bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1893: The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of T-ALL
Authors: Diamond Melody , Lo Yvonne , Chadderton Antony , Ye Min , Roman Valerie , Weber Michael , He Chunhong , Wu Liangxing , Yeleswaram Swamy , Roberts Alan , Yao Wenqing , Hollis Gregory , Huber Reid , Scherle Peggy , Ruggeri Bruce , Lee Sang Hyun 
Published: August 2018

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological tumor that is derived from the clonal expansion of immature T-cell progenitors. Multiple genetic and epigenetic alterations are attributed to the development of malignant T cell transformation. Among these, there is supporting evidence for a role of lysine specific demethylase (LSD1) in T-ALL. Oncogenic transcription factors, such as TAL-1, Notch, and ZEB2, form a complex with LSD1 to alter gene expression in T-ALL cells. In addition, LSD1 is aberrantly expressed in ALL, including B-ALL and T-ALL. Furthermore, the overexpression of LSD1 under control of the Sca-1 promoter in transgenic mice triggered T leukemogenesis via acquisition of self-renewal activity and alteration in the differentiation program to T-cell lineages. Together with the known function of LSD1 in regulating the activity of self-renewal in hematological malignancies, these studies prompted evaluation of the efficacy of the potent, selective, and orally bioavailable FAD-directed LSD1 inhibitor, INCB059872, in preclinical models of T-ALL. Expression of LSD1 was abundant in human-T-ALL cell lines as detected by immunoblotting. In vitro, INCB059872 treatment significantly inhibited the proliferation of a subset of human T-ALL cell lines. In vivo, once daily oral administration of INCB059872 inhibited tumor growth significantly in multiple human T-ALL subcutaneous xenograft models including Molt-4, RPMI-8402, CCRF-HSB-2, and CCRF-CEM, but was ineffective against DND-41 xenografts. The anti-tumor efficacy observed with INCB059872 had no clear genetic correlation with Notch mutation status of T-ALL tumors. Combination efficacy studies of INCB059872 with standard care of agents or targeted therapeutic agents in T-ALL models are currently being evaluated. These data suggest exploring the potential clinical development of INCB059872 as a therapy for T-ALL patients.
Citation Format: Melody Diamond, Yvonne Lo, Antony Chadderton, Min Ye, Valerie Roman, Michael Weber, Chunhong He, Liangxing Wu, Swamy Yeleswaram, Alan Roberts, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri, Sang Hyun Lee. The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of T-ALL [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 1893.
Abstract 1899: Targeting interferon induced transmembrane protein-1 (IFITM1) attenuates the aggressive phenotype of inflammatory breast cancer
Authors: Provance Olivia , Geanes Eric , Ogony Joshua , Lui Asona , Young Eric , Gunewardena Sumedha , Lewis-Wambi Joan 
Published: August 2018

Abstract
Inflammatory breast cancer (IBC) is the most aggressive and lethal subtype of breast cancer, with triple-negative IBC being the most difficult to treat IBC subgroup. Improved understanding of mechanisms that lead to aggressiveness of triple-negative IBC could provide a basis for therapeutic targets. Our laboratory has identified a novel interferon (IFN)-α signaling target called interferon induced transmembrane protein-1 (IFITM1), which we hypothesize to promote the aggressive phenotype of triple-negative IBC. CRISPR/CAS9 was utilized to silence IFITM1 in SUM149 TN-IBC cells. In vitro, we found that knockout of IFITM1 increased in colony and mammosphere formation, inhibited migration as observed by the wound healing assay, and enhanced sensitivity to mainstay chemotherapeutic agents (taxol and doxorubicin) analyzed by flow cytometry, MTT and Tunel staining. Western blot analysis shows a decrease in c-Src and p-Src, vimentin, and CD44v expression, which are important regulators of migration and invasion. RNA sequencing analysis further indicates that knocking down IFITM1 promotes overall downregulation of pathways including breast cancer invasion, supporting our in vitro findings. In vivo, IFITM1-CRISPR/KD SUM149 cells were injected into the mammary fat pads of immunosuppressed female NSG mice to assess tumor growth. We found that mice injected with IFITM1-CRISPR/KD SUM149 cells showed significantly reduced tumor growth compared to mice injected with CRISPR/control SUM149 cells, which was observed at all time points examined. We used the mammary intraductal (MIND) method to assess tumor invasion in vivo. IFITM1-CRISPR/KD SUM149 cells showed decreased invasion outside of the mammary duct and decreased vimentin expression, further corroborating our in vitro data. Lastly, through tail vein injections to model metastasis, 33% of mice injected with SUM149 wildtype cells developed liver metastasis while 0% of mice injected with IFITM1-CRISPR/KD SUM149 mice developed liver metastasis. We have ongoing studies to further understand the mechanism by which IFITM1 regulates cellular migration, as well as invasion and angiogenesis in triple-negative IBC, which are all shown to be downregulated through RNA sequencing analysis. Overall, these findings indicate that IFITM1 may be driving the aggressiveness of triple-negative IBC and they suggest that IFITM1 may serve as a potential therapeutic target.
Citation Format: Olivia Provance, Eric Geanes, Joshua Ogony, Asona Lui, Eric Young, Sumedha Gunewardena, Joan Lewis-Wambi. Targeting interferon induced transmembrane protein-1 (IFITM1) attenuates the aggressive phenotype of inflammatory breast 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 1899.
Abstract 1900: Disruption of EGFR and integrin b1 signaling in triple-negative breast cancer through targeting SHC1
Authors: Chang Ya-Fang , Cordell Elizabeth , Wang Yuhao , Greene Geoffrey 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases and is more prevalent among young women and African American women. SHC1 (Src Homology 2 Domain Containing Transforming Protein 1) is an adaptor protein that can transmit cell surface receptor signaling and activate the Ras-ERK pathway. SHC1 is found to be overexpressed in breast cancers and is important in the regulation of tumor progression and drug resistance in ER+ breast cancer. Elevated SHC1 correlates with poor prognosis in breast cancer patients. However, the biological significance of SHC1 in TNBC is not known. In this study, we performed siRNA-mediated knockdown to determine the importance of SHC1 in cell proliferation and drug response in TNBC. We found that although siSHC1 slightly inhibited the tumor growth of TNBC cells, siSHC1 + paclitaxel significantly decreased cell proliferation and increased caspase-3/7 activity in vitro. In invasion assays, siSHC1 significantly decreased the invasion of TNBC cells. To better understand the systemic regulation by SHC1, proteomic analysis was performed after siSHC1 or Scr transfection. Pathway analysis revealed the involvement of PI3K/AKT, FAK, and actin cytoskeleton pathways, by disruption of EGFR and integrin β1 signaling, in the control of TNBC progression and drug sensitivity. In tumor explant studies, siSHC1 significantly enhanced paclitaxel-induced tumor shrinkage and reduced lung metastasis. Our data suggest that SHC1 is a potential therapeutic target in TNBC.
Citation Format: Ya-Fang Chang, Elizabeth Cordell, Yuhao Wang, Geoffrey Greene. Disruption of EGFR and integrin b1 signaling in triple-negative breast cancer through targeting SHC1 [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 1900.
Abstract 1918: Patient-derived hormone-naive prostate cancer xenograft models reveal GRB10 as an AR-repressed gene driving the development of castration-resistant prostate cancer
Authors: Hao Jun , Ci Xinpei , Xue Hui , Wu Rebecca , Dong Xin , Zhang Fang , Qu Sifeng , Zhang Fan , Haegert Anne M. , Gout Peter W. , Collins Colin , Gleave Martin E. , Lin Dong , Wang Yuzhuo 
Published: August 2018

Abstract
Prostate cancer is the most commonly diagnosed noncutaneous cancer and the leading cause of cancer-related death in North American men. Although androgen-deprivation therapy is initially effective in controlling the growth of hormone-naive prostate cancers (HNPC) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. Thus, we aim to identify CRPC driver genes that may provide new targets to enhance CRPC therapy. In this study, patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. Eighty genes were found to be significantly upregulated at the CRPC stage while 7 of them also showed elevated expression prior to CRPC development. Among the latter, Growth Factor Receptor Bound Protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, we found GRB10 expression was elevated in clinical CRPC compared to HNPC in several clinical cohorts. Further investigation suggests that GRB10 is transcriptionally regulated by androgen receptor through an androgen-responsive element located in GRB10's intron. Functionally, we found that GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. Also, a positive correlation between AKT activity and GRB10 expression was found in clinical cohorts. In conclusion, GRB10 acts as a driver of CRPC and sensitizes AR pathway inhibitors, and hence GRB10-targeting provides a novel therapeutic strategy for the disease.
Citation Format: Jun Hao, Xinpei Ci, Hui Xue, Rebecca Wu, Xin Dong, Fang Zhang, Sifeng Qu, Fan Zhang, Anne M. Haegert, Peter W. Gout, Colin Collins, Martin E. Gleave, Dong Lin, Yuzhuo Wang. Patient-derived hormone-naive prostate cancer xenograft models reveal GRB10 as an AR-repressed gene driving the development of castration-resistant 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 1918.
Abstract 192: Preclinical evaluation of TQBWX220, a small-molecule inhibitor of IDO1
Authors: Liu Shilan , Liang Guibai , Wang Dahai , Chen Shuhui , Qian wenyuan , Chan Chi-Chung , Zhang Xiquan , Yang Lin , Tian Xin , Gao Yong , Dong Tiantian , Liu Mei , He Lihua 
Published: August 2018

Abstract
Objective: Indoleamine-2, 3-dioxygenase-1 (IDO1) catalyzes conversion of tryptophan to kynurenine (Kyn), which triggers signaling through GCN2, mTOR and AHR and affects differentiation and proliferation of T cells. Expression of IDO1 by tumor cells or host APCs can inhibit tumor-specific effector CD8+ T cells and enhance the immunosuppressing activity of regulatory T cells. Targeting the IDO pathway via inhibition of IDO1 or blocking its downstream signaling pathways is recognized as one of the prime immunomodulation approaches to unleash antitumor immunity in the tumor microenvironment. As reported, inhibition of IDO1 pathway may also synergize with inhibitory Abs of immune checkpoint proteins, PD-1 and CTLA-4, etc. We report herein TQBWX220, a potent small-molecule inhibitor of IDO.
Method: Potency of TQBWX220 was determined by corresponding IDO1 biochemical and cell assays. Antitumor efficacy of TQBWX220 was evaluated in the syngeneic CT26 xenograft colon cancer model. CT26 cells were engrafted onto the back of BALB/c mice. BID oral administration of vehicle, positive control (INCB024360, 100 mg/kg) and TQBWX220 at different doses were performed. Tumor volumes and mouse body weight were measured at time points after the start of the treatments. Other assays were carried out by using standard methods.
Result: TQBWX220 displayed good IDO1 enzymatic (IDO1 IC50=22 nM) and cellular (Hela EC50=117 nM) potency. It has excellent solubility (&gt;500uM pH7.4) and low inhibition on CYPs and hERG. TQBWX220 significantly inhibited tumor growth at tested doses (60% TGI at 50 mpk/PO BID and 73% TGI at 100 mpk /PO BID) (P&lt;0.05) in the CT-26 syngeneic model. As a result of IDO1 inhibition, reduction of Kyn level in the tumor was also observed.
Conclusion: The promising preclinical antitumor results and its favorable DMPK properties indicate that TQBWX220 has high potential in the clinic as a cancer immunotherapy in combination with checkpoint inhibitors such as anti-PD1 antibodies.
Citation Format: Shilan Liu, Guibai Liang, Dahai Wang, Shuhui Chen, wenyuan Qian, Chi-Chung Chan, Xiquan Zhang, Lin Yang, Xin Tian, Yong Gao, Tiantian Dong, Mei Liu, Lihua He. Preclinical evaluation of TQBWX220, a small-molecule inhibitor of IDO1 [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 192.
Abstract 1924: Role of CXCL16 and ADAM10 in ovarian cancer pathogenesis
Authors: Mir Hina , Kapur Neeraj , Lillard James W. , Singh Shailesh 
Published: August 2018

Abstract
Ovarian cancer is the leading cause of death from gynecological malignancies. The five-year survival rate of ovarian cancer ranges from 30 to 92%, depending on the severity of the disease. Our laboratory has shown the role of chemokines and chemokines receptors in cancer, including ovarian cancer. In this study, we have shown higher expression of CXCR6, which is the only receptor of chemokine CXCL16, in ovarian cancer cell lines and clinical samples. We have tested the biological significance of CXCR6 and soluble CXCL16 (sCXCL16) using ovarian cancer cell lines in vitro. We show higher migratory and invasive potential of high CXCR6 expressing ovarian cancer cell lines in the response of sCXCL16. Migratory and invasive potential in response to sCXCL16 was significantly inhibited when CXCR6 and CXCL16 interaction was blocked using anti-CXCR6 monoclonal antibody. ADAM10 basal mRNA level was higher in cells with high migratory and invasive potential. Similar to cell lines, higher expression of CXCR6 and CXCL16, as well as ADAM10, was observed in tissue, which showed a positive correlation with tumor stage. These results suggest the clinical and biological significance of CXCR6-CXCL16 axis in the pathogenesis of ovarian cancer. Therefore, therapeutics directed to the CXCR6-CXCL16 axis may provide better therapeutic outcome and overall survival.
Citation Format: Hina Mir, Neeraj Kapur, James W. Lillard, Shailesh Singh. Role of CXCL16 and ADAM10 in ovarian cancer pathogenesis [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 1924.
Abstract 1953: Expression and activity of MT1-MMP in endothelial cells is regulated by Semaphorin 4D
Authors: Bugshan Amr , Khoury Zaid , Buhamrah Asma , Basile John R. 
Published: August 2018

Abstract
The semaphorins and plexins, originally shown to control axon growth cone guidance, are now known to influence many aspects of cell adhesion and migration. Our group and others have demonstrated that carcinomas over express Semaphorin 4D (S4D), particularly under conditions of hypoxia, for the purpose of supporting tumor-induced angiogenesis. However, S4D is a transmembrane protein that must be proteolytically cleaved to attract endothelial cells into a malignancy, a process that in head and neck squamous cell carcinoma (HNSCC) is controlled by membrane type 1-matrix metalloproteinase (MT1-MMP). We wanted to test the possibility that S4D acts through its receptor, Plexin-B1 (PB1), to enhance activity of endothelial cell MT1-MMP, facilitating extracellular matrix degradation and further promoting angiogenesis. We observed upregulated transcription, expression and cell surface localization of MT1-MMP in endothelial cells treated with S4D, occurring in a PB1, RhoA and NF-κB-dependent manner. We also demonstrated that S4D-induced endothelial cell collagen degradation, migration and capillary tube formation are suppressed when PB1 is silenced or its downstream effectors RhoA and NF-κB are inhibited. Endothelial MT1-MMP contributes to the ability of these cells to digest their way through the basement membrane and extracellular matrix, a requirement for the creation of the vascular networks that supply a developing tumor with oxygen and nutrients and allow it access to the systemic circulation for metastasis. These results demonstrate that S4D promotes angiogenesis at multiple levels, and suggest that it would be a valid target for anti-angiogenic intervention in the treatment of solid malignancies.
Citation Format: Amr Bugshan, Zaid Khoury, Asma Buhamrah, John R. Basile. Expression and activity of MT1-MMP in endothelial cells is regulated by Semaphorin 4D [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 1953.
Abstract 1955: Suppression of hormone receptor-positive and triple-negative breast cancers by new inhibitors of the transcription factor FOXM1
Authors: Laws Mary J. , Kim Sung Hoon , Ziegler Yvonne , Bindman Noah , Gong Ping , Guillen Valeria Sanabria , Yasuda Mayuri , Singh Divya , El-Ashry Dorraya , Katzenellenbogen John A. , Katzenellenbogen Benita S. 
Published: August 2018

Abstract
The transcription factor FOXM1 is up-regulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, and is associated with less good patient survival. FOXM1 pathway signaling is also a key driver in other aggressive cancers including those in prostate, lung, ovary, and gastrointestinal tract, and in glioblastoma. Therefore, our goal has been to identify FOXM1 inhibitors effective in suppressing breast cancer proliferation both in vitro and in vivo and displaying potency, selectivity and good pharmacokinetic properties for in vivo efficacy. We screened large chemical libraries of over 130,000 compounds from which several were identified and characterized as potential FOXM1 inhibitors. These were then chemically modified and optimized for potency and good pharmacokinetic properties. The best were shown to effectively suppress the proliferation of FOXM1 expressing breast cancer cells, decrease the expression of FOXM1 and FOXM1- regulated genes, and inhibit the chromatin binding of FOXM1 to FOXM1 binding sites in these genes. Inhibitors that had long half-lives (t1/2 greater than 24H) were selected for studies in experimental preclinical mouse models. One inhibitor had good oral efficacy in suppressing the growth of FOXM1-containing breast tumors in NOD-SCID-gamma (NSG) mice, and several others had good efficacy in tumor suppression by subcutaneous but not oral administration. Our findings identify and characterize several compounds that effectively antagonize FOXM1 actions and tumor growth that may be suitable for further clinical evaluation in targeting aggressive breast cancers driven by FOXM1.
Citation Format: Mary J. Laws, Sung Hoon Kim, Yvonne Ziegler, Noah Bindman, Ping Gong, Valeria Sanabria Guillen, Mayuri Yasuda, Divya Singh, Dorraya El-Ashry, John A. Katzenellenbogen, Benita S. Katzenellenbogen. Suppression of hormone receptor-positive and triple-negative breast cancers by new inhibitors of the transcription factor FOXM1 [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 1955.
Abstract 1966: A novel small-molecule compound targeting PBX1-DNA interaction impedes cancer cell survival and carboplatin resistance
Authors: Shen Yao-An , Jung Jin , Rahmanto Yohan Suryo , Selleri Licia , Shih Ie-Ming , Chuang Chi-Mu , Wang Tian-Li 
Published: August 2018

Abstract
Pre-B-cell leukemia homeobox-1 (PBX1), a transcriptional factor and downstream effector of Notch signaling pathway, plays pivotal roles in a wide spectrum of tumors, as well as developmental, inflammatory, autoimmune, and neurodegenerative disorders. Exploiting the crystal structure of the Pbx1-DNA complex, we developed a novel small-molecular inhibitor T417 that can directly block Pbx1-binding to DNA, unlike other existing compounds that interfere with protein-protein interactions. When T417 docks into the hydrophobic pocket of Pbx1 protein, the small molecule can dampen PBX1 transcription activity by hindering its binding to the promoter regions of PBX1 downstream target genes. Intriguingly, the amount of PBX1 expression in cells can dictate its response to T417. Increment of PBX1 expression is found in the high-grade serous carcinoma (HGSC) and carboplatin-resistant (CR) cells, and its expression is generally low in normal tissues as compared to the transformed tissues, making it such an arguably unique therapeutic target in ovarian cancer cells. This expression pattern illustrates the very minimal toxicity of T417 on normal tissues and organs in animal models, while it imposed in vitro and in vivo detrimental effects toward HGSC and CR cells. Besides, T417 holds synergistic cytotoxic effects with DNA damage-related drugs including PARP inhibitor and platinum-based drug. As PBX1 was shown to participate in maintaining cancer stem cell (CSC)-like phenotypes and promoting resistance to antitumor drugs, T417 is able to hammer out the stemness traits of CR cells to revert to a differentiated status through tacking PBX1 signaling cascade. The novel PBX1-targeting compound selectively interferes with PBX1-binding to DNA, which potentially points to powerful therapeutics and broad applications for the treatment of different human malignancies and stem cell therapy.
Citation Format: Yao-An Shen, Jin Jung, Yohan Suryo Rahmanto, Licia Selleri, Ie-Ming Shih, Chi-Mu Chuang, Tian-Li Wang. A novel small-molecule compound targeting PBX1-DNA interaction impedes cancer cell survival and carboplatin resistance [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 1966.