bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3244: Design, synthesis and biological evaluation of substituted furo[2,3-d]pyrimidines as potent microtubule targeting antitumor agents that circumvent Pgp and βIII-tubulin mediated resistance
Authors: Gangjee Aleem , Zhang Xin , Namjoshi Ojas , Devambatla Ravi Kumar Vyas , Hamel Ernest , Mooberry Susan L. 
Published: June 2012

Abstract
Despite the unprecedented success of microtubule targeting agents such as paclitaxel in cancer chemotherapy, overexpression of P-glycoprotein (Pgp) and/or βIII-tubulin can cause clinical resistance to these agents. This limits their utility as cancer chemotherapeutic agents. In addition, several antitubulin agents, particularly the taxoids, have poor water solubility, so that their administration requires formulations that generate hypersensitivity reactions. Recently, we reported two analogs based on 2,6-dimethylcyclopenta[d]pyrimidine and pyrrolo[2,3-d]pyrimidine scaffolds that circumvent both these drawbacks. To study the structure-activity relationship of these new antimitotic agents, we have designed furo[2,3-d]pyrimidines as isosteres of pyrrolo[2,3-d]pyrimidines. We synthesized 2-methyl- and 2-desmethylfuro[2,3-d]pyrimidines AG1 and AG16 from the corresponding 4-chloro and 4-amino analogs, respectively, by treatment with N-methyl-4-methoxyaniline or with 4-methoxyiodobenzene followed by N4-methylation. The synthesis of the 4-chloro analog involved the reaction between acetamidine chloride and diethyl 2-(prop-2-ynyl)malonate in the presence of sodium metal, followed by base-catalyzed cyclization and chlorination. The 4-amino analog was synthesized by treating 1-hydroxypropan-2-one with malononitrile followed by cyclization using formamidine. The compounds AG1 and AG16 inhibit the growth of all the tumor cells in the NCI 60-cell panel with two-digit nanomolar GI50 values and also depolymerize cellular microtubules at low nanomolar concentrations. These compounds inhibit the assembly of purified tubulin (AG1, IC50 = 1.9 ± 0.1 µM; AG16, IC50 = 3.3 ± 0.5 µM) and the binding of colchicine to tubulin (AG1, 63% inhibition at 1 µM, 86% at 5 µM; AG16, 71% at 1 µM, 96% at 5 µM). These compounds are fully active in tumor cells overexpressing either Pgp or βIII-tubulin, thus overcoming two important mechanisms associated with tumor resistance to paclitaxel. We have thus identified a potentially important new scaffold, the furo[2,3-d]pyrimidine, for antitubulin agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3244. doi:10.1158/1538-7445.AM2011-3244
Abstract 3249: Design and synthesis of imidazopyridine derivatives as novel HSP90 inhibitors for the treatment of cancer
Authors: Cai Xiong , Zhai Hai-Xiao , Wang Jing , Samson Maria , Atoyan Ruzanna , Forrester Jeffrey , Qu Hui , Yin Ling , Wang Dagong , Zifcak Brian , DellaRocca Steven , Xu Guang-Xin , Lai Cheng-Jung , Bao Rudi , Simonin Marie-Paule , Keegan Mitchell , Pepicelli Carmen V. , Qian Changgeng 
Published: June 2012

Abstract
The molecular chaperone heat shock protein 90 (HSP90) is involved in folding and stabilization of a wide range of client proteins, including key proteins involved in cancer. Through structure-based design, we synthesized a novel imidazopyridine class of potent HSP90 inhibitors. The synthesis and SAR surrounding this class of compounds will be discussed. The extensive SAR study and lead optimization resulted in the identification of the development candidate CUDC-305, later renamed Debio 0932. Debio 0932 displays high oral bioavailability (96% in mouse), high drug concentrations and a prolonged half-life (20 hr) in tumor tissues. In vitro, Debio 0932 displays potent HSP90 inhibitory activity (IC50, 100 nM) as well as anti-proliferation and apoptosis-inducing activities against a broad range of cancer cell lines (IC50, 40 – 900 nM). In vivo, Debio 0932 is highly effective against various cancer models including NSCLC, AML, breast and colorectal cancers, as well as brain cancers, benefited by its ability to cross the blood-brain barrier to reach therapeutic levels in brain tissue. Debio 0932 also exhibits high selectivity and a favorable safety profile. It was therefore selected as a drug candidate and is currently in Phase 1 clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3249. doi:10.1158/1538-7445.AM2011-3249
Abstract 3252: Potent Aurora kinase inhibitors based on a pyrimidine scaffold: Synthesis, SAR and X-ray crystallography studies
Authors: Luo Yunting , Martin Mathew , Kendig Robert , Pireddu Roberta , Yang Hua , Betzi Stephane , Books Wesley , Yu Huidong , Schonbrunn Ernst , Lawrence Nicholas , Cheng Jin , Sebti Said , Lawrence Harshani 
Published: June 2012

Abstract
Aurora kinases belong to the serine/threonine subclass of kinases involved in the regulation of mitosis. Out of the three isoforms of Aurora kinases; Aurora A, B and C, studies have shown Aurora A and B are up-regulated in many cancers including breast and colorectal cancers. Deregulated Aurora kinase activity has been linked to genetic instability, defects in centrosome function, spindle assembly, chromosome alignment and cytokinesis, all of which can lead to tumorigenesis. Inhibition of Aurora kinase A and B is emerging as target-based therapy in cancer treatment. HLM-8598 was identified from our in-house chemical library as a potent and highly selective inhibitor for Aurora A (IC50 value of 0.073 ± 0.002 μM) over Aurora B (IC50 = 5.4 ± 1.8 μM). HLM-8598 with pyrimidine scaffold represents 3-4 points of diversity for focused library synthesis. X-ray crystallography studies of HLM-8598 bound to Aurora A confirmed HLM-8598 is a type-1 kinase inhibitor that interacts with the ATP binding site of the enzyme. Synthetic modifications around HLM-8598 and focused library synthesis was carried out to explore structure activity relationship studies. The HLM-8598-Aurora A structure assisted the generation of new analogs with improved affinity (IC50 = 40 nM). The synthesis of HLM-8598 analogs, structure activity relationship studies along with X-ray crystallography will be discussed as a part of our efforts to identify Aurora kinase inhibitors. We will discuss the use of kinase structural elements to rationally guide compound synthesis and improve design strategy. The activity of this class of compounds in cells and animal models will be discussed as Aurora inhibitors as potential anti-cancer agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2011-3252
Abstract 326: Investigation of molecular subtypes within FFPE breast cancer tumors using the Breast Cancer DSA®
Authors: Deharo Steve , Mulligan Jude M. , McDyer Fionnuala A. , Bylesjo Max , Halfpenny Iris , Delaney Thomas , Quinn Jennifer E. , Couch Fergus J. , Proutski Vitali , Harkin Paul D. , Kennedy Richard D. 
Published: June 2012

Abstract
Microarray gene expression profiling has facilitated identification of molecular subtypes which can be associated with disease outcome and treatment response. However current platforms lack disease focus, potentially missing vital information contained in patient tissue samples. Moreover, a wide range of FFPE sample cohorts are available but their use is limited by the mRNA degradation inherent to the sample fixation process.
By combining the Breast Cancer DSA® with powerful data analysis methodology, we reproduced the five major molecular subtypes in breast cancer based on a cohort of 107 FFPE samples. Furthermore, we showed that the established subtypes do not extend to BRCA1 and BRCA2 mutant tumours, necessitating expansion of the original breast cancer subtypes definition.
Following RMA pre-processing of the 107 raw profiles, the data was transformed to overcome the association between profile quality and expression variability. If left untreated, this technical variability, often observed with FFPE tissues, can impair the study of inherent biological variations. Using the intrinsic list of 277 genes previously identified as differentiating breast cancer subtypes in fresh frozen samples [Sorlie et al., 2003], initially the sporadic samples were examined using hierarchical agglomerative clustering. All five original subtypes were identified, verifying the ability to detect subtypes in FFPE samples using the breast cancer DSA®. When the intrinsic list was applied to all 107 samples including BRCA1 and BRCA2 mutant samples, the subtypes were still distinguishable, although 31% of the mutant tumors were unclassified suggesting that specific biological processes defining BRCA1/BRCA2 mutant tumours are not captured by the original breast cancer molecular classification.
We have successfully overcome the limitation imposed by FFPE sample microarray profiling by using the Breast Cancer DSA® and advanced data manipulation and exploration to reproduce molecular subtypes previously identified using fresh frozen samples. Further investigation to extend the previously identifed subtypes will progress the investigation of the heterogeneous biology underlying breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 326. doi:10.1158/1538-7445.AM2011-326
Abstract 3298: Structure-based computer-aided drug design to discover novel small molecules that target brain tumor stem cells
Authors: Gu Chunyu , Mahasenan Kiran V. , Auvil Tyler , Joshi Kaushal , Gupta Snehalata , Mattson Anita , Li Cheng , Nakano Ichiro 
Published: June 2012

Abstract
INTRODUCTION. Malignant glioma is one of the most lethal diseases in adulthood and remains refractory to the current therapies including chemoradiotherapies. The cancer stem cell theory dictates that brain tumor stem-like cells (BTSC) account for such intractability of malignant glioma. Recently, several molecularly-targeted therapies have demonstrated a varying degree of success in treatment of cancers including leukemia and breast cancer. In this study, we sought to determine the key kinases that regulate survival, self-renewal, and proliferation of BTSC, and to design novel small molecules by using the structure-based computantional modeling system.
RESULTS. With the neurosphere cultures derived from our glioma patients, we identified 3 kinases that play vital roles in survival and/or proliferation of BTSC in vitro; Fibroblast Growth Factor Receptor 1, Aurora kinase B, and Maternal Embryonic Leucine-zipper Kinase. Structure-based computational modeling allowed us to perform in silico docking of various small molecule candidates to these kinases. As a result, four novel small molecules demonstrated highly specific targeting of the key structural elements of these kinases. We then synthesized these identified candidate compounds and confirmed their in vitro inhibition of the targeting kinase activities. Finally, we will also present our data about the treatment effect with these compounds on the in vitro BTSC growth and the in vivo tumor growth.
CONCLUSION. Structure-based drug design will likely open up a new avenue to discover novel anti-cancer stem cell agents that can selectively target the key kinases in BTSC, leading to the growth arrest of malignant glioma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3298. doi:10.1158/1538-7445.AM2011-3298
Abstract 33: Microarray analysis of zeranol induced gene expression in primary cultured human breast cancer epithelial cells
Authors: Ye Weiping , Xu Pingping , Zhong Saiyi , Lin Shu-Hong , Liu Jie-Yu , Lin Young C. 
Published: June 2012

Abstract
Zeranol (Z) is a nonsteroidal mycotoxin with potent estrogenic activity. Z is one of six growth promoters approved by the FDA for use in the U.S. beef industry to accelerate weight gain, improve feed efficiency and increase the lean meat-to-fat ratio. Recently, the safety meat products from Z-implanted beef has been questioned on the basis that increased exposure of bioactive Z residues may have adverse health implications. Our previous study showed that serum, meat and meat extracts derived from beef cattle implanted with Z significantly stimulated the proliferation of primary cultured human normal and cancerous breast epithelial cells, primary cultured human breast pre-adipocytes, and human breast cancer cell lines. However, little is known about the mechanisms of Z stimulation on the growth of different types of breast cells. To systematically investigate gene expression patterns in primary cultured human breast cancer epithelial cells (PCHBCECs) after Z treatment, we performed DNA microarray analysis. After PCHBCECs were isolated from breast cancer tissue, they were treated with 30 nM Z or 0.1% DMSO, as a vehicle control, for 48 hr, and then mRNA was isolated and purified for gene expression analysis using the Human Genome U133 Plus 2.0 Array TM (Affymetrix Co. Ltd) in the Microarray Shared Resources at The Ohio State University Comprehensive Cancer Center. DNA microarray data were generated on the basis of the criteria of signal intensity and signal ratio. Our results showed that 10 genes were down-regulated and 25 genes were up-regulated in PCHBCECs treated with 30 nM Z as compared to the controls. Among the genes regulated by Z were, limb-bud and heart (LBH) and annexin-1 (ANXA1) which were decreased 2.27 and 2 fold, respectively and human HMG-CoA synthase 1 (HMGCS1) and methyltransferase like 7A (METTL7A) which were up-regulated to 3.8 and 3.25 fold, respectively compared with the controls. Our preliminary data also showed that Z decreased the expression of several tumor suppressor genes, such as protein tyrosine phosphatase γ (PTPγ), p16, p21, and increased DNMT1 expression in PCHBCECs which suggests epigenetic modification of Z in their promoter regions. Our results indicate that long term consumption of beef products with low level of Z or its metabolites might have adverse health effects on human breast. Further validation of our DNA microarray results is in progress in our laboratory (Supported by NIH R01Grant ES 015212).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 33. doi:10.1158/1538-7445.AM2011-33
Abstract 3324: Evidence for label-retaining tumor initiating cells in human glioblastoma
Authors: deleyrolle Loic P. , Harding Angus , Cato Kathleen , Siebzehnrubl Florian , Rahman Maryam , de Assis Denis , Azari Hassan , Olson Sarah , Gabrielli Brian , Osborne Geoffrey , Vescovi Angelo , Reynolds Brent 
Published: June 2012

Abstract
Individual tumor cells display diverse functional behaviors in terms of proliferation rate, cell-cell interactions, metastatic potential and sensitivity to therapy. Moreover, sequencing studies have demonstrated surprising levels of genetic diversity between individual patient tumors of the same type. Tumor heterogeneity presents a significant therapeutic challenge as diverse cell-types within a tumor can respond differently to therapies, and inter-patient heterogeneity may prevent the development of general treatments for cancer. One strategy that may help overcome tumor heterogeneity is the identification of tumor subpopulations that drive specific disease pathologies for the development of therapies targeting these clinically relevant subpopulations. Here we have identified a dye-retaining brain tumor population that displays all the hallmarks of a tumor-initiating subpopulation. Using a limiting dilution transplantation assay in immuno-compromised mice, label-retaining brain tumor cells display elevated tumor initiation properties relative to the bulk population. Importantly, tumors generated from these label-retaining cells exhibit all the pathological features of the primary disease. Together, these findings confirm dye-retaining brain tumor cells as drivers of tumor initiation and therefore viable targets for the development of therapeutics targeting this subpopulation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3324. doi:10.1158/1538-7445.AM2011-3324
Abstract 3325: Phenotypic heterogeneity and distribution of human glioblastoma tumour-initiating cells
Authors: Piccirillo Sara GM , Watts Colin 
Published: June 2012

Abstract
In the last years the idea that tumours arise from a sub-population of cells endowed with “stem cell” features completely revolutionized the field of Oncology. This hypothesis found its initial confirmation by studies on non-solid tumours and then has been extended also to solid tumours. It is a common believe that the so called “cancer stem cells” concept could also provide new insights into the cellular and molecular mechanism of tumour growth and to the development of new therapeutic strategies for the treatment of incurable cancers.
The most lethal tumour of the Central Nervous System is Glioblastoma Multiforme (GBM) which accounts for over 60% of brain tumours. Median life expectancy in optimally managed patients is only 12-14 months with only 25% surviving 24 months. The current clinical management of patients diagnosed with a GBM involves a combination of surgery, radiotherapy and chemotherapy. Radiotherapy has been the principle therapeutic modality since the late seventies and additional targeted chemotherapy is of only modest benefit. Thus the need for new treatments is an unmet clinical need.
It is hypothesized that “cancer stem cells” are a significant factor in gliomagenesis and in the emergence of treatment resistant clones in GBM. However, it is not known how these cells contribute to the heterogeneity of this process.
Here we report the isolation and genetic characterization of distinct “cancer stem cell” populations from different areas of the same GBM specimens: margin, necrotic and core mass. Our results demonstrated that only the cells derived from the core mass retain stem cell features, such as clonogenicity and multipotency, and possess long-term self-renewal and tumour-initiating capacity, therefore can be considered as bona fide “cancer stem cells”. On the contrary, cancer stem cells are rarely found in the other areas.
Most importantly, cells derived from margin areas are not endowed with migratory ability and are genetically aberrant, displaying patterns of karyotypic alterations that overlap only partially with those present in core mass cells. This approach could help us in increasing our understanding of the heterogeneity of cell populations in human GBM in relation to the concept of a stem cell hierarchy in tumours.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3325. doi:10.1158/1538-7445.AM2011-3325
Abstract 3340: Expansion of human breast cancer stem /progenitor cell subpopulation through histone deacetylase inhibitors
Authors: Debeb Bisrat G. , Lacerda Lara , Xu Wei , Robertson Fredika , Ueno Naoto T. , Lucci Anthony , Reuben James M. , Buchholz Thomas A. , Woodward Wendy A. 
Published: June 2012

Abstract
We recently demonstrated that valproic acid, an histone deacetylase (HDAC) inhibitor, radiosensitized breast cancer cells grown on plastic with serum while it radioprotected cells grown in stem cell promoting culture conditions (Debeb et al., 2010) and recently, it has been shown that differentiated cancer cells can de-differentiate into the cancer stem cell phenotype (Meyers et al., 2009; Gupta et al., 2009). Based on these data, we hypothesized that HDAC inhibitors can increase the cancer stem cell population via dedifferentiation of differentiated cancer cells. To examine our hypothesis, Sum159 breast cancer cells were FACS-sorted based on ALDH activity and subsequently treated with one of two known HDAC inhibitors, valproic acid or SAHA. After sorting, ALDH-negative cells were treated either with valproic acid, SAHA, or vehicle. After a week, the percentage of ALDH-positive cells (passage 0, P0) was examined with flow cytometry while the remaining cells were passaged and incubated with and without valproic acid or SAHA for a week and the percentage of ALDH-positive cells again evaluated (P1). This was repeated for the third time (P2). Samples from each generation were also used to assay for, mammosphere formation efficiency, cell cycle analysis as well as to assess RNA and protein expression. In P0 cells, a 3-fold increase in ALDH positive cells was seen in valproic acid-treated cells (35.6% vs.12.6%) and a 1.5-fold increase in SAHA-treated cells (41% vs. 28%) compared to vehicle-treated controls. Moreover, HDAC inhibitors significantly increased primary and secondary mammosphere formation by 3.1 to 13.4-fold. Also, while the percentage of cells in the G0/G1 phase is increased with treatment, the percentage of cells in the S-phase of the cell cycle is significantly reduced. These effects were maintained through multiple passages. Furthermore, the mRNA and protein expression of Beta-catenin and EMT associated genes like vimentin, fibronectin and n-cadherin was significantly increased with treatment in initial and passaged cells. Further functional endpoint studies are being conducted in-vivo to validate these findings.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3340. doi:10.1158/1538-7445.AM2011-3340