bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract DDT01-01: Discovery of CGM097 as a novel Mdm2 inhibitor
Authors: Masuya Keiichi , Furet Pascal , Stutz Stefan , Holzer Philipp , Pissot-Soldmann Carole , Buschmann Nicole , Valat Thérèse , Ferretti Stéphane , Ruetz Stephan , Rynn Caroline , Berghausen Joerg , Jacoby Edgar , Lang Marc , Gabriel Tobias , Hofmann Francesco , Kallen Joerg , Jeay Sébastien , Gessier Francois 
Published: May 2015

Abstract
The antiproliferative transcriptional activity of the p53 tumor suppressor is inhibited by the binding of its transactivation domain to the regulator protein Mdm2. Overexpression of Mdm2 or amplification of its gene, leading to a loss of p53 function, has been observed in various tumors. An attractive approach to restore p53 activity in such tumors and to inhibit their growth is to prevent the association of the two proteins by blocking the p53 binding pocket of Mdm2 with a small molecule. In this presentation, we report how the starting point of CGM097 was discovered and how innovative medicinal chemistry efforts led to further optimization of the potency and physico-chemical properties, resulting in CGM097, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction.
Citation Format: Keiichi Masuya, Pascal Furet, Stefan Stutz, Philipp Holzer, Carole Pissot-Soldmann, Nicole Buschmann, Thérèse Valat, Stéphane Ferretti, Stephan Ruetz, Caroline Rynn, Joerg Berghausen, Edgar Jacoby, Marc Lang, Tobias Gabriel, Francesco Hofmann, Joerg Kallen, Sébastien Jeay, Francois Gessier. Discovery of CGM097 as a novel Mdm2 inhibitor. [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 DDT01-01. doi:10.1158/1538-7445.AM2014-DDT01-01
Abstract LB-10: Rational design of small molecules targeting the Ras GEF, SOS1
Authors: Evelyn Chris , Duan Xin , Biesiada Jacek , Seibel William , Meller Jaroslaw , Zheng Yi 
Published: May 2015

Abstract
Ras GTPases regulate multiple intracellular signaling processes involved in gene expression, cell proliferation, and cell survival. Driver mutations of Ras signaling components including K,N,H-Ras, EGFR, PDGFR, Raf, PI3K, and Akt have been found in many types of human cancers. The activation of Ras is catalyzed by guanine-nucleotide exchange factors (GEFs), which stimulate the exchange of GDP for GTP. SOS1 is a major RasGEF that transduces receptor tyrosine kinase signals to Ras and associated ERK/Akt pathways. SOS1 gain-of-function mutations have been found in Noonan syndrome patients. In addition, SOS1 has been shown to be differentially expressed in prostate and breast cancer cells, and is involved in malignancies dependent upon aberrant Ras signaling. In the current studies, we undertake a structure-based virtual screening approach, coupled with biochemical and cell biological validations, to identify lead chemical inhibitors targeting the Ras catalytic domain of SOS1. From a 118,500 compound subset of the NCI/DTP Open Chemical Repository, 135 showed optimal docking energy to a grid of the SOS1 catalytic site from which 36 were selected for experimental screening by a guanine nucleotide exchange assay, i.e. FL-GDP dissociation of Ras under the catalysis of SOS1. Two compounds were confirmed as true hits (NSC-674954 and NSC-658497), of which NSC-658497 displayed micromolar IC50s in both inhibiting FL-GDP dissociation (IC50 - 22.2 µM) from Ras and TR-GTP loading (IC50 - 40.8 µM) of Ras catalyzed by Sos1. In addition, NSC-658497 displayed a target binding Kd of ∼7.0 µM as assayed by microscale thermophoresis, along with dose-dependently disrupting the SOS1 interaction with Ras as assayed by a GST-Ras pull-down analysis. Mutagenesis studies mapped NSC-658497 action site to the catalytic site in SOS1, involving specifically residues I825, T828, T829, and Y912. SAR analysis revealed that NSC-658497 elicits its inhibitory effect on SOS1 through a benzopyran and nitrophenyl moiety. In fibroblast cells, NSC-658497 showed dose-dependent efficacy in inhibiting EGF-stimulated Ras and ERK/AKT activities. Furthermore, NSC-658497 dose-dependently inhibited NIH/3T3, MEF, and MIA-PaCa-2 pancreatic cancer cell proliferation in conjunction with their respective downstream Ras-dependent ERK/AKT activities. Thus, we have identified a class of lead chemical inhibitors targeting SOS1 that can serve as useful tools for studying SOS1 mediated oncogenesis and as hits for further development of future cancer therapeutics.
Citation Format: Chris Evelyn, Xin Duan, Jacek Biesiada, William Seibel, Jaroslaw Meller, Yi Zheng. Rational design of small molecules targeting the Ras GEF, SOS1. [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 LB-10. doi:10.1158/1538-7445.AM2014-LB-10
Abstract LB-107: Inhibiting TNKS sensitizes KRAS mutant cancer cells to MEK inhibitors by suppressing FGFR2 feedback signaling
Authors: Shao Wenlin , Schoumacher Marie , Hurov Kristen , Lehar Joseph , Yan-Neale Yan , Mishina Yuji , Sonkin Dmitriy , Korn Joshua , Flemming Daisy , Jones Michael , Antonakos Brandon , Cooke Vessilina , Stump Mark , Danial Nika , Sellers William 
Published: May 2015

Abstract
Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis and mitosis, and are therefore considered as attractive targets for anti-cancer treatment. Using unbiased combination screens in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors in KRAS mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and anti-tumor activity both in vitro and in vivo than effects observed by previously reported MEK inhibitor combinations. Altogether, our data provides a strong rationale for combined targeting of TNKS and MEK in KRAS mutant cancers.
Citation Format: Wenlin Shao, Marie Schoumacher, Kristen Hurov, Joseph Lehar, Yan Yan-Neale, Yuji Mishina, Dmitriy Sonkin, Joshua Korn, Daisy Flemming, Michael Jones, Brandon Antonakos, Vessilina Cooke, Mark Stump, Nika Danial, William Sellers. Inhibiting TNKS sensitizes KRAS mutant cancer cells to MEK inhibitors by suppressing FGFR2 feedback signaling. [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 LB-107. doi:10.1158/1538-7445.AM2014-LB-107
Abstract LB-109: Therapeutic targeting of Heat shock factor 1 in chronic lymphocytic leukemia
Authors: Rao Rekha M. , Abdulraheem Yacoub , Kambhampati Suman , Ganguly Siddhartha 
Published: May 2015

Abstract
Heat shock factor 1 (HSF1) is a stress-activated transcription factor, that up-regulates the transcription of heat shock proteins (Hsps) and a growing list of tumor-promoting genes. HSF1-induced genes promote protein folding and maturation (through Hsps and associated co-chaperones) as well as orchestrate the transcription of tumor-promoting genes (for e.g., VEFGR, HIF1-alpha, GLUT-1, etc). In this study we propose to evaluate the efficacy of inhibiting HSF1 in Chronic Lymphocytic Leukemia (CLL), a disease that invariably relapses after patients show complete or partial response to first line chemotherapy. Consistent with the established tumor-promoting roles of HSF1, we report that CD19+ B cells isolated from relapsed/refractory CLL patients show high levels of immunofluorescent, nuclear HSF1 staining compared to normal CD19+ B cells, where it is weakly expressed and pre-dominantly cytosolic. CD19+ B primary CLL cells also show enhanced expression of HSF1 as assessed by immunoblot analysis compared to normal CD19+ cells. Treatment of cultured and primary CLL CD19+ B cells with the HSF1 inhibitor triptolide causes a dose-dependent increase in apoptosis, while relatively sparing normal CD19+ B cells. Treatment with triptolide results in the reduced expression of Hsp40, Hsp70 and Hsp27 proteins and a concomitant increase in the PARP cleavage and Caspase 3 cleavage in cultured and primary CLL cells. Lentiviral shRNA-mediated knockdown of HSF1 or triptolide treatment decreased the levels of Bcl-XL and pro-survival signaling molecules, phosphorylated STAT3 (Y-705) and AKT (S473). Based on the established role of Hsps in cytoprotection and resistance to chemotherapy, we hypothesized that inhibition of HSF1 would sensitize CLL cells to agents that promote the accumulation of misfolded proteins (for e.g. Hsp90 inhibitors) or inhibit their disposal (for e.g. treatment with autophagy inhibitors) by inducing proteotoxicity. Consistent with this hypothesis, knockdown of HSF1 or co-treatment with triptolide and the autophagy inhibitor chloroquine resulted in superior anti-CLL activity compared to treatment with either agent alone. Similarly, knockdown of HSF1 or its inhibition with triptolide also sensitized CLL cells to the Hsp90 inhibitor, 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). These pre-clinical studies provide a strong rationale to test the in vitro and in vivo activity of HSF1 inhibitors in combination with agents that promote proteotoxic stress against CLL.
Citation Format: Rekha M. Rao, Yacoub Abdulraheem, Suman Kambhampati, Siddhartha Ganguly. Therapeutic targeting of Heat shock factor 1 in chronic lymphocytic leukemia. [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 LB-109. doi:10.1158/1538-7445.AM2014-LB-109
Abstract LB-132: The central role of EED in orchestration of polycomb group complexes
Authors: Cao Qi , Wang Xiaoju , Zhao Meng , Yang Rendong , Malik Rohit , Qiao Yuanyuan , Poliakov Anton , Cao Xuhong , Harris Clair , Feng Felix Y. , Kalantry Sundeep , Qin Zhaohui , Dhanasekaran Saravana M. , Chinnaiyan Arul M. 
Published: May 2015

Abstract
Polycomb Group (PcG) proteins play a vital role in establishing and maintaining gene expression patterns during cellular differentiation and development. They are epigenetic regulators that are responsible for the repression of target genes involved in development and cell fate specification. PcG proteins function as multimeric, chromatin-associated protein complexes. In mammals, there are two major Polycomb Repressive Complexes, PRC1 and PRC2 that possess histone-modifying activity crucial for their role in gene repression through methylation of histone H3K27, as well as the mono-ubiquitination of histone H2AK119. Components of both PRC1 and PRC2 have been shown to be elevated in a number of tumor types and play an important role in neoplastic progression.
Major components of human PRC2 include the histone methyltransferase, Enhancer of Zeste Homolog 2, and its known binding partners, Embryonic Ectoderm Development (EED) and Suppressor of Zeste 12 (SUZ12) that collectively function as a multi-subunit complex trimethylating histone H3K27. Fundamental collaborators of PRC2 in epigenetic silencing include human PRC1 which consists of B lymphoma Mo-MLV insertion region 1 (BMI1), RING1A (also known as RING1), and RING1B (also known as RING2 or RNF2). Together, they function as a multi-protein complex to ubiquitinate histone H2A at lysine 119 (uH2A). The leading hypothesis regarding PRC2 and PRC1 interaction is that PRC2-mediated tri-methylation of H3K27 recruits PRC1 to genomic loci leading to chromatin condensation and epigenetic silencing of target genes. While the evidence linking PRC1 and PRC2 is circumstantial, a physical or molecular link between these complexes has not been established. In this study, we make an unexpected observation that EED, previously considered a critical component of PRC2, is instead a shared component of PRC2 and PRC1 that functions to interchange these epigenetic complexes at sites of histone modification. This observation markedly enhances our understanding of how PRC2 and PRC1 coordinate epigenetic regulation and may have implications in therapeutically targeting these master regulators of transcription.
Citation Format: Qi Cao, Xiaoju Wang, Meng Zhao, Rendong Yang, Rohit Malik, Yuanyuan Qiao, Anton Poliakov, Xuhong Cao, Clair Harris, Felix Y. Feng, Sundeep Kalantry, Zhaohui Qin, Saravana M. Dhanasekaran, Arul M. Chinnaiyan. The central role of EED in orchestration of polycomb group complexes. [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 LB-132. doi:10.1158/1538-7445.AM2014-LB-132
Abstract LB-138: Autophagy regulator BECN1 acts as a context-dependent tumor suppressor opposing parity-associated and WNT1-driven mammary tumorigenesis
Authors: Cicchini Michelle , Chakrabarti Rumela , Kongara Sameera , Price Sandy , Nahar Ritu , Lozy Fred , Zhong Hua , Vazquez Alexei , Kang Yibin , Karantza Vassiliki 
Published: May 2015

Abstract
Earlier studies reported allelic deletion of the essential autophagy regulator BECN1 in breast cancers implicating BECN1 loss and defective autophagy in tumorigenesis. Recent studies questioned the tumor suppressive role of autophagy, as Atg defects, including Becn1 deletion, suppress tumorigenesis in mouse tumor models. For the first time, we report that monoallelic Becn1 loss has a context-specific tumor-promoting function in parity-associated and WNT-driven mammary tumorigenesis. Our studies demonstrate that Becn1 heterozygocity promotes immature mammary epithelial cell expansion, Receptor Activator of NFκB (RANK) signaling and mammary tumorigenesis in cooperation with the progenitor cell-transforming WNT pathway. Similar to our mouse model, low BECN1 expression and WNT pathway activation in human breast tumors correlate with triple negative breast cancers (TNBCs), RANK axis activation and poor prognosis. Our results provide novel insight in the seemingly paradoxical role of BECN1 in tumorigenesis and the basis for further studies on pathophysiology and treatment of clinically aggressive TNBCs.
Citation Format: Michelle Cicchini, Rumela Chakrabarti, Sameera Kongara, Sandy Price, Ritu Nahar, Fred Lozy, Hua Zhong, Alexei Vazquez, Yibin Kang, Vassiliki Karantza. Autophagy regulator BECN1 acts as a context-dependent tumor suppressor opposing parity-associated and WNT1-driven mammary tumorigenesis. [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 LB-138. doi:10.1158/1538-7445.AM2014-LB-138
Abstract LB-142: Selective inhibition of BET bromodomains epigenetic signaling interferes with the bone-associated tumor vicious cycle
Authors: Lamoureux Francois , Baud'Huin Marc , Calleja Lidia Rodriguez , Jacques Camille , Redini Francoise , Bradner James E. , Heymann Dominique , Ory Benjamin 
Published: May 2015

Abstract
Selective BET bromodomains epigenetic signaling inhibition as a therapeutic strategy in primary bone tumors
The vicious cycle established between bone associated tumors and bone resorption is the central problem with therapeutic strategies against primary bone tumors and bone metastasis. The bromodomain and extra-terminal domain (BET) protein family is an important class of “histone reading protein” capable to recognize the N-acetylation of lysine residues on histone tails. BET bromain proteins have recently been described as regulators of MYC expression in various tumors. In this study, we report data to support inhibition of BET bromodomain as a novel and promising therapeutic strategy that target simultaneously the three partners of the vicious cycle. Treatment with JQ1, a unique BET bromodomain inhibitor, reduced cell viability and induced apoptosis in osteosarcoma cells and, inhibited osteoblastic differentiation in vitro. In vivo, BET inhibitor (IP; 50mg/kg) significantly inhibits tumor growth by 70% and prolongs survival in both POS-1 syngenic and MMNG/HOS xenograft models compared to control. Additionally, these results were accompanied by a decrease of associated bone lesions.
These effects were associated with transcriptional silencing of MYC and RUNX2, resulting from the depletion of BRD4 from their respective loci. Moreover, JQ1 also inhibited osteoclast differentiation by interfering with BRD4-dependent RANKL activation of NFATC1 transcription. Collectively, our data indicates that JQ1 is a potent inhibitor of osteoblast and osteoclast differentiation as well as bone tumor development.
Citation Format: Francois Lamoureux, Marc Baud'Huin, Lidia Rodriguez Calleja, Camille Jacques, Francoise Redini, James E. Bradner, Dominique Heymann, Benjamin Ory. Selective inhibition of BET bromodomains epigenetic signaling interferes with the bone-associated tumor vicious cycle. [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 LB-142. doi:10.1158/1538-7445.AM2014-LB-142
Abstract LB-144: GPR56 internalizes and degrades TG2 in melanoma
Authors: Yang Liquan , Friedland Scott , Corson Nancy , Xu Lei 
Published: May 2015

Abstract
Excessive accumulation of extracellular matrix (ECM) is a hallmark of tumor microenvironment and plays active roles during tumor progression. How this process is regulated and whether it is reversible for cancer treatment are outstanding questions. Our earlier study showed that an adhesion G protein-coupled receptor (GPCR), GPR56, inhibits melanoma growth and metastasis and binds to tissue transglutaminase (TG2), a major cross-linking enzyme in ECM. To understand the function of TG2 in GPR56-mediated melanoma inhibition, we generated immunodeficient Tg2-/- mice and performed xenograft transplantation studies in these mice. Our results revealed an antagonistic relationship between GPR56 and TG2 during melanoma growth: whereas TG2 promotes melanoma growth, GPR56 antagonizes this effect via receptor-mediated internalization and degradation. Furthermore, the down-regulation of TG2 by GPR56 is associated with a reduction in the levels of fibronectin and focal adhesion kinase (FAK), suggesting that the fibronectin-mediated cell adhesion is compromised upon GPR56 expression in melanoma. Taken together, our findings provide genetic evidence for the function of TG2 in GPR56-mediated melanoma inhibition. The uncovered antagonistic relationship between GPR56 and TG2 proposes a mechanism by which ECM accumulation/crosslinking may be reversed, and thus might be exploited for cancer control and treatment.
Citation Format: Liquan Yang, Scott Friedland, Nancy Corson, Lei Xu. GPR56 internalizes and degrades TG2 in melanoma. [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 LB-144. doi:10.1158/1538-7445.AM2014-LB-144
Abstract LB-15: Enhancement of radiotherapeutic efficacy by cisplatin-incorporated bionanocapsule without nephrotoxicity
Authors: Shin Seol Hwa , Park Seok Soon , Jeong Joohee , Choi Jinhyang , Park Jaesook , Lee Jae Hee , Park Hye Ji , Song Si Yeol , Jeong Seong-Yun , Kuroda Shun'ich , Choi Eun Kyung 
Published: May 2015

Abstract
Radiotherapy is one of the most effective tools in the clinical treatment for many types of solid tumors, but the therapeutic efficacy is often limited because of resistance to ionizing radiation. Although cisplatin (CDDP) is widely used as a radiosensitizer to improve therapeutic outcomes, its side effect such as acute nephrotoxicity limits application. To overcome the hurdle of CDDP, it is extremely necessary to apply a delivery system that can enhance the radiotherapeutic efficacy and reduce CDDP-induced side effects. Bionanocapsule (BNC) consisting of hepatitis B virus surface antigen (HBsAg) L protein is approximately 50-nm hollow particles displaying a human hepatocyte-recognizing molecule (pre-S1 peptide). BNC-liposome complex has been developed suitable to deliver drugs and genes to human hepatocytes specifically in vivo. Utilizing the character of BNC targeting hepatocytes and its property to carry anti-cancer agents, we designed a BNC complex incorporating liposomal CDDP (BNC-LP-CDDP) for hepatocellular carcinoma (HCC). HCC is the fifth most common cancer and the third most common cause of cancer related death worldwide. Although surgical resection is the optimal treatment approach, only a small proportion of patients are qualified for surgery and there is a high rate of tumor recurrence. BNC-LP-CDDP has been produced to destroy HCC without nephrotoxicity, and we aimed in this study to confirm the effect enhancing the radiotherapeutic efficacy in vitro and in vivo. The in vitro HCC-specific cytotoxicity of BNC-LP-CDDP was confirmed by comparison between human HCC Hep3B and human NSCLC A549 cells. The result of clonogenic assay to evaluate chemoradiotherapeutic efficacy of BNC-LP-CDDP demonstrated that survival fraction of hep3B showed radiosensitivity efficacy by BNC-LP-CDDP with IR. In vivo, treatment with BNC-LP-CDDP (2 mg/kg) and IR (3 Gy) delayed tumor growth accompanying increased apoptotic cell death more than that of other groups. Furthermore, BNC-LP-CDDP displayed decreased nephrotoxicity of CDDP.
Collectively, our results demonstrate that BNC-LP-CDDP in combination with ionizing radiation enhanced radiotherapeutic efficacy by human liver-pinpoint delivery and eliminated CDDP-induced nephrotoxicity.
Citation Format: Seol Hwa Shin, Seok Soon Park, Joohee Jeong, Jinhyang Choi, Jaesook Park, Jae Hee Lee, Hye Ji Park, Si Yeol Song, Seong-Yun Jeong, Shun'ich Kuroda, Eun Kyung Choi. Enhancement of radiotherapeutic efficacy by cisplatin-incorporated bionanocapsule without nephrotoxicity. [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 LB-15. doi:10.1158/1538-7445.AM2014-LB-15