bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1631: Structural activity relationship studies of aza-podophyllotoxin derivatives on breast cancer cell line
Authors: Santana Michael Concepcion , Kumar Ajay , Kumar Vineet , Alegria Antonio E. , Malhotra Sanjay V. 
Published: May 2015

Abstract
Podophyllotoxin is a natural precursor for the semi-synthesis of novel anticancer drugs and its an anti-tumor and antibacterial ligand derived from Podophyllum peltatum and Podophyllum emodi (Berberidaceae). Etoposide, etopophoside and tenoposide are anti-cancer drugs in pharmaceutical clinics since 1989 derived from a natural lignin podophyllotoxin. Synthesis of podophyllotoxin in a laboratory is one of the tedious and biggest challenges. In our previous work we developed a very simple method to synthesize extensively modified libraries of several novel derivatives, which were previously impossible to synthesize from podophyllotoxin (Kumar and Alegría, 2010). This method also allows us to explore the synthesis and applications of novel aza-podophyllotoxin derivatives which led to several new analogs with anti-cancer potential. Most of the compounds were found very active against Colon cancer, Melanoma, Ovarian, Renal, prostate and breast cancers at NCI upon a panel of 60 types of human cancer cell lines (Kumar, et.al. 2011). Based on structure activity relationship (SAR) of our compounds and their recent unpublished extraordinary activity especially against colon cancer (COLO 205) cell lines, we designed and synthesized novel aza-podophyllotoxin derivatives using microwave synthesis technique. We will be discussing the synthesis, SAR and biological activity of our novel 2,3-didehyropodophyllotoxin derivatives.
Keywords: Pharmacology, Organic Chemistry and Toxicology
Disclosure of Chemical Structure: The complete chemical structures of the compounds of the compounds used will be disclosed at the time of presentation at the meeting.
Funded by INBRE-NIGMS-NIH gran #8 P20 GM 102475 and REU NSF 1262826
Citation Format: Michael Concepcion Santana, Ajay Kumar, Vineet Kumar, Antonio E. Alegria, Sanjay V. Malhotra. Structural activity relationship studies of aza-podophyllotoxin derivatives on breast cancer cell line. [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 1631. doi:10.1158/1538-7445.AM2014-1631
Abstract 1632: Discovery of a novel series of androgen receptor antagonists with potential therapeutic applications in castration-resistant prostate cancer
Authors: Li Huifang , Hassona Mohamed DH , Lack Nathan A. , Axerio-Cilies Peter , Leblanc Eric , Guns Emma T. , Rennie Paul S. , Cherkasov Artem 
Published: May 2015

Abstract
The human androgen receptor (AR) represents a well-established drug target for prostate cancer treatment. All clinically used antiandrogens, such as Bicalutamide and Enzalutamide, possess similar chemical structures and bind to the AR in the androgen binding site (ABS). These AR antagonists are initially effective, but resistance invariably developed in the castration-resistant prostate cancer (CRPC). Even in late-stage patients, the AR activity is still persistent in the progression of the disease. Thus, there is a continuing need for novel chemical classes of AR antagonists that could overcome the drug resistance.
In this study, we performed a virtual screening against the AR ABS, and identified novel AR antagonists with chemical structures completely different from existing antiandrogens. A 10-(4-Hydroxybenzylidene)anthracen-9(10H)-one compound was discovered that not only effectively inhibits AR transcription and strongly displaces androgen in the ABS, but induces AR degradation in prostate cancer cells. Starting from the initial hit compound, a series of 10-benzylidene-10H-anthracen-9-ones were synthesized and evaluated by in vitro assays. A close analogue with enhanced potency was identified as a lead compound, which demonstrated strong androgen displacement potency, effective AR transcriptional inhibition, and a profound ability to cause degradation of AR. Notably, it exhibited significant activity against MDV3100-resistant prostate cancer cells. This lead compound was evaluated in both non-castrated and castration-resistant LNCaP xenograft models, and demonstrated significant effect on inhibiting tumor growth and reducing prostate specific antigen (PSA). This series of compounds were predicted to adopt a different binding mode from current antiandrogens, which may circumvent the resistance rendered by identified gain-of-function mutations. Further development of this series of AR antagonists may have great therapeutic potential in CRPC.
Citation Format: Huifang Li, Mohamed DH Hassona, Nathan A. Lack, Peter Axerio-Cilies, Eric Leblanc, Emma T. Guns, Paul S. Rennie, Artem Cherkasov. Discovery of a novel series of androgen receptor antagonists with potential therapeutic applications in castration-resistant prostate cancer. [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 1632. doi:10.1158/1538-7445.AM2014-1632
Abstract 1634: A novel small molecule inhibitor of IRE1alpha reverses endocrine resistance in breast cancer cells
Authors: Shajahan-Haq Ayesha N. , Smith Jacqueline , Dakshanamurthy Siva , Wang Difei , Eltayeb Ahreej E. , Brown Milton L. , Clarke Robert 
Published: May 2015

Abstract
Over two-thirds of all breast cancer patients are estrogen receptor alpha positive (ER+). However, almost 50% of all ER+ breast tumors do not respond or respond and later fail on endocrine therapy. Resistance to endocrine therapy remains a significant clinical problem and advanced ER+ breast cancer is largely an incurable disease. The mechanisms of resistance to endocrine therapy remain unclear. We have reported that the unfolded protein response (UPR), a stress-induced cellular adaptive mechanism, acts as a switch controlling the balance between cell death and cell survival in response to these therapies. UPR is activated by three molecular sensors: IRE1alpha, ATF6, PERK. Several components of the UPR, including IRE1alpha, are up-regulated in endocrine resistant cells. We now report a novel small molecule inhibitor of IRE1alpha: N-(4-Phenoxy-phenyl)-2-(5-pyridin-3-yl-2H-[1,2,4]triazol-3-ylsulfanyl)-acetamide (NPPTA). We show that NPPTA interacts with IRE1alpha in vitro and can decrease IRE1alpha protein levels. NPPTA treatment alone inhibits cell proliferation in antiestrogen resistant ER+ breast cancer cells more effectively than in sensitive cells, and in a dose- and time-dependent manner. Normal breast epithelial cells are unaffected by NPPTA. In addition, NPPTA and TAM synergistically inhibit cell proliferation in TAM resistant breast cancer cells. NPPTA's activities are associated with induced G1 cell cycle arrest, increased apoptosis/necrosis, and inhibition of anti-apoptotic signaling. Targeting IRE1alpha may be a new and effective strategy to reverse endocrine resistance in breast cancer.
Citation Format: Ayesha N. Shajahan-Haq, Jacqueline Smith, Siva Dakshanamurthy, Difei Wang, Ahreej E. Eltayeb, Milton L. Brown, Robert Clarke. A novel small molecule inhibitor of IRE1alpha reverses endocrine resistance in breast cancer cells. [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 1634. doi:10.1158/1538-7445.AM2014-1634
Abstract 1636: NMR discovery and molecular-basis of small molecule inhibitors of STAT3
Authors: Namanja Andrew T. , Buettner Ralf , Jove Richard , Chen Yuan 
Published: May 2015

Abstract
Hyperactivation of the signal transducer and activator of transcription 3 (STAT3) transcription factor is a critical molecular anomaly that promotes the constitutive transcription of pro-oncogenic genes in many tumor cells. Therefore, the direct inhibition of STAT3 signaling is a promising strategy to treat cancer. However, targeting transcription factors with small molecule drugs has proved to be challenging. To facilitate the generation of inhibitor leads with good ADME (absorption, distribution, metabolism, and excretion) attributes, we employed fragment-based screening by nuclear magnetic resonance spectroscopy (NMR) in conjunction with electrophoretic mobility shift assay (EMSA) to identify small molecule inhibitors of STAT3. The inhibitors confer specificity for STAT3; inhibit the activation and nuclear accumulation of STAT3; inhibit STAT3 transcription of cell cycle regulatory genes and the proliferation of STAT3-dependent cancer cell lines. We have used two-dimensional methyl NMR of STAT3 to reveal atomic resolution insights on the basis for inhibition. Our results establish an innovative approach to targeting STAT3 that may also be applied to other transcription factors associated with cancer and other diseases.
Citation Format: Andrew T. Namanja, Ralf Buettner, Richard Jove, Yuan Chen. NMR discovery and molecular-basis of small molecule inhibitors of STAT3. [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 1636. doi:10.1158/1538-7445.AM2014-1636
Abstract 1638: Effect of the phytochemical crinumaquine on prostate mesenchymal type cells
Authors: Marvyin Kristo , Liu Run-hui , Jin Huizi , Hua Yaping , Qu Yi , Ke Xisong , Kalland Karl-Henning , Zhang Wei-dong , Oyan Anne Margrete 
Published: May 2015

Abstract
In a prostate carcinogenesis cell culture model benign EP156T prostate epithelial cells underwent epithelial to mesenchymal transition (EMT), and a series of progeny EPT mesenchymal type cells accumulated malignant features in a stepwise fashion. Through the screening of phytochemicals using this model, we have found that crinumaquine inhibited proliferation of mesenchymal type EPT1 and EPT2 cells more efficiently than the compound inhibited epithelial type EP156T cells. Genome-wide gene expression analysis revealed a pattern where crinumaquine induced patterns associated with cell cycle arrest at both G1-S and G2-M phase checkpoints and strong up-regulation of genes involved in DNA repair and CDKN1A and CDKN1C and chromatin rearrangement. Differentially expressed genes were uploaded to the Connectivity Map tools (The Broad Institute, MA, USA) and the highest score was associated with histone deacetylase inhibitors. ChemMap analysis based on its chemical structure indicated that crinumaquine targets ER-β and cyclines. Crinumaquine was also found to induce up-regulation of CDH1 and other genes associated with an incomplete mesenchymal to epithelial transition (MET) of EPT1 and EPT2 cells, and this was associated with increased apoptosis markers in gene expression and Western blot analyses. Due to the selective inhibition of mesenchymal type and more malignant cells of the model, crinumaquine will be further explored concerning its anti-cancer leading compound potential.
Citation Format: Kristo Marvyin, Run-hui Liu, Huizi Jin, Yaping Hua, Yi Qu, Xisong Ke, Karl-Henning Kalland, Wei-dong Zhang, Anne Margrete Oyan. Effect of the phytochemical crinumaquine on prostate mesenchymal type cells. [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 1638. doi:10.1158/1538-7445.AM2014-1638
Abstract 1639: Development of novel thiobarbituric acid derivatives as potential cancer therapeutics
Authors: Ramisetti Srinivasa R. , Lee Sang Y. , Pandey Manoj K. , Amin Shantu G. , Sharma Arun K. 
Published: May 2015

Abstract
Chemotherapy drugs for the treatment of cancer are generally directed to inhibit the reproduction of malignant cells and killing cells, thereby preventing tumor growth or reducing tumor size. Many of these drugs develop resistance to tumor cells by different mechanisms. Therefore a significant clinical need exists for the development of additional chemotherapeutic agents that are toxic to a wide range of tumor cells, in particular tumors that are resistant to current treatments such as radiotherapy and chemotherapy. From recent past, it has been known that barbituric acid derivatives exhibit different biological activities such as anti-depressant, anti-convulsant, anti-viral and anti-cancer activities. Among them some thiobarbituric acid derivatives, such as merocyanine and merbarone have been proposed as possible modulators of apoptosis in several cancer cells including glioblastoma multiforme (GBM), lung, melanoma, leukemia, breast cancer, prostate cancer, and cervical cancer; albeit not particularly for cancers that are resistant to current therapy. We designed and synthesized novel thio- and seleno- barbituric derivatives by varying the substituents at N1, N3 (ethyl, methyl, allyl, and phenyl) and C5 tethered with dienyl and trienyl moieties attached with different substituents like phenyl, 2-furanyl, 2-thiophenyl, 1-naphthyl & 3-pyridyl. These compounds were tested against both chemotherapy sensitive and resistant, melanoma (UACC903 and CHL-1), GBM (U87-MG, T98G, and CCF-STTG1) , and lung cancer (A549, H460, H520and H69) cells. Most of these compounds reduced cell viability in a dose and time dependent manner. Among all the compounds ASR-198, ASR-199, ASR-243 and ASR-244 were most cytotoxic to both chemotherapy resistant and sensitive cells. In addition, these compounds triggered a dose dependent induction of apoptosis by activation of caspase-3 and PARP cleavage in melanoma cells. Overall compound ASR-198, having a 2-thiophen-dienyl substitution and C-5 position, emerged as the most efficacious compound in all three cancer cell lines. Interestingly its isosteric selenium analogs were relatively less cytotoxic. In summary, this structure-activity relationship study clearly indicates that more efficacious compounds, compared to existing thiobarbituric analogs, can be developed based on barbituric acid scaffold, by rational modifications of the chemo type compounds. Detailed results of these investigations will be presented.
Citation Format: Srinivasa R. Ramisetti, Sang Y. Lee, Manoj K. Pandey, Shantu G. Amin, Arun K. Sharma. Development of novel thiobarbituric acid derivatives as potential cancer therapeutics. [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 1639. doi:10.1158/1538-7445.AM2014-1639
Abstract 1651: Profiling immune cells within the tumor microenvironment for optimal model selection for pre-clinical investigations
Authors: Leishman Andrew , Harris Olivia , Ulrichsen Jane Coates , Harper James , Popple Amy , Papaspyridonos Marianna , Williams Geoff , Mullins Stefanie , Valge-Archer Viia , Stewart Ross , Sainson Richard , Morrow Michelle , Wilkinson Robert 
Published: May 2015

Abstract
Infiltrating host immune cells can have a significant impact on the growth and outcome of many tumor types. Several leukocyte populations have been implicated in establishing an immune suppressive microenvironment (e.g. myeloid derived suppressor cells [MDSCs) and regulatory T cells [Treg cells]) and thus making it harder for anti-tumor immune effector cells to function (e.g. CD8 cytotoxic T cells). Immune-Mediated Therapy (IMT) is emerging as a key strategy for the treatment of cancer through by enhancing a patient's anti-tumor immune response. In order to maximise the potential of IMT strategies it is important to understand the immune status within the tumor microenvironment as well as systemically. Therefore, fully immune-competent preclinical models are valuable tools to enable the study of the immune system, both locally within the tumor and systemically, to understand the mechanism of action of IMT monotherapies and combination therapies in vivo. Consequently, we have profiled the immune status of a panel of syngeneic mouse tumor models to assist optimal model selection to aid these investigations. We developed multi-parameter flow cytometry techniques to identify specific immune subsets in both the tumor microenvironment and the periphery. These investigations revealed a number of tumor infiltrating immune cell end-points that can be used to correlate with response to IMT depending on the syngeneic model being used. For example, we observed differences in the MDSC and Treg cell populations across the models investigated, which will influence optimal model selection depending on the mechanism of action of the IMT being tested.
Citation Format: Andrew Leishman, Olivia Harris, Jane Coates Ulrichsen, James Harper, Amy Popple, Marianna Papaspyridonos, Geoff Williams, Stefanie Mullins, Viia Valge-Archer, Ross Stewart, Richard Sainson, Michelle Morrow, Robert Wilkinson. Profiling immune cells within the tumor microenvironment for optimal model selection for pre-clinical investigations. [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 1651. doi:10.1158/1538-7445.AM2014-1651
Abstract 1660: Retroviral replicating vector transduced alloresponsive T lymphocytes retain mobility and cytotoxic functionalities
Authors: Erickson Kate L. , Malone Colin C. , Hickey Michelle J. , Owens Geoffrey C. , Kato Yuki , Prins Robert M. , Kasahara Noriyuki , Kruse Carol A. 
Published: May 2015

Abstract
The radial monolayer cell migration assay was originally developed to measure the infiltrative properties of adherent tumor cells on individual extracellular matrix (ECM) proteins, or on ECM extracted from tumor cell monolayers. For this assay a single cell suspension of tumor cells is seeded using a cell sedimentation manifold (CSM), precisely into the center of Teflon-masked, ECM-coated slide wells. The adherent tumor cells establish a focal, circular monolayer from which horizontal motility can be microscopically-viewed and photographed over time. We adapted use of the CSM to evaluate the in vitro mobility of non-adherent effector T cells on confluent tumor cell monolayers or on ECM extracts from them. Cytotoxic T lymphocytes (CTL) sensitized to the human leukocyte antigens (HLA) on 13-06-MG glioma cells or on brain-tropic breast MDA-MB-231 carcinoma cells were generated by one-way mixed lymphocyte tumor cell reactions. These alloresponsive CTL were then transduced with retroviral replicating vectors (RRV) coding for green fluorescent protein (GFP). Using the CSM, the RRV-GFP transduced CTL were seeded into the center of wells with a confluent monolayer of glioma cells that were partially HLA matched to 13-06-MG. By light and fluorescence microscopy, we visualized not only the a) mobility of individual GFP+ T cells, but b) the cytotoxicity engendered to the underlying adherent glioma cell monolayer by the overlaid nonadherent CTL, in addition to c) transfer of RRV from the CTL to tumor cells. The in vitro cytotoxic functionality of the RRV-transduced CTL was confirmed by real-time xCELLigence impedance cytotoxicity assays. In other experiments, the RRV-GFP transduced CTL were also stained with a vital fluorescent red dye, CMPTX, to distinguish transduced from nontransduced CTL. The CTL were placed into the center of wells coated with ECM harvested from MDA-MB-231BR cells and radial movement of the transduced and nontransduced CTL was also observed over 72 hr time. We conclude that effector T cells transduced with RRV maintain mobility and cytotoxic functionality, and further, are capable of transmitting RRV to tumor cells. Thus, transduced alloresponsive CTL can facilitate immunogene therapy by their capability of gene delivery to infiltrating tumor cells in the brain.
Citation Format: Kate L. Erickson, Colin C. Malone, Michelle J. Hickey, Geoffrey C. Owens, Yuki Kato, Robert M. Prins, Noriyuki Kasahara, Carol A. Kruse. Retroviral replicating vector transduced alloresponsive T lymphocytes retain mobility and cytotoxic functionalities. [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 1660. doi:10.1158/1538-7445.AM2014-1660
Abstract 1661: The pro-inflammatory role of the putative oncogene Bcl-3
Authors: Tang Wanhu , Wang Hongshan , Claudio Estefania , Siebenlist Ulrich 
Published: May 2015

Abstract
Bcl-3 is an oncogene first identified by its translocation into the immunoglobulin alpha-locus in some cases of chronic B cell lymphocytic leukemia. Bcl-3 is an atypical member of the IκB family that exhibits unique properties compared with classic IκBs. It readily enters nuclei, where it interacts with p50/NF-κB1 or p52/NF-κB2 homodimers to transcriptional activity. Depending on the cellular context and target gene, Bcl-3 may promote or inhibit gene expression. Recently it was reported that Bcl-3 could promote tumor growth as well as metastasis in several mouse tumor models. Bcl-3 is also known to play important roles in innate and adaptive immunity. For example, mice lacking Bcl-3 become highly susceptible to various pathogens, including T. gondii and K. pneumoniae, but the underlying mechanisms remain poorly understood. In addition, little is known about potential roles of Bcl-3 in inflammation that may contribute to cancers. Here we report that in a mouse model of colitis, which is dependent on the functions of Th1 cells, Bcl-3 had an intrinsic role to maintain Th1 cells and thus promote inflammation over time. This could also be demonstrated in vitro, where Bcl-3 had no effect on differentiation of Th1 cells per se, but was required for their maintenance. We will show how Bcl-3 promoted the maintenance of specifically Th1, but not Th17 cells. We will also provide evidence that Bcl-3 likely mediated these effects via p52/NF-κB2. Our data demonstrate that the oncoprotein Bcl-3 can contribute to chronic inflammatory conditions that in turn may be associated with cancer development.
Note: This abstract was not presented at the meeting.
Citation Format: Wanhu Tang, Hongshan Wang, Estefania Claudio, Ulrich Siebenlist. The pro-inflammatory role of the putative oncogene Bcl-3. [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 1661. doi:10.1158/1538-7445.AM2014-1661