bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1145: Overcoming chemoresistance and blocking metastasis in breast cancer by targeting HuR
Authors: Wu Xiaoqing , Marquez Rebecca , Han Shuang , Lan Lan , Dixon Dan A. , Aubé Jeffrey , Welch Danny R. , Xu Liang 
Published: July 2017

Abstract
Patients with metastatic breast cancer have a dismal 5-year survival rate of only 24%. Chemoresistance is another contributor to the high mortality of advanced breast cancer. The RNA-binding protein, Hu antigen R (HuR), is overexpressed at all stages of breast cancer development. Cytoplasmic HuR accumulation correlates with high-grade malignancy, poor distant disease-free survival and serves as a prognostic factor for poor clinical outcome in breast cancer. HuR promotes tumorigenesis by promoting mRNA stability and translation of proteins implicated in proliferation, survival, angiogenesis, invasion, and metastasis. HuR also modulates sensitivity of breast cancer cells to chemotherapy. Taken together, HuR is an emerging target for breast cancer therapy, especially metastatic breast cancer. Using shRNA and CRISPR technologies to modulate HuR expression in breast cancer cells, we found that cells with HuR KD/KO were less invasive and more sensitive to chemotherapy. In an effort to discover small molecules that disrupt the HuR-mRNA interaction and block HuR functions in breast cancer progression, metastasis and chemoresistance, high throughput screening (HTS) was carried out in several chemical libraries (~23,000 compounds) using fluorescence polarization (FP) assay, which identified several initial hits with sub-micromolar inhibitory constants (Ki). Those potential inhbitors were then validated by ALPHA assay (Amplified Luminescent Proximity Homogeneous Assay), confirmed by Surface Plasmon Resonance (SPR). In cell-based assays, top hit KH-3 and its optimized analogs, specifically shortened HuR target mRNA half-lifes and decreased the level of the encoded proteins. Moreover, those compounds inhibited invasion and restored chemosensitivity. qPCR arrays focusing on specific pathways revealed that HuR inhibitors potently upregulated metastatic suppressors and downregulated genes frequently overexpressed in lung metastases. In animal studies, KH-3 not only exhibited potent antitumor efficacy in orthotopic xenografts of breast cancer, but also efficiently blocked experimental metastasis. In conclusion, we identified potent and specific small molecule inhibitors of HuR-mRNA interaction for potential anti-metastatic therapy for breast cancer with HuR overexpression.
Citation Format: Xiaoqing Wu, Rebecca Marquez, Shuang Han, Lan Lan, Dan A. Dixon, Jeffrey Aubé, Danny R. Welch, Liang Xu. Overcoming chemoresistance and blocking metastasis in breast cancer by targeting HuR [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 1145. doi:10.1158/1538-7445.AM2017-1145
Abstract 1164: A novel hypoxia-inducible factor-1 inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth
Authors: Won Misun , Ban Hyun Seung , Lee Kyeong , Lee Hongsub , Kim Bo-Kyung , Kim Hwan Mook , Naik Ravi , Park Song-Kyu , Park Joon-Tae , Kim Inhyub , Nam Miso , Hwang Geum-Sook 
Published: July 2017

Abstract
HIF-1 is associated with poor patient prognosis and therapeutic resistance of cancer. We have developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, as a clinical candidate for cancer therapy. Under hypoxic condition, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells. IDF-11774 suppressed the angiogenesis of cancer cells by reducing the expression of HIF-1 target genes. Moreover, IDF-11774 reduced glucose uptake, leading sensitizing cell growth on low glucose condition. IDF-11774 also decreased the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Metabolic profile of IDF-11774-treated cells revealed low levels of NAD+, lactate, and intermediates in glycolysis and tricarboxylic acid (TCA) cycle. More importantly, we observed elevated AMP and diminished ATP level, leading high AMP/ATP ratio. Apparently, phosphorylation of AMPK increased, leading inhibition of mTOR signaling in cells. In vivo xenograft assays demonstrated that IDF11774 has significant anti-cancer efficacy by targeting cancer metabolism in mouse models containing the KRAS, PTEN or VHL mutation, which often occurs in many malignant cancers. Collectively, IDF-11774 suppresses the hypoxia-induced HIF-1α accumulation, thereby repressing tumor growth by regulating cancer metabolism.
Citation Format: Misun Won, Hyun Seung Ban, Kyeong Lee, Hongsub Lee, Bo-Kyung Kim, Hwan Mook Kim, Ravi Naik, Song-Kyu Park, Joon-Tae Park, Inhyub Kim, Miso Nam, Geum-Sook Hwang. A novel hypoxia-inducible factor-1 inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth [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 1164. doi:10.1158/1538-7445.AM2017-1164
Abstract 1184: Characterization of novel STAT5 inhibitors to interfere with the oncogenic activities of STAT5 in hematopoietic diseases
Authors: Wingelhofer Bettina , Maurer Barbara , Heyes Elizabeth C. , Freund Patricia , Cumaraswamy Abbarna A. , Park Jisung , Kubicek Stefan , Valent Peter , Gunning Patrick T. , Moriggl Richard 
Published: July 2017

Abstract
Activation of the transcription factor STAT5 is essential for the pathogenesis of acute myeloid leukemia (AML) containing the FLT3 internal tandem duplication (ITD). FLT3 ITD is a constitutively active tyrosine kinase (TK) that drives the activation of STAT5 leading to the growth and survival of AML cells. Although there has been some success in identifying TK inhibitors that block the function of FLT3 ITD, treatment options are still limited. This is mainly due to drug resistance development by mutations that allow for the continued activation of STATs. Since STAT5 represents a critical mediator of malignant cellular behavior and sits at the convergence point of many kinase pathways, the direct targeting of STAT5 may be an effective means of overcoming this resistance to TK inhibitors. First, we screened a library of potential STAT5 inhibitors for specific SH2 domain binders using a fluorescent polarization assay. Thereby, we identified small inhibitory molecules, called AC-3-019 and AC-4-130, that bind to the SH2 domain of STAT5, subsequently resulting in the disruption of the reciprocal STAT5-phosphopeptide interactions. They efficiently blocked kinase-mediated phosphorylation, dimer formation, nuclear translocation, DNA binding and STAT5 mediated target gene expression. Further, we observed a time- and dose-dependent impairment of proliferation, blocked cell cycle progression and increased apoptosis. Studies with human AML patient-derived samples similarly showed an induction of apoptotic cell death and decreased colony forming capabilities. A combinatorial drug screen revealed synergistic effects with TK inhibitors, as well as with drugs standardly used in the treatment of AML patients, e.g. Cytarabine. Finally, AC-3-019 and AC-4-130 significantly suppressed tumor growth in vivo without general toxicity in healthy organs. Overall, our findings indicate that AC-3-019 and AC-4-130 are potent and selective inhibitors of STAT5. These compounds provide lead structures for further chemical modifications and clinical development for the identification of compounds to improve existing therapies.
Citation Format: Bettina Wingelhofer, Barbara Maurer, Elizabeth C. Heyes, Patricia Freund, Abbarna A. Cumaraswamy, Jisung Park, Stefan Kubicek, Peter Valent, Patrick T. Gunning, Richard Moriggl. Characterization of novel STAT5 inhibitors to interfere with the oncogenic activities of STAT5 in hematopoietic diseases [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 1184. doi:10.1158/1538-7445.AM2017-1184
Abstract 1187: Synthetic lethality screening reveals ATR as responsible for oxaliplatin resistance in colorectal cancer cells
Authors: Combes Eve , Faria-Andrade Augusto , Tosi Diego , Martineau Pierre , Rio Maguy Del , Beijersbergen Roderick , Vie Nadia , Gongora Céline 
Published: July 2017

Abstract
Despite the recent advances achieved in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. Our work was aimed to determine the molecular mechanisms involved in the resistance to oxaliplatin, an anticancer agent widely used in colorectal cancer treatment. To this end, we establish an oxaliplatin-resistant cellular model from the colon adenocarcinoma cell line HCT-116. Among cellular clones obtained, we used one displaying mild resistance (10 fold called HCT116-R1) to perform short hairpin RNA-based loss of function genetic screen in order to identify genes that can modulate the cellular response to oxaliplatin by revealing genes the silencing of which causes drug sensitivity (synthetic lethal interactions with the drug). Using this screen, we have identified ATR (Ataxia-telangiectasia mutated and rad3 related), a protein that plays a key role in the repair of DNA double-strand breaks induced by various DNA damaging agents, including platinum derivatives. We further validated ATR implication in oxaliplatin resistance by showing that (i) shRNA-mediated repression of ATR in HCT116-R1 oxaliplatin-resistant CRC cells sensitizes such cells to the drug; (ii) co-incubation with the ATR inhibitor VE-822 (or VX-970) and oxaliplatin led to a dramatic synergistic effect in six different CRC cell lines (two oxaliplatin-sensitives: HCT116 and SW48; and four oxaliplatin-resistant: HCT116-R1, HCT116-R2, SW48-R1 and SW48-R2) using 2D and 3D cell growth inhibition assays and in vivo. The synergistic effect was evaluated using dose matrix data (an algorithm that was implemented in our group); (iii) the synergistic effect of oxaliplatin and VE-822 was accompanied by an increase of ssDNA, DNA double-strand breaks, growth arrest and apoptosis induction. In conclusion, our preliminary data confirm the results of our screen by demonstrating for the first time the functional role of ATR in the sensitivity to oxaliplatin.
Citation Format: Eve Combes, Augusto Faria-Andrade, Diego Tosi, Pierre Martineau, Maguy Del Rio, Roderick Beijersbergen, Nadia Vie, Céline Gongora. Synthetic lethality screening reveals ATR as responsible for oxaliplatin resistance in colorectal 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 1187. doi:10.1158/1538-7445.AM2017-1187
Abstract 1191: The dopamine (DA) D3 receptor antagonists (PG01037, NGB2904, SB-277011A, and U99194) significantly attenuate ABCG2-mediated multidrug resistance
Authors: Hussein Noor , Amawi Haneen , Ashby Charles R. , Chandrabose Karthikeyan , Mittal Roopali , Christman Ryann , Trivedi Piyush , Tiwari Amit 
Published: July 2017

Abstract
ATP-binding family G2 (ABCG2) transporters are known to produce multidrug resistance (MDR) and limit successful cancer chemotherapy. Using molecular modeling, we obtained data indicating that highly potent and selective dopamine (DA) D3 receptor antagonists had significant docking scores for the active site of the ABCG2 transporter. In this in vitro study, we determined the effect of the D3 receptor antagonists (PG01037, NGB2904, SB-277011A, and U99194) on MDR resulting from the overexpression of ABCG2 transporters. The D3 receptor antagonists alone did not significantly affect the viability of HEK293/ABCG2, H460/MX-20, S1-M1-80 or A549-MX-10 cells, which overexpress ABCG2 transporters. However, the D3 receptor antagonists (PG01037, NGB2904, SB-277011A, and U99194) significantly increased the efficacy of the anticancer drugs mitoxantrone and doxorubicin in the above mentioned cell lines. Efflux studies indicated that both PG01037 and NGB2904 significantly decreased the efflux of rhodamine 123 from H460-MX20 cells. Interestingly, PG01037 and NGB2904 significantly decreased the expression levels of the ABCG2 protein levels as shown by immunocytochemical and Western blot analysis. This suggests that D3 antagonists inhibit both function and expression of ABCG2 transporters at relevant non-toxic concentrations. In conclusion, our in vitro results indicate that PG01037, NGB2904, SB-277011A, and U99194 reverse resistance to mitoxantrone and doxorubicin mediated by overexpression of ABCG2 transporters. Further mechanistic and animal studies are warranted to establish the clinical use of D3 receptor antagonists in reversing ABCG2-mediated MDR.
Citation Format: Noor Hussein, Haneen Amawi, Charles R. Ashby, Karthikeyan Chandrabose, Roopali Mittal, Ryann Christman, Piyush Trivedi, Amit Tiwari. The dopamine (DA) D3 receptor antagonists (PG01037, NGB2904, SB-277011A, and U99194) significantly attenuate ABCG2-mediated multidrug resistance [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 1191. doi:10.1158/1538-7445.AM2017-1191
Abstract 1202: Targeting PIK3C3 to overcome drug resistance resulted from prosurvival autophagy in cancer cells
Authors: CHEN CHUN-HAN 
Published: July 2017

Abstract
Autophagy is an important cellular recycling mechanism in which portions of cytosol or organelles are sequestered into a double-membrane structure and delivered to lysosome for degradation. PIK3C3 is the only class III PI3K, which specifically generates phosphatidylinositol 3-phosphate (PtdIns3P). It in turn recruits proteins containing FYVE or PX domains, thereby initiating various complexes at the membranes of endosomes, phagosomes and autophagosomes. Recently, several studies have shown that autophagy is upregulated in cancer cells when exposing to chemotherapy and radiotherapy. Therefore, the rationale of targeting autophagy addiction in cancer was proposed by combining autophagy inhibition with agents that induce autophagy as a pro-survival response to increase their therapeutic efficacy. We stably knocked down PIK3C3 in cancer cell lines and combined with clinical therapeutic agents reportedly induce pro-survival autophagy. Cell viability was examined by MTT assay and combination index was determined by Compusyn software. The autophagy flux was evaluated by detecting protein levels of LC-3II and p62 through western blot analysis. The results showed PIK3C3 knockdown synergistically sensitize the killing effects of gefitinib and gemcitabine in A549 cells and Panc1 cells, respectively. Both of gefitinib and gemcitabine increased autophagy flux, as evidence by the increase of LC3-II and decrease of autophagy substrate, p62. However, the combination of PIK3C3 knockdown and therapeutic agents increased both of the protein levels of LC3-II and p62. These data suggest incomplete autophagy when the function of PIK3C3 was inhibited. The phenomenon was confirmed by bombing autophagy inducer and PIK3C3 inhibitors. Moreover, no appreciable apoptotic cell death was observed. Taken together, our study revealed a potential strategy by targeting PIK3C3 to overcome drug resistance associated with the pro-survival autophagy in cancer.
Citation Format: CHUN-HAN CHEN. Targeting PIK3C3 to overcome drug resistance resulted from prosurvival autophagy in 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 1202. doi:10.1158/1538-7445.AM2017-1202
Abstract 1208: Analysis of the combinatorial antiproliferative effect of pan RAF inhibitor AZ-628 and MEK1-inhibitor AZD-6244 on a large panel of tumor cell lines
Authors: Chakrabarti Alokta , Feger Daniel , Umber Sarah , Stus Orysya , Birkle Marianne , Siedentopf Oliver , Ehlert Jan E. 
Published: July 2017

Abstract
Cancer is a highly complex, multigenic disease with tumor cells underlying constant transition. Single drug treatments against specific targets frequently result in only partial success because mutations and redundant pathways cause drug resistance. Therefore, drug combinations that effect different synergistically acting targets in the cancer cell in parallel have become a promising strategy to improve the success in many fields of cancer therapy. One example for such an approach is the co-treatment of B-Raf driven tumors with Raf and MEK1 inhibitors. In our study, we determined the combinatorial effect of the pan-Raf inhibitor AZ-628 and the MEK1 inhibitor AZD-6244 on the viability of a large panel of more than 100 tumor cell lines. Whittaker et al. (Mol.CancerTher, 2015) could already show that this drug combination has a significant synergistic effect in several melanoma and colon cancer cell lines. The authors showed evidence that synergistic activity was correlated with enhanced mutation-triggered RAS/RAF/MAPK signaling with a special role for C-Raf in resistance due to a negative feedback mechanism. We here applied the combination of AZD-6244 and AZ-628 in a broad checkerboard pattern to a multitude of cell lines from other entities beyond melanoma and colorectal cancer. Based on these results we correlated the observed synergistic and non-synergistic effects with gene expression profiles of these cell lines and analyzed the requirement of a MAPK activating signaling. Our approach revealed that synergistic activity is not confined to melanoma and colon cancer but is observed in tumors from other entities as well. This observation may expand the usefulness of MEK/Raf inhibitor co-treatment to a larger panel of cancer types.
Citation Format: Alokta Chakrabarti, Daniel Feger, Sarah Umber, Orysya Stus, Marianne Birkle, Oliver Siedentopf, Jan E. Ehlert. Analysis of the combinatorial antiproliferative effect of pan RAF inhibitor AZ-628 and MEK1-inhibitor AZD-6244 on a large panel of tumor cell lines [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 1208. doi:10.1158/1538-7445.AM2017-1208
Abstract 121: Identification and characterization of calcium channel blockers as inhibitors of YAP/TAZ and glioblastoma cells
Authors: Li Wei , Liu Zhijun , Xavier Jennifer , Wang Hong-Gang 
Published: July 2017

Abstract
Glioblastomas (GBM) are the most aggressive primary brain tumors. Despite major advances in neuroimaging and neurosurgical techniques over the past decades, the neurosurgical management of GBM patients remains challenging. Median survival of the patients is about 14.6 months. In order to radically alter the clinical course of these tumors, it is important to develop targeted therapies based on identified oncogenic mutations and signaling pathways that drive their development and sustain their maintenance. In a screen for small molecules, which can inhibit the growth of human glioblastoma cells, we identified a set of calcium channel blockers (CCB). We found that these CCB induce cell death through an apoptosis-independent process. To understand the mechanisms of the non-apoptotic cell death induced by these CCB, we dissected cellular signaling which is responsible for the cell death induction. We found that these CCB are able to inhibit YAP and TAZ, two oncogenic effectors of the Hippo tumor suppressor pathway. Importantly, GBM cells expressing the YAP active mutant or overexpressing YAP are less sensitive to these CCB. These results suggested that inhibition of YAP/TAZ is a mechanism by which CCB suppress tumor cell growth. The Hippo pathway is an essential signaling network in regulating tissue homeostasis. In this pathway, the transcription co-activators YAP and TAZ promote a gene expression program favoring cell proliferation, survival and self-renewal. In normal brain, the nuclear accumulation of YAP is largely limited to regions harboring neural progenitor cells. However, increased nuclear accumulation of YAP is found in various brain tumors, especially those more aggressive subsets of gliomas. In addition, high expression of YAP is associated with reduced mean survival in astrocytoma patients. Our results identified a novel approach to target the Hippo pathway for GBM treatment. We will present our work in further characterizing these regulations and therapeutic potentials of these calcium channel blockers in the conference.
Citation Format: Wei Li, Zhijun Liu, Jennifer Xavier, Hong-Gang Wang. Identification and characterization of calcium channel blockers as inhibitors of YAP/TAZ and glioblastoma 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 121. doi:10.1158/1538-7445.AM2017-121
Abstract 1212: Co-targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase overcomes EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models
Authors: Ouyang Xiaoming , Barling Ashley , Lesch Aletha , Tyner Jeffrey , Jeng Sophia , Zheng Christina , Courtneidge Sara A. , McWeeney Shannon , Kulesz-Martin Molly 
Published: July 2017

Abstract
Background: HNSCC is the sixth most common cancer worldwide. EGFR is overexpressed in up to 90% of HNSCC and associated with poor outcome. An EGFR monoclonal antibody is the only approved molecular targeted therapy for HNSCC, however, resistance eventually occurs in all patients.
Methods: Functional screens including a small-molecule kinase inhibitor panel and an RNAi screen panel were used to identify agents that synergized with EGFR inhibitors in reducing cell viability in HNSCC patient-derived tumor cells. Effective combination therapies were validated in scale-up experiments in 2D and 3D, and their true targets were evaluated using siRNAs to rule out off-target effects of the drugs. Cell viability, cell number and cell colony formation ability were tested upon siRNA treatment. qRT-PCR and immunofluorescent staining was used to test ALK expression in tumor cells before and after anti-EGFR treatment.
Results: Two ALK inhibitors on the drug screen panel showed synergistic effects with EGFR inhibitors in 6/8 HNSCC patients’ tumor cells, despite ineffectiveness of single drug. Scale-up dose-response experiments confirmed patient cell sensitivity to 4 different ALK inhibitors in combination with the EGFR inhibitor Gefitinib. siRNA targeting ALK synergized with Gefitinib in reducing cell viability in the patient cells that responded to EGFR/ALK inhibitor combinations, indicating specificity to ALK. Scale-up RNAi experiments confirmed synergy between siRNAs targeting ALK and EGFR in reducing cell viability, cell number, and colony formation ability. Inhibition of EGFR by siRNA or Gefitinib each increased ALK expression at the mRNA level and protein level, suggesting induction of ALK as a novel mechanism of EGFR inhibitor resistance in HNSCC.
Conclusion: We identified EGFR/ALK inhibitor combinations as a potential strategy for treating EGFR inhibitor resistant HNSCC.
Citation Format: Xiaoming Ouyang, Ashley Barling, Aletha Lesch, Jeffrey Tyner, Sophia Jeng, Christina Zheng, Sara A. Courtneidge, Shannon McWeeney, Molly Kulesz-Martin. Co-targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase overcomes EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models [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 1212. doi:10.1158/1538-7445.AM2017-1212