim, Suk Kyeong Lee, Woo-Ick Jang, Hyun Cheol Chung, Sun Young Rha. Regulation of proliferation and invasion through the inhibition of IGF signaling pathway on Epstein-Barr virus associated gastric 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 21. doi:10.1158/1538-7445.AM2017-21
Abstract 2106: In-depth profiling of the energy depletion-mediated cancer cytotoxicity by passively delivered zinc complexes via PARP1 activation
Authors: Chung Jinhyuk F. , Park Tae Jung , Norihisa Yoko 
Published: July 2017

Abstract
Dysfunctional apoptotic function from impaired p53 tumor suppressor activity leads to poorer prognosis in cancer patients by compromising drug sensitivity and promoting drug resistance development. Programmed necrosis following energy crisis is a theoretically proposed cytotoxic mechanism for circumventing this problem. Herein we demonstrate that a biodegradable zinc complex is capable of triggering the programmed necrosis via activation of PARP1/PARG/MPTP, which consistently resulted in p53-independent broad spectrum cytotoxicity in vitro across all 20 cancer cell lines tested including many with reported drug resistance phenotypes. Additionally, we investigated its possible interaction with agents that influence p53 for possible antagonism/synergism. Supporting in vivo evidence in both animal models and clinical case studies involving terminal chemo-resistant gastric cancer patients upon oral administration (30 mg Zn/day) are presented. These results implicate macromolecular biodegradable zinc complexes as promising antitumor agents of simple compositions for overcoming the current hurdles in clinics, and warrant further clinical investigations. We plan to advance the studies through non-invasive smart devices reporting real-time blood glucose, blood pressure, microperfusion, and other hemodynamic parameters.
Citation Format: Jinhyuk F. Chung, Tae Jung Park, Yoko Norihisa. In-depth profiling of the energy depletion-mediated cancer cytotoxicity by passively delivered zinc complexes via PARP1 activation [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 2106. doi:10.1158/1538-7445.AM2017-2106
Abstract 2108: Imatinib-induced downregulation of Skp2 inhibits cell growth in human squamous cell carcinoma
Authors: Jeong Hyo Jin 
Published: July 2017

Abstract
It is apparent that Skp2(S-phase kinase associated protein) plays a crucial role in tumorigenesis of various human cancers. Imatinib, inhibitor of BCR-ABL tyrosine kinase, KIT and PDGF receptor, has been approved for the treatment and investigation of chronic myeloid leukemia, gastrointestinal stromal tumors and additional various solid tumors. But An area of skin cancer has not been yet investigated. The aim of this study was to explore the role of the Skp2 in Imatinib antitumor effect on human skin cancer. To explore Imatinib effect on growth of A431 cells (squamous cell carcinoma / skin cancer) we conducted CCK8 assay and Flow cytometry. Western blot assay was performed for determining the functions and molecular mechanism of Imatinib in A431 cells. we found that Imatinib significantly inhibited cell growth and induced cell cycle arrest at G0/G1 phase. Furthermore, we observed that depletion of Skp2 triggered cell cycle arrest and colony formation inhibition by Imatinib. Mechanistically we identified that Imatinib markedly downregulated Skp2 protein expression and subsequently upregulated p21 expression via increased protein stability. In conclusion, Imatinib exerts its antitumor activity via inhibition of Skp2 - p21 axis and these findings suggest that targeting Skp2 by Imatinib could be promising therapeutic approach for Squamous cell carcinoma therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Hyo Jin Jeong. Imatinib-induced downregulation of Skp2 inhibits cell growth in human 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 2108. doi:10.1158/1538-7445.AM2017-2108