bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3768: Targeting of epithelial-to-mesenchyme transition by a novel small molecule inhibitor attenuates prostate and breast cancer invasiveness and bone metastases
Authors: Kroon Jan , van Hooij Onno , Zoni Eugenio , van der Mark Maaike , van der Horst Geertje , Tijhuis Johan , van Rijt-van de Westerlo Cindy , Verhaegh Gerald , Viëtor Henk , Wellink Antoine , Maas Peter , Schalken Jack , van der Pluijm Gabri 
Published: July 2016

Abstract
Transformed epithelial cells can activate embryonic programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype also referred to as epithelial-to-mesenchymal transition (EMT). EMT is associated with poor prognosis in patients with osteotropic cancers. E-cadherin (CDH1) is an essential homotypic cell adhesion molecule that is often down regulated during this process.
EMT-like processes are increasingly linked to therapy resistance and metastasis-initiating cells, thus providing the rationale for the development of novel small-molecule inhibitors that a) block the acquisition of an invasive phenotype in osteotropic cancer cells via EMT or b) revert their invasive, mesenchymal phenotype into epithelial phenotype (MET) by upregulation of CDH1 expression.
High throughput screening of &gt;43,000 LMW compounds, followed by compound design & optimization in vitro led to the identification ten candidate therapeutic compounds. These compounds displayed significant inhibitory effects on cancer cell invasion (&gt;80%) and induced E-cadherin (re)expression, most likely through interference with the binding of transcriptional repressors to the CDH1 E-box elements. We identified a unique compound, OCD155, can effectively and dose-dependently block the acquisition of an invasive phenotype in osteotropic prostate and breast cancer cells (PC-3M-Pro4luc2 and MDA-MB-231/Bluc). When tested in our in vivo models of prostate and breast cancer bone metastasis, treatment of mice with OCD155 strongly and dose-dependently inhibited skeletal metastasis (number of metastases, tumor burden) according to preventive and curative protocols. At the dosages tested, no adverse effects of OCD155 were observed (body weight, liver toxicity parameters). To the best of our knowledge, our studies are the first to demonstrate the efficacy of new small molecule EMT inhibitor in the treatment of experimental skeletal metastasis.
Citation Format: Jan Kroon, Onno van Hooij, Eugenio Zoni, Maaike van der Mark, Geertje van der Horst, Johan Tijhuis, Cindy van Rijt-van de Westerlo, Gerald Verhaegh, Henk Viëtor, Antoine Wellink, Peter Maas, Jack Schalken, Gabri van der Pluijm. Targeting of epithelial-to-mesenchyme transition by a novel small molecule inhibitor attenuates prostate and breast cancer invasiveness and bone metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3768.
Abstract 3772: SHP-1 determines the radiosensitivity of liver cancer cell and dovitinib acts as a novel radiosensitizer in hepatocellular carcinoma via targeting SHP-1/STAT3 signaling
Authors: Hung Man-Hsin , Huang Chao-Yuan , Tai Wei-Tien , Tsai Ming-Hsien , Shin Chih-Ting , Wu Szu-Yuan , Shiau Chung-Wai , Chen Kuen-Feng 
Published: July 2016

Abstract
Background
Hepatocellular carcinoma (HCC) is one of the most lethal human malignancies and curative therapy is not an option for most patients. There is growing interest in the potential benefit of radiotherapy (RT)-integrated therapy. This study aimed to investigate the biological impacts of a novel tumor suppressor Src homology 2 (SH2) domain-containing phosphatase 1 (SHP-1) and its downstream effecter, STAT3, in regulating the radiosensitivity of HCC cells. Furthermore, we explored the efficacy and mechanism of an investigational drug, dovitinib, used in combination with RT.
Material and methods
To understand the impacts of SHP-1/STAT3 signaling affects radiosensitivity, HCC cells with ectopic expression of STAT3, SHP-1 and a catalytic mutant SHP-1 were treated with or without radiotherapy and analyzed by flow cytometry and colony formation assay. Furthermore, five HCC cell lines (PLC5, Hep3B, SK-Hep1, HA59T and Huh-7) were treated with dovitnib, RT or both. The in vitro and in vivo effects of above-mentioned treatments were analyzed.
Results
By sub-G1 analysis and colony formation, we found that HCC cell with ectopic expression of SHP-1 was much more sensitive to RT-induced apoptotic effects, while overexpression of STAT3 or catalytic-dead mutant SHP-1 restored RT-induced reduction of HCC cell survival. Next, we investigated the effects of dovitinib, which showed that dovitinib treatment resulted in SHP-1-mediated downregulation of p-STAT3 and promoted potent apoptosis of HCC cells. Ectopic expression of STAT3, or inhibition of SHP-1 diminished the effects of dovitinib on HCC cells. Furthermore, by ectopic expression and purified recombinant proteins of various mutant forms of SHP-1, the N-SH2 domain of SHP-1 was found to be required for dovitinib treatment.
Importantly, we found that dovitinib potentiated the in vitor and in vivo effects of RT in HCC cells through affecting the SHP-1/STAT3 signaling.
Conclusions
SHP-1/STAT3 signaling is critically associated with the radiosensitivity of HCC cells. A combination therapy with RT and the SHP-1 agonist, such as dovitinib, resulted in enhanced in vitro and in vivo anti-HCC effects.
Citation Format: Man-Hsin Hung, Chao-Yuan Huang, Wei-Tien Tai, Ming-Hsien Tsai, Chih-Ting Shin, Szu-Yuan Wu, Chung-Wai Shiau, Kuen-Feng Chen. SHP-1 determines the radiosensitivity of liver cancer cell and dovitinib acts as a novel radiosensitizer in hepatocellular carcinoma via targeting SHP-1/STAT3 signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3772.
Abstract 3774: KD06 is a novel anti-cancer drug that causes cell death in triple-negative breast cancer cell lines and tumor xenografts
Authors: Ebelt Nancy D. , Taveres Clint D J , Xie Xuemei , Naguib Youssef W. , Jose Jiney , Ruwona Tinashe B. , Devkota Ashwini K. , Park Jihyun , Kaoud Tamer S. , Anslyn Eric V. , Chang Jeffrey T. , Cui Zhengrong , Bartholomeusz Chandra , Dalby Kevin N. 
Published: July 2016

Abstract
Development and screening of small molecule compounds for anti-cancer activity has been of prime interest to the scientific community following the success of targeted, large anti-cancer molecules such as therapeutic antibodies. Small molecules pass more easily through cell membranes and may cross the blood-brain barrier. KD06 is a small molecule triptan-like compound whose parent molecule binds and inhibits serotonin receptors. This compound increases apoptosis of the triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-157 via caspase activation. Treatment with KD06 also causes increased autophagy as well as activation of ER stress responses. The growth of tumor xenografts of MDA-MB-231 cells in nude mice are significantly inhibited by twice weekly treatment with 30mg/kg KD06. Analysis of signaling changes by KD06 using reverse phase protein array (RPPA) revealed significant decreases in Akt/mTOR signaling leading to decreased activation of the translation initiation factor 4E-BP1. Other notable changes included decreased expression of proteins important for mitosis such as Cyclin B1, Aurora B and PLK1, and increased phosphorylation of EGFR and increased expression of PDGFR. Analysis of PIP3 and ATP levels showed no change after treatment with KD06, indicating that decreased signaling through Akt/mTOR is not likely due to PI3K inhibition or AMPK activation. Immunofluorescence with KD06 treated cells revealed a change in cell shape after 4 hours of treatment that was reminiscent of cells treated with microtubule binding drugs. Akt localization was affected. These results imply that KD06 may have anti-cancer activity through its effect on microtubule dynamics, inhibiting proper localization and signaling of molecules important for survival and protein translation such as Akt and mTOR.
Citation Format: Nancy D. Ebelt, Clint D J Taveres, Xuemei Xie, Youssef W. Naguib, Jiney Jose, Tinashe B. Ruwona, Ashwini K. Devkota, Jihyun Park, Tamer S. Kaoud, Eric V. Anslyn, Jeffrey T. Chang, Zhengrong Cui, Chandra Bartholomeusz, Kevin N. Dalby. KD06 is a novel anti-cancer drug that causes cell death in triple-negative breast cancer cell lines and tumor xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3774.
Abstract 378: Exploring intermittent dosing schedules for the Pan PI3K/mTor inhibitor PQR309
Authors: Jorga Karin , Schmitz Debora , Cmiljanovic Natasa , Fabbro Doriano , Dimitrijevic Sasa 
Published: July 2016

Abstract
Introduction
PQR309 is a novel oral balanced dual pan-PI3K and mTOR inhibitor currently in clinical development for the treatment of solid tumors and hematological malignancies. Eighty mg PQR309 given once daily (q.d.) has been established as the MTD in patients with advanced solid cancers. This dose and regimen was associated with plasma concentrations that were pharmacologically active in pre-clinical experiments. However, there is emerging evidence that continuous inhibition of PI3K/mTOR may not be needed to achieve the full effect of PQR309 on tumor growth inhibition and therefore further intermittent dosing regimens will be explored.
Methods
In vivo xenograft studies in nude male rats bearing PC3-derived tumors were conducted with continuous and intermittent dosing schedules to estimate effective plasma concentrations. Pharmacokinetic (PK) data from cancer patients were used to establish a 2-compartment PK model with first order absorption. The model was applied to simulate PK profiles after various intermittent dosing schedules including 2 daily administrations followed by a 5 day wash-out period in a 7 day cycle (2 days ON/5 days OFF) and a regimen with administrations on days 1 and 4 in a 7 day cycle (eg MON/THUR).
Results
A maximum plasma concentration (Cmax) of 800-1200ng/mL PQR309 and an impulse interval of 72 hours or less was associated with maximum effect in the rat xenograft model. In rats PQR309 is rapidly eliminated from plasma but in humans the compound has an elimination half-life of about 40 hours and accumulates upon multiple dosing. The applied model predicts that PQR309 administration given 2 days ON/5 days OFF will build up drug exposure to reach levels that strongly inhibit the targeted signalling pathways. During the 5 day wash-out period, PQR309 levels will decrease significantly, thereby reducing the probability of adverse events. For the alternative dosing regimen MON/THUR, the model predicts a sharp Cmax lasting for a few hours followed by a decrease in drug levels over the following 3 or 4 days, thus minimizing accumulation and drug exposure that could lead to adverse events.
Conclusions
Both intermittent regimens are expected to strongly inhibit the targeted signalling pathways with high transient concentrations around Cmax followed by wash-out periods for healthy tissue recovery to optimize the benefit/risk of the compound. These regimens are currently being explored in clinical studies.
Citation Format: Karin Jorga, Debora Schmitz, Natasa Cmiljanovic, Doriano Fabbro, Sasa Dimitrijevic. Exploring intermittent dosing schedules for the Pan PI3K/mTor inhibitor PQR309. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 378.
Abstract 3783: Co-treatment of metastasis-derived colon cancer cells with bromoethyl indole (BEI) enhances camptothecin or TNF alpha-induced cell death
Authors: Chowdhury Rupak , Miller Sonni A. , Gales Dominique , White Jason , Manne Upender , Samuel Temesgen 
Published: July 2016

Abstract
Colorectal cancer is still the third most deadly cancer in the United States. Currently, there are limited choices of targeted anticancer agents that are durably effective against colorectal cancer. Therefore, chemotherapeutic regimens containing the drugs Camptothecin (CPT), 5-FU and Oxaliplatin remain the mainstays for the treatment of advanced colorectal cancer. We recently found that the indole-derivative small compound Bromoethyl Indole (BEI) potently inhibits the proliferation of colon cancer cells and also suppresses NF-kB activation. In this study, we investigated if the combination of BEI with either CPT or TNFα would enhance cell death in vitro. Metastasis-derived parental or engineered NF-kB-reporter colon cancer cells were used to examine 1) the activation of NF-kB signaling by clinically used drugs, 2) the potential for BEI to inhibit drug-induced NF-kB activation, and 3) the potential for combination treatment to enhance cell death in vitro. Cells were treated with either the drugs alone or in combination with BEI at varying concentrations. NF-kB-inducing concentration of CPT (0.6 to 2.5 μM), TNFα (25 to 50 ng/ml), and BEI concentrations of 1 to 50 μM range were tested. Cell cycle profiles and cell death markers were assessed to determine the effects of single or co-treatments. The expressions of Bcl-xL and cIAP2 (BIRC3) proteins were examined to monitor the targets of NF-kB activation.
Our results show that 1) both TNFα and CPT induce NF-kB signaling in metastasis-derived colon cancer cells, 2) combination of BEI and TNFα or CPT inhibits such a drug-induced NF-kB activation and reduces the expression of NF-kB responsive genes, 3) sequential treatment of the cells with CPT and BEI delivers the best outcome, increasing cell death by up to 3-fold compared to either CPT or BEI alone, and 4) co-treatment of the cells with TNFα and BEI increases cell death by up to 2-fold compared to either TNFα or BEI alone, 5) BEI is most effective in inducing cell death at concentrations between 2 and 10 μM.
We anticipate that BEI will improve the therapeutic index of some chemotherapeutic drugs. Therefore, the potential benefit for combination of BEI with NF-kB activating drugs needs to be evaluated in vivo.
Citation Format: Rupak Chowdhury, Sonni A. Miller, Dominique Gales, Jason White, Upender Manne, Temesgen Samuel. Co-treatment of metastasis-derived colon cancer cells with bromoethyl indole (BEI) enhances camptothecin or TNF alpha-induced cell death. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3783.
Abstract 3790: Targeting the one-carbon metabolism protein MTHFD2 for cancer therapy: Exploiting the unique redox status of cancer cells
Authors: Glasauer Andrea , Steckel Michael , Haegebarth Andrea , Bauser Marcus , Toschi Luisella 
Published: July 2016

Abstract
Two well-established hallmarks of cancer are the need for nucleotides to support continuous cell proliferation and the requirement for cancer cell redox balance. In that respect cancer cells are characterized by an increased rate of reactive oxygen species (ROS) production which can be toxic to cancer cells. In this sense, cancer cells often display an increased ROS scavenging capacity, through antioxidants and NADPH that prevents ROS levels from reaching cytotoxic levels. Mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a critical component of one-carbon metabolism and promotes the reaction of 5, 10-methylene tetrahydrofolate to 10-formyl tetrahydrofolate which is coupled to purine synthesis and the production of NAD(P)H. In its role, MTHFD2 is required for maintaining nucleotide biosynthesis and cancer cell redox balance. Recent studies have shown that MTHFD2 expression is elevated in many cancers compared to normal tissue and expression is correlated with poor survival in breast cancer. In order to validate MTHFD2 as a potential cancer target we show that genetic knockdown of MTHFD2 led to impaired cancer cell survival and proliferation. In breast cancer cells MTHFD2 inhibition caused a decrease in NADPH, an increase in the levels of oxidized glutathione and also promoted the expression of DNA damage and death markers specifically in cancer cells with high MTHFD2 protein expression. Interestingly, ROS-scavenging antioxidants reversed these phenotypes in the presence of MTHFD2 knockdown. Normal cells and low MTHFD2 expressing breast cancer cells had a higher tolerance for the inhibition of the protein. Based on our data, MTHFD2 inhibition leads to the impairment of cancer cells’ antioxidant capacity and ROS-mediated cell death. Therefore, MTHFD2 inhibition may have clinical potential for the treatment of patients with breast cancer, and potentially various other cancers.
Citation Format: Andrea Glasauer, Michael Steckel, Andrea Haegebarth, Marcus Bauser, Luisella Toschi. Targeting the one-carbon metabolism protein MTHFD2 for cancer therapy: Exploiting the unique redox status of cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3790.
Abstract 3801: Pro-chemotherapeutic effects of antibody against extracellular domain of claudin-4 in bladder cancer
Authors: Kuwada Masaomi , Chihara Yoshitomo , Luo Yi , Sasaki Takamitsu , Fujimoto Kiyohide , Kondou Masuo , Kuniyasu Hiroki 
Published: July 2016

Abstract
Bladder cancer displays an aggressive phenotype in the muscle-invasive phase, and is associated with a high mortality rate. Therefore, novel molecular therapeutic targets are needed to improve patient survival. A monoclonal antibody against the extracellular domain of the claudin-4 (CLDN4) tight junction protein was established by immunizing rats with a plasmid vector encoding human CLDN4. A hybridoma clone, producing a rat monoclonal antibody recognizing CLDN4 (clone 4D3), was obtained. Immunohistochemistry by using the 4D3 antibody showed that CLDN4 expression was associated with local invasion, nodal metastasis, distant metastasis, and advanced stage in 86 cases of bladder cancer. The 4D3 antibody inhibited growth, invasion, and survival, associated with abrogation of the intratumoral microenvironment; lowered concentrations of epidermal growth factor and vascular endothelial growth factor were found in 3-dimentional cultures of T24 and RT4 cells. In combination with cisplatin therapy, 4D3 enhanced cisplatin cytotoxicity by increasing cellular permeability, leading to increased intracellular cisplatin concentrations. In mouse models of subcutaneous tumors and lung metastasis, 4D3 enhanced tumor growth inhibition, alone and with concurrent cisplatin treatment. The anti-tumor activity of the newly established 4D3 antibody suggests that it may be a powerful tool in CLDN4-targeting therapy, and in combination with chemotherapy.
Citation Format: Masaomi Kuwada, Yoshitomo Chihara, Yi Luo, Takamitsu Sasaki, Kiyohide Fujimoto, Masuo Kondou, Hiroki Kuniyasu. Pro-chemotherapeutic effects of antibody against extracellular domain of claudin-4 in bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3801.
Abstract 3803: Development of genetic and chemical tools for understanding the recruitment of DOT1L in MLL-fusion driven leukemia and normal hematopoiesis
Authors: Grigsby Sierrah , Chase Jennifer , Ropa James , Serio Justin , Shen Chenxi , Larsen Martha , Donover Preston , Reichman Melvin , Muntean Andrew , Maillard Ivan , Nikolovska-Coleska Zaneta 
Published: July 2016

Abstract
Leukemias harboring rearrangements of mixed-lineage leukemia gene (MLL1) are associated with poor clinical outcomes, and new therapeutic approaches are needed. Rearrangements of the MLL1 gene generate fusion oncoproteins which drive the high expression of the clustered homeobox (HOX) genes and induce leukemic transformation. Genome wide histone methylation studies have revealed that the abnormal expression of MLL1 fusion target genes is associated with high levels of histone H3 lysine 79 (H3K79) methylation. Recruitment of DOT1L (disruptor of telomeric silencing 1-like), a unique histone methyltransferase that catalyzes methylation of H3K79, proved to be essential for the transforming activity of multiple MLL fusion proteins. To gain insights into the unique functions of DOT1L in MLL-driven leukemia, we elucidated the mechanisms of DOT1L recruitment to the MLL fusion partners. The binding site was mapped to a short segment of 10 amino acids in DOT1L and peptides derived from this region disrupted the interaction between DOT1L and MLL-AF9. DOT1L mutants lacking these 10 residues did not support transformation by MLL-AF9. This discovery has established a foundation for disease-specific therapies that target chromatin modifications in highly malignant leukemias. Applying high throughput screening approach several different chemical classes of small molecules that disrupt the protein-protein interactions between DOT1L and oncogenic MLL-fusion proteins were identified and validated. To evaluate if the AF9-binding domain of DOT1L is critical for its functions in normal hematopoietic stem cells as opposed to leukemias driven by MLL fusion proteins, genetic tools were developed to functionally investigate the importance of the DOT1L AF9-binding domain in MLL-AF9-driven leukemia and its role in the physiological functions of DOT1L in normal hematopoiesis. Our findings demonstrate that pharmacological inhibition of the DOT1L complex through disrupting the AF9-DOT1L interactions may provide therapeutic benefits in an array of malignancies with abnormal HOXA gene expression.
Citation Format: Sierrah Grigsby, Jennifer Chase, James Ropa, Justin Serio, Chenxi Shen, Martha Larsen, Preston Donover, Melvin Reichman, Andrew Muntean, Ivan Maillard, Zaneta Nikolovska-Coleska. Development of genetic and chemical tools for understanding the recruitment of DOT1L in MLL-fusion driven leukemia and normal hematopoiesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3803.