bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 736: Novel, potent MEK inhibitor CIP-1374 for the treatment of cancer
Authors: Chordia Mahendra , Khire Uday , Bhargava Ajay 
Published: February 2011

Abstract
Mitogen-activated protein kinases (MAPKs) are clinically validated, well-established targets for seeking anti-cancer therapy. MAPKs specifically phosphorylate serine/threonine residues of proteins, which are activated by variety of external stimuli (for example mitogens and growth factors) to manifest its actions inside the cell. The activation of MAPKs regulates many functions of the cells with profound physiological implications such as cell growth, survival, apoptosis, differentiation, proliferation and gene expression. MEK 1 and 2 are two human kinases presented in the middle of the classical MAPK-cascade involving upstream RAS-RAF and downstream ERKs. This signal transduction cascade ending in phophorylation of ERKs is extensively studied in cancer pathology. The phosphorylated-ERK upon its translocation to nucleus activates several transcription factors to induce the expression of many genes required for cell survival and proliferation. Because of very high selectivity conferred on MEKs to phophorylate only ERK1 and ERK2, targeting its inhibition offers a very attractive strategy for anti-cancer drug discovery. In addition, the mechanism of action of the known MEK inhibitors such as PD98059 and U0126 is non ATP-competitive (binding to allosteric site) and thus may have least side effects in clinical utility sets in high priority to discover new inhibitors. Currently there are few MEK inhibitors undergoing clinical studies, these includes ARRY-162 (Array Biopharma), RDEA-119 (Ardea biosciences) in combination with sorafenib displaying significant response in sorafenib resistant hepatoma cells and XL-518 (Exelixis) for solid tumors. We present here the discovery of a potent novel MEK inhibitor CIP-1374 for the treatment of cancer. The preliminary in vitro data including inhibition of ERK phophorylation, and whole cell anti-proliferation assays in variety of cancer cell lines will be presented. CIP-1374 exhibited MEK-1 IC50 21.0 nM. In the presence of 1.0 mM ATP, CIP-1374 retained inhibitory activity indicating allosteric mode of binding in ATP non-competitive fashion. The selectivity for MEK inhibition leading to non-proliferation will be presented from the cells without RAS mutation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 736.
Abstract 74: Differential regulation of Erk signaling by mitochondrial superoxide controls the metastatic potential of bladder cancer cells
Authors: Ye Hanqing , Hempel Nadine , Moore Erin , Mian Badar , Melendez Juan A. 
Published: February 2011

Abstract
Microarray profiling and analysis of in vivo-selected metastatic bladder cancer has revealed a strong association between manganese superoxide dismutase (Sod2) expression and invasiveness. However, whether increased Sod2 expression contributes to progression from transitional cell carcinoma (TCC) to invasive bladder cancer has not been established. To test this hypothesis we evaluated the impact of Sod2 overexpression on invasive and migratory properties of two distinct TCC cell lines (UC3 and UC6). Sod2 overexpression increased wound healing and matrigel transwell migration of UC6 while inhibiting these activities in the UC3 cell line. Increases or decreases in invasiveness were accompanied by parallel shifts in the levels of matrix metalloproteinases and VEGF. The opposing effects of Sod2 on TCC invasion and the secretory phenotype were associated with differential Erk activation. Sod2-dependent suppression of Erk activation and MMP-1 expression was reversed by EGF activation in UC3 cells while Erk inhibition blocked the Sod2-mediated elevation in ERK activity, MMP-1 and VEGF levels. Activation or inhibition of Erk by Sod2 in the UC6 and UC3 cell lines, respectively, was driven by superoxide (O2−.) and not H2O2. Increasing mitochondrial superoxide by treatments with complex I or III inhibitors reversed the effects of Sod2 overexpression in both cell lines. Sod2-dependent inhibition of invasion in vitro was associated with impairment in growth of orthotopically implanted tumors. These findings unveil distinct redox regulated attributes of TCC that participate in controlling their invasiveness both in vitro and in vivo. In addition, we have identified the ERK signaling network as a primary target for controlling divergent tumorigenic responses to Sod2 overexpression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 74.
Abstract 740: Oncodesign translational drug discovery process
Authors: Mirjolet Jean-Francois , Bichat Francis , Tizon Xavier , Serin Guillaume , Koob Zina , Duchamp Olivier , Blom Petra , Berthet Cyril , Genne Philippe , Hoflack Jan 
Published: February 2011

Abstract
Despite major advances in translational methods, oncology drug discovery remains a largely sequential process, in most cases starting from a molecular target with some initial but often limited relevance to the disease. It takes multiple years and investments in the order of 5-10 million US$ before a compound is validated in advanced efficacy and safety models. In addition, due to the remoteness of many of the models to real disease pathophysiology, attrition rates in clinical phases remain very high.
We have developed and validated a flexible and iterative “Translational Drug Discovery Process”, in which multiple translational research platforms create a tight link between molecule development and cancer pathophysiology.
Our “Translational Drug Discovery process” is based on multiple research platforms that are used as flexible building blocks to design an optimal process to advance compounds and position them towards precise oncology applications. These platforms include cellular models, in vivo tumourgrafts, phenotypic models and a multi-modality imaging platform. Recent additions that are based on fresh patient-derived tumour tissue include ex vivo 3D models and low passage tumourgrafts. We have also initiated a program to discover 18F-labeled kinase inhibitor based biomarkers/imaging tracers for use in PET applications. Our research base was recently completed with the addition of a diverse collection of potent and selective kinase inhibitors and the associated proprietary chemical technology.
We will describe how we have validated the ex vivo 3D model, based on tumour tissue collected directly in patients or from low passage tumourgrafts in mice. After mincing in small fragments and culturing in poly-HEMA coated plates, the tumour fragments are treated with drug for 24h. Tissue-microarrays are created by fixing and embedding the fragments in paraffin. Different classes of reference compounds were analysed by immunohistochemistry of Ki67 (proliferation) and M30 (apoptosis) using automated quantification. Following this validation, the model is used to select promising new compounds from our internal collection for further optimization or to position advanced compounds from our clients.
We will finally demonstrate how our “Translational Drug Discovery process” has allowed the identification of attractive compounds of high disease relevance at a fraction of the typical drug discovery cost within reduced timelines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 740.
Abstract 747: Development and evaluation of rational combination therapy with imidazoacridinones for human bladder cancer patients through the COXEN algorithm
Authors: Smith Steven C. , Havaleshko Dmytro , Moon Kihyuck , Baras Alexander S. , Bekiranov Stefan , Burke Daniel J. , Lee Jae K. , Theodorescu Dan 
Published: February 2011

Abstract
In most patients, bladder cancer metastasis is incurable with current chemotherapy. To try to address this challenge, we have recently employed the novel COXEN algorithm (1) for in silico drug discovery. This approach utilized publicly available gene expression and in vitro sensitivity data for &gt;40k compounds in NCI-60 cell line screen, from which concordant gene expression prediction models from COXEN enabled our discovery of an imidoazacridinone drug, NSC-637993, with high activity in vitro against forty bladder cancer cell lines (2). Examination of additional “hits” provided by COXEN revealed another compound in this class, C1311 (NSC-645809, Symadex) which is undergoing clinical trials in other tumor types.
Our objective was to develop the foundation for use of C1311 in bladder cancer, alone and in rational combination with other clinically relevant agents. Herein, we demonstrate in a panel of 40 human bladder cancer cells that in vitro cytotoxicity profile for C1311 closely correlates that of NSC-637993 and compares favorably to that of standard of chemotherapeutics. Using genome-wide patterns of synthetic lethality of C1311 with ORF knockouts in budding yeast, we determined that combining C1311 with taxanes could provide mechanistically rational combinations for patients that have failed first line therapy with platinum based chemotherapy. To evaluate the biological relevance of these yeast findings in bladder cancer, we evaluated C1311 singly and in doublet combination with paclitaxel in the hollow fiber assay in mice, observing striking efficacy of the agents in vivo. Last, applying COXEN gene expression prediction from 40 bladder cancer cell lines to human patient tumors with known cisplatin-based chemotherapy response data (N=30) (3), we provide evidence that signatures of C1311 sensitivity exist even within patients exhibiting no change or progressive disease on standard of care agents.
Taken together, these findings provide an exemplar for COXEN-based drug discovery and development, while demonstrating the utility of yeast genetics in guidance of rational combinations in vivo. Most importantly, the high activity of these agents in vitro and in vivo calls for clinical trials of these agents, while COXEN provides genomic biomarkers that may be used for patient selection.
(1) Crunkhorn S. Nat Rev Drug Discov 2007;6:782-3.
(2) Lee JK et al. PNAS 2007;104:13086-91.
(3) Als et al. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4407-14.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 747.
Abstract 754: Development of death receptor agonists for breast cancer therapy
Authors: Srivastava Rakesh K. , Jackman Chris , Davis Rachel , Shankar Sharmila 
Published: February 2011

Abstract
TRAIL and death receptor (TRAIL-R1 and TRAIL-R2) agonistic antibodies have been shown to induce apoptosis in cancer cells and their clinical trials have produced positive results. However, there are no small organic molecular weight compounds that bind to TRAIL-death receptors and induce apoptosis specifically in cancer cells. The purpose of this study was to identify and characterize death receptor agonists (DRAs)/ small molecular weight organic compounds that induce apoptosis in breast cancer cells. The pharmacokinetics of the DRA with a single oral dose was characterized in nude mice. Blood was collected over 72 hour period after drug administration, and analyzed by HPLC-MS/MS for plasma drug concentration. The Cmax, tmax, and AUC of DRA was measured. DRAs inhibited cell viability and colony formation, and induced apoptosis in estrogen-dependent (MCF-7) and independent (MDA-MB-231 and MDA-MB-468) human breast cancer cell lines, but had no effect on human normal mammary epithelial cells and hepatocytes. The ability of DRAs to induce apoptosis was further enhanced in the presence of TRAIL. DRAs formed active TRAIL-DISC (death-inducing signaling complex) similar to that of TRAIL. DRAs inhibited the growth of orthotopically implanted MDA-MB-231 and MDA-MB-468 tumors in nude mice. Histological examination of tumor tissues derived from DRAs-treated nude mice revealed massive caspase-3 activation and apoptosis. Pharmacokinetic data demonstrate that DRA possesses a long terminal half-life, which is acceptable for further clinical development. In conclusion, we have identified, for the first time, DRAs that can be used in the clinic for the treatment of human breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 754.
Abstract 757: Identification and characterization of small molecule activators of BRCA1 expression
Authors: Harlan-Williams Lisa M. , Overton Jeffrey A. , Stecklein Shane R. , Wang Wenjia , Jensen Roy A. 
Published: February 2011

Abstract
Breast cancer susceptibility gene 1 (BRCA1) has been intensely investigated in normal and cancerous cells and mutations in the BRCA1 gene have been found to account for half of the hereditary breast cancer cases. Although the role of BRCA1 in sporadic breast cancer is still uncertain, 30-40% of such cases show downregulation of BRCA1 expression. Because BRCA1 is a tumor suppressor gene, decreased expression of BRCA1 accelerates growth of mammary tumor cells, while increased expression leads to growth arrest and apoptosis. Furthermore, overexpression of BRCA1 in the murine mammary gland provides protection against mutagen-induced mammary neoplasia. In 2009, the American Cancer Society estimates that 254,650 new cases of invasive and in situ breast cancer will be diagnosed among women. Based on estimates of BRCA1 dysfunction in sporadic breast cancers, over 80,000 newly diagnosed malignancies would have decreased BRCA1 expression. Therefore, a novel prevention or therapeutic strategy targeting BRCA1 could have significant impact on incidence and/or survival.
We developed an MCF-7 breast cancer cell line containing stably integrated copies of a BRCA1 promoter-driven firefly luciferase reporter plasmid and screened over 100,000 compounds for their ability to increase BRCA1-firefly luciferase expression. Six hundred and sixty two compounds (hits) increased BRCA1-firefly luciferase activity greater than 2 standard deviations above the control, DMSO. Secondary dose-response BRCA1-firefly luciferase assays confirmed 27 of the top 32 hits as true active compounds. Potency and efficacy of the active compounds were characterized quantitatively as effective concentration (EC50) and area under the curve (AUC), respectively. Cell viability assays determined that the active compounds had little cytotoxic effects. Non-cytotoxic compounds that increased BRCA1-firefly luciferase activity in a dose-dependent manner with a potency (EC50) and efficacy (AUC) greater than or equal to that of genistein, the positive control, were selected to move forward as lead compounds. Thus far, several lead compounds have been identified. Western blot analysis indicates lead compound 17 increases endogenous BRCA1 expression. Furthermore, DNA foci formation assays indicate compound 17 enhances the ability of BRCA1 to localize to sites of ionizing radiation-induced DNA damage. Because BRCA1 appears to play a role as a growth inhibitor and tumor suppressor in adult breast tissues, identification and characterization of a plausible active compound that enhances BRCA1 expression could potentially translate into a novel prevention or therapeutic option for patients afflicted with breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 757.
Abstract 759: Discovery of MK-8033, a highly specific c-Met/Ron dual inhibitor for the treatment of cancer
Authors: Northrup Alan 
Published: February 2011

Abstract
MK-8033 is a highly specific c-Met/Ron dual inhibitor currently under investigation in Phase I clinical trials for the treatment of cancer. The discovery of MK-8033 is described including the first public disclosure of its structure. Additionally, an X-ray co-crystal structure of MK-8033 with the activated form of c-Met will be discussed to address why, contrary to established dogma, an inhibitor of an activated kinase conformation can lead to high specificity. The in vitro and in vivo properties of MK-8033 as well as aspects of the structure-activity relationships in this class will also be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 759.
Abstract 762: 14-Aminocamptothecin: Synthesis, preclinical activity, and potential use for cancer treatment
Authors: Duan Jian-Xin , Cai Xiaohong , Sun Jessica D. , Meng Fanying , Liu Qian , Bhupathi Deepthi , Ahluwalia Dharmendra , Huang Heli , Jung Don , Hart Charles , Matteucci Mark 
Published: February 2011

Abstract
Topoisomerase I targeted camptothecin analogs are currently employed in a number of different anti-cancer therapeutic regimens. Although efficacious, there continue to be active efforts to develop new camptothecin analogs that avoid deficiencies of the current drugs. The extensive historical SAR efforts on camptothecin and its analogs have largely ignored the 14 position. Only the chloro derivative has been reported, and it is inactive, suggesting a lack of tolerance for substitution at that position. We have developed a highly regioselective process for the synthesis of 14-nitro and 14-aminocamptothecin. 14-aminocamptothecin (TH-1320) demonstrated comparable cytotoxic potency relative to the parent camptothecin, and to clinically relevant camptothecin analogs (topotecan, SN-38) when tested on a panel of human cancer cell lines in vitro (H460, PC3, HT29). Unlike most camptothecin analogs in clinical trials, TH-1320 is not a substrate for any of the major clinically relevant efflux pumps, (MDR1, MRP1, and BCRP). Unlike camptothecin, the potency of TH-1320 is minimally affected by the addition of human serum albumin to cell culture media. TH-1320 showed good bioavailability and brain penetration when dosed orally in mice. TH-1320 is tolerated up to 30 mg/kg with daily oral dosing (MTD). An H460 human NSCLC xenograft model in nude mice was produced by s.c. implantation of 1 ×106 cells into the flank of the animals. When tumor size was approximately 150mm3, animals were randomized into groups of 10 mice each for dosing. 30mg/kg of TH-1320 treatment yielded 79% tumor growth inhibition (TGI) and 15 days tumor growth delay (TGD), while the body weight loss was less than 4%, which suggested a good therapeutic index. Two out of 10 animals showed complete response in the study. However, in same model, Topotecan daily dose at 2mg/kg (MTD) showed only 46% TGI. A xenograft model of metastatic ovarian cancer was set up by the intraperitoneal (i.p.) injection of 3×106 IGROV1 human ovarian cancer cells in nude mice. Mice were evaluated twice a week for morbidity and mortality. Kaplan-Meier survival curves were plotted. Vehicle treated animals had a median survival time (MST) of 39 days. TH-1320 treatment significantly prolonged the survival time. MST of 2/3 MTD dose of TH-1320 (20mg/kg, QDx5/wk x 2wks) was 78 days (p&lt;0.05 vs. vehicle by Logrank test), which was similar to the MTD dose of Topotecan (2mg/kg) or Karenitecin (1.5mg/kg) (MST was 72.5 and 71 days, respectively). Given the favorable properties of TH-1320, further effort is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 762.
Abstract 764: 6-Bromoindirubin-3′-oxime induces apoptosis of human melanoma cells associated with inhibition of JAK/STAT3 signaling
Authors: Liu Xiangli , Nam Sangkil , Tian Yan , Kritsanida Marina , Magiatis Prokpios , Skaltsounis Leandros , Jove Richard 
Published: February 2011

Abstract
Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively activated in many diverse human tumors and contributes to malignant progression in part by preventing apoptosis. Janus kinases (JAKs), which are receptor-associated tyrosine kinases, phosphorylate STAT3 in normal as well as tumor cells in response to stimulation with cytokines or growth factors. Thus, the JAK/STAT3 signaling pathway has emerged as a promising new target for development of anti-cancer therapeutics. Previous studies demonstrated that bromoindirubin derivatives have anti-cancer activity with enhanced solubility and bioavailability compared to indirubin, which is a natural product with anti-tumor activity found in traditional herbal medicines. The marine natural product derivative 6-bromoindirubin-3′-oxime (6-BIO) has been shown to inhibit kinase activity of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3β (GSK-3β). Here, we report that 6-BIO induces apoptosis of A2058 melanoma cells, associated with inhibition of JAK/STAT3 signaling. Our data show that 6-BIO inhibits viability and induces apoptosis of melanoma cells with an IC50 value of 5 µM, consistent with reduction of phosphorylation of JAK family kinases (JAK1, JAK2 and TYK2) and STAT3 in both dose- and time-dependent manners. Expression of STAT3 downstream targets involved in preventing apoptosis, particularly Mcl-1, was decreased through inactivation of STAT3 by 6-BIO at similar IC50 values. In contrast to the decreased levels of phosphorylation of JAKs and STAT3, phosphorylation levels of the AKT and MAPK signaling proteins were not inhibited in the cells treated with 6-BIO. Taken together, these data demonstrate that JAK/STAT3 signaling was selectively inhibited by 6-BIO associated with induction of tumor cell apoptosis. Our findings support further development of 6-BIO as a potential anti-cancer therapeutic agent that targets JAK/STAT3 signaling in tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 764.