bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A24: Network models of signaling and drug response in melanoma.
Authors: Korkut Anil , Wang Weiqing , Molinelli Evan , Miller Martin , Kaushik Poorvi , Aksoy Arman , Jing Xiaohong , Gauthier Nick , Sander Chris 
Published: August 2014

Abstract
Novel combination therapies are potentially key to preventing emergence of resistance to initially successful single agent therapies such as RAF inhibitors in melanoma. In order to systematically nominate novel and effective drug combinations, we have developed an integrated systems biology technology (perturbation biology) for inferring quantitative and predictive network models of signaling. Our modeling strategy combines systematic perturbation experiments, measurement of response profiles to perturbations, inference of network models and simulation of models with in silico perturbations. As a key component of the overall strategy, we have adapted the belief propagation (BP) inference algorithm from statistical physics to construct signaling models with several hundreds of measured entities. In parallel, we have developed a pathway informatics tool to automatically extract prior information from multiple signaling databases. We applied this approach to derive signaling network models in RAF inhibitor resistant melanoma cells and nominate drug combinations to overcome resistance in melanoma. First, we systematically perturb melanoma cells with a set of targeted drugs as single and paired agents. Next, we quantitatively measured proteomic (total and phospho-protein levels) and phenotypic (e.g. cell cycle arrest, cellular viability) responses to perturbations. We incorporated the generic prior information and context specific perturbation response data to construct quantitative network models, which capture multiple oncogenic pathways in melanoma. As shown by cross validation calculations, use of prior information significantly improved predictive power of models. Using the inferred network models of signaling, we systematically predicted response to tens of thousands of in silico perturbations. Our modeling and simulation strategy expanded the volume of drug response profile from few thousand experimental data points to millions of in silico data points. In addition, our models provided quantitative descriptions of signaling events in melanoma. Our perturbation biology technology is suitable for applications in diverse areas of molecular biology beyond cancer research.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A24.
Citation Format: Anil Korkut, Weiqing Wang, Evan Molinelli, Martin Miller, Poorvi Kaushik, Arman Aksoy, Xiaohong Jing, Nick Gauthier, Chris Sander. Network models of signaling and drug response in melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A24.
Abstract A240: A mechanism linking Id2-TGFβ crosstalk to reversible adaptive plasticity in neuroblastoma.
Authors: Chakrabarti Lina , Wang Bi-Dar , Lee Norman H. , Sandler Anthony 
Published: August 2014

Abstract
The ability of high-risk neuroblastoma to survive unfavorable growth conditions and multimodal therapy has produced an elusive childhood cancer with a remarkably poor prognosis. A novel phenomenon enabling neuroblastoma to survive selection pressure is its capacity for reversible adaptive plasticity. This plasticity allows cells to transition between highly proliferative anchorage dependent (AD) and slow growing anoikis resistant anchorage independent (AI) phenotypes. The differential gene expression profile of the two cellular phenotypes in the mouse Neuro2a cell line delineated pathways of proliferation in AD cells or tyrosine kinase activation/ apoptosis inhibition in AI cells. A 20 fold overexpression of inhibitor of differentiation 2 (Id2) was identified in AD cells while up-regulation of genes involved in anoikis resistance like PI3K/Akt, Erk, Bcl2, and integrins was observed in AI cells. Similarly, differential expression of Id2 and other genes of interest were also observed in the AD and AI phenotypes of human neuroblastoma cell lines, SK-N-SH and IMR-32; as well as in primary human tumor specimens. Forced down-regulation of Id2 in AD cells or overexpression in AI cells induced the cells to gain characteristics of the other phenotype. Id2 binds both TGFβ and Smad2/3 and appears critical for maintaining the proliferative phenotype at least partially through negative regulation of the TGFβ/ Smad pathway. Simultaneously targeting the differential molecular pathways governing reversible adaptive plasticity resulted in cure of established tumors in a mouse model of neuroblastoma. We present a mechanism that accounts for reversible adaptive plasticity and a molecular basis for combined targeted therapies in neuroblastoma.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A240.
Citation Format: Lina Chakrabarti, Bi-Dar Wang, Norman H. Lee, Anthony Sandler. A mechanism linking Id2-TGFβ crosstalk to reversible adaptive plasticity in neuroblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A240.
Abstract A251: MGMT inhibition decreases survivin expression in pancreatic cancer.
Authors: Bobustuc George C. , Patel Anand , Thompson Michael , Kalkunte Srivenugopal S. , Frick Jacob , Weese James , Konduri Santhi D. 
Published: August 2014

Abstract
Survivin is an antiapoptotic gene negatively regulated by p53 tumor suppressor. Survivin is overexpressed in human cancers and one of its functions is to reduce the efficacy of chemotherapy. We report that O6-benzylguanine (BG), a potent inhibitor of MGMT (O6-methyl guanine DNA methyl transferase), a DNA repair protein, curtails the expression of survivin in pancreatic cancer cells. We also show that BG, either alone or in combination with gemcitabine, inhibits survivin and PCNA expression both at the mRNA and protein levels in Panc1 and L3.6pl cells. Further, BG, either alone or in combination with gemcitabine, significantly decreases survivin promoter activity in these cells. We also show that these combinations decrease survivin protein expression in pancreatic tumors derived from orthotopic xenografts developed in nude mice. Immunohistochemistry confirms the reduced expression of survivin and PCNA in tumor sections after BG or BG plus gemcitabine treatments. We also show the enhanced recruitment of p53 protein to the survivin promoter in BG-treated pancreatic cancer cells. Further, BG promotes p53 function leading to growth inhibition. Taken together our data suggests that BG induced partial restoration of p53 activity suppresses survivin function and enhances gemcitabine effect in pancreatic cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A251.
Citation Format: George C. Bobustuc, Anand Patel, Michael Thompson, Srivenugopal S. Kalkunte, Jacob Frick, James Weese, Santhi D. Konduri. MGMT inhibition decreases survivin expression in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A251.
Abstract A253: HO-3867, a safe STAT3 inhibitor, is selectively cytotoxic to ovarian cancer.
Authors: Selvendiran Karuppaiyah , Rath Kellie S. , Naidu Shan , Latha Pushpa , Hemant Bid , McCann Georgia A. , Bravo Veronica , Houghton Peter , Leone Gustavo , Hideg Kálmán , Kuppusamy Periannan , Cohn David E. 
Published: August 2014

Abstract
We have developed a novel class of bi-functional compounds based on a diarylidenyl-piperidone (DAP) backbone conjugated to an N-hydroxypyrroline (-NOH; a nitroxide precursor) group which selectively inhibits STAT3 activation, translocation, and DNA binding activity, without affecting the expression of other pSTATs. This new STAT3 inhibitor offers advantages when compared to other STAT3-targeting molecules currently available, under development or undergoing preclinical trials. Most notably, these compounds exhibit minimal toxicity toward normal cells and tissues while inducing apoptosis in ovarian cancer cells, and exhibit good oral bioavailability. Results show that selective cytotoxicity of the lead compound, HO-3867, towards cancer cells is multi-faceted. AutoDock molecular modeling indicates that the DAP compounds interact with STAT3 at the DNA-binding domain. Liquid chromatography / Mass spectroscopy analysis demonstrates greater bioabsorption and bioavailability of active (cytotoxic) metabolites in cancer cells when compared to normal cells. Differential activation of the Akt pathway was demonstrated using Akt siRNA in normal versus cancer cells. Knockdown of STAT3 expression using two different shRNAs shows the requirement of STAT3 for HO-3867-mediated apoptosis. In vivo testing shows that HO-3867 inhibits xenograft tumor growth without toxic side effects. In addition, HO-3867 significantly inhibited cell survival, migration/invasion and induced cell death in primary ovarian cancer cell populations isolated from ascites of patients with recurrent and advanced ovarian cancer. This study provides evidence of a safe, targeted STAT3 inhibitor (HO-3867) with demonstrated efficacy in treating multiple ovarian cancer models. This suggests significant translational potential of these compounds for the treatment of ovarian cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A253.
Citation Format: Karuppaiyah Selvendiran, Kellie S. Rath, Shan Naidu, Pushpa Latha, Bid Hemant, Georgia A. McCann, Veronica Bravo, Peter Houghton, Gustavo Leone, Kálmán Hideg, Periannan Kuppusamy, David E. Cohn. HO-3867, a safe STAT3 inhibitor, is selectively cytotoxic to ovarian cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A253.
Abstract A254: Systemic injection of human neural stem cells expressing anti-cancer agent targets invasive gliomas and induces tumor regression in combination with a cardiac glycoside.
Authors: Teng Jian , Hejazi Seyedali , Badr Christian E. , Tannous Bakhos A. 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most common and most aggressive malignant form of brain tumors in human. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as an anticancer agent, however, a considerable number of tumor types, including GBM, are resistant to TRAIL. Also, TRAIL therapeutic use in vivo is limited by a short half-life in plasma due to a rapid clearance by the kidney and a poor penetration across the blood-brain barrier. The tumor-tropic properties of neural stem cells (NSCs) could serve as a novel strategy to deliver therapeutic genes to tumors in the brain. Furthermore, we have previously reported that the cardiac glycoside lanatoside C sensitizes GBM cells to TRAIL-induced apoptosis. In this study, we engineered human neural stem cell to synthesize and secrete an active form of TRAIL (NSC-sTRAIL) as well as the secreted Gaussia luciferase (Gluc) as a blood marker for cell proliferation. We showed that these cells selectively migrate toward GBM stem-like cells (GSCs) in a transwell assay. However, GSCs’ growth was only decreased by 11.6%. When this co-culture was treated with lanatoside C, GSCs’ growth was inhibited by 81.5% in a caspase-mediated manner. We then tested this combined therapy in an invasive orthotopic model using primary GSC neurospheres expressing firefly luciferase. Upon systemic injection, Gluc blood assay showed that at the next day at least 30% of NSC-sTRAIL, and after 5 weeks up to 0.5% of these cells survived. Histological analysis showed that the NSC-sTRAIL cells crossed the blood-brain barrier and migrated toward invasive GSC tumors. Bioluminescence imaging showed that tumors in mice treated with NSC-sTRAIL cells in combination with lanatoside C resulted in significant tumor regression and mouse survival elongation as compared to single therapy. Taken together, this study demonstrated that systemic injection of neural stem cells targets invasive brain tumors and could be used to deliver an anticancer agent such as sTRAIL which yields significant tumor regression when used in combination with lanatoside C.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A254.
Citation Format: Jian Teng, Seyedali Hejazi, Christian E. Badr, Bakhos A. Tannous. Systemic injection of human neural stem cells expressing anti-cancer agent targets invasive gliomas and induces tumor regression in combination with a cardiac glycoside. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A254.
Abstract A257: Stereospecific trapping of PARP-DNA complexes by BMN 673 and comparison with olaparib and rucaparib.
Authors: Murai Junko , Huang Shar-yin N. , Renaud Amelie , Zhang Yiping , Ji Jiuping , Takeda Shunichi , Morris Joel , Teicher Beverly , Doroshow James H. , Pommier Yves 
Published: August 2014

Abstract
Anti-poly(ADP-ribose)polymerase (PARP) drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. Yet, several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP-DNA complexes; both olaparib and niraparib act as PARP poisons at pharmacological concentrations (Murai et al., Cancer Res, 2012). Here, we evaluate the novel PARP inhibitor, BMN 673, and compare its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically-modified chicken DT40 and human cancer cell lines. We show that BMN 673, olaparib, and rucaparib are similarly potent at inhibiting PARP catalytic activity. At the same time, BMN 673 is ∼100-fold more potent at trapping PARP-DNA complexes and more cytotoxic as a single agent than olaparib, while olaparib and rucaparib show similar potencies in trapping PARP-DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient, and that BMN 673 is more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sulfonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor to date with the highest efficiency at trapping PARP-DNA complexes.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A257.
Citation Format: Junko Murai, Shar-yin N. Huang, Amelie Renaud, Yiping Zhang, Jiuping Ji, Shunichi Takeda, Joel Morris, Beverly Teicher, James H. Doroshow, Yves Pommier. Stereospecific trapping of PARP-DNA complexes by BMN 673 and comparison with olaparib and rucaparib. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A257.
Abstract A262: Antiandrogen modulation of prostate-specific membrane antigen (PSMA): Dynamics and synergy with PSMA-targeted therapy.
Authors: Murga Jose D. , Magargal Wells W. , Moorji Sameer M. , DiPippo Vincent A. , Olson William C. 
Published: August 2014

Abstract
Introduction: Recent approvals of new prostate cancer (PCa) drugs and a growing number of pipeline agents have created opportunities for designing rational drug combinations. Potent antiandrogens such as enzalutamide and abiraterone affect expression of numerous androgen-regulated molecules, including PSMA, a well-characterized cell-surface target for PCa therapy.
Methods: Cytotoxicity and the kinetics of antigen expression were evaluated in PCa cell lines (LNCaP, C4-2 and 22Rv1) that vary according to androgen dependence and level of PSMA expression. Expression of PSMA and prostate-specific antigen (PSA) was evaluated over time in cells cultured in enzalutamide or abiraterone. Reversibility was examined following drug washout. Cells were tested for susceptibility to antiandrogens used alone and in combination with PSMA ADC, which is a fully human PSMA monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE). Potential drug synergy or antagonism was evaluated using the Combination Index and Bliss independence methods.
Results: In androgen-dependent LNCaP cells, enzalutamide and abiraterone exerted antiproliferative effects that were accompanied by a 2- to 3-fold increase in PSMA expression and a decrease in PSA expression. PSMA expression reached maximum levels after four weeks’ culture in enzalutamide and returned to baseline levels within days following enzalutamide removal. In androgen-independent C4-2 cells, enzalutamide and abiraterone increased PSMA expression in the absence of any significant anti-proliferative effect. PSMA ADC exhibited synergistic antitumor activity with both enzalutamide and abiraterone in LNCaP and C4-2 cells. Lesser effects were observed using 22Rv1 cells, an androgen-independent cell line with low basal expression of PSMA.
Conclusions: Enzalutamide and abiraterone significantly and reversibly augmented PSMA expression and potentiated the activity of PSMA ADC in androgen-dependent and -independent PCa cell lines in vitro. In androgen-independent cells, the effects on PSMA expression and PSMA ADC activity were uncoupled from any anti-proliferative effect of the antiandrogens. The findings support clinical exploration of regimens that combine potent antiandrogens and PSMA-targeted therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A262.
Citation Format: Jose D. Murga, Wells W. Magargal, Sameer M. Moorji, Vincent A. DiPippo, William C. Olson. Antiandrogen modulation of prostate-specific membrane antigen (PSMA): Dynamics and synergy with PSMA-targeted therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A262.
Abstract A279: Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor.
Authors: Dai Kang , Keegan Kathleen , Li Zhihong , Ji Ma , Li Cong , Eksterowicz John , Suzanne Coberly , Hollenback David , Weidner Margret , Huard Justin , Liang Lingming , Alba Grace , Orf Jessica , Lo Mei-Chu , Zhao Sharon , Ngo Rachel , Chen Ada , Liu Lily , Carlson Timothy , McGee Lawrence R. , Medina Julio , Kamb Alexander , Wickramasinghe Dineli 
Published: August 2014

Abstract
Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard care treatment, the disease eventually relapses. Activating FLT3 mutations are found in approximately 30% of AML patients. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here preclinical evaluation of AMG 925, a potent, selective and bioavailable FLT3/CDK4 dual kinase inhibitor. The compound inhibited AML xenograft tumor growth by &gt;99% without detectable body weight loss. AMG 925 was also found to inhibit FLT3 mutants (e.g, D835Y) that are resistant to the current FLT3 inhibitors (e.g., quizartinib/AC220, sorafenib). CDK4 is a cyclinD-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-Rb pathway in cancer development has been well established. CDK4 specific inhibitors are being developed for treating Rb positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve clinical response rates.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A279.
Citation Format: Kang Dai, Kathleen Keegan, Zhihong Li, Ma Ji, Cong Li, John Eksterowicz, Coberly Suzanne, David Hollenback, Margret Weidner, Justin Huard, Lingming Liang, Grace Alba, Jessica Orf, Mei-Chu Lo, Sharon Zhao, Rachel Ngo, Ada Chen, Lily Liu, Timothy Carlson, Lawrence R. McGee, Julio Medina, Alexander Kamb, Dineli Wickramasinghe. Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A279.
Abstract A289: Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation.
Authors: Narita Yusuke , Okamoto Kiyoshi , Kawada Megumi Ikemori , Takase Kazuma , Minoshima Yukinori , Kodama Kotaro , Iwata Masao 
Published: August 2014

Abstract
Many clinical cases of acquired resistance to the BRAF inhibitor vemurafenib have recently been reported. One of the causes of this acquired resistance is the BRAF downstream kinase point mutation MEK1-C121S. This mutation confers resistance to not only vemurafenib, but also to the allosteric MEK inhibitor selumetinib (AZD6244). Here, we investigated the pharmacological activities and effectiveness of the novel MEK inhibitor E6201 against BRAF-V600E mutant melanoma harboring the MEK1-C121S mutation. A cell-free assay confirmed that E6201 is an ATP-competitive MEK inhibitor meaning it has a different binding mode with MEK compared with allosteric MEK inhibitors. E6201 is more effective against BRAF-V600E mutant melanoma compared with BRAF wild-type melanoma based on MEK inhibition. We found that the acquired MEK1-C121S mutation in BRAF-V600E mutant melanoma conferred resistance to both vemurafenib and selumetinib but not E6201. The effectiveness of E6201 is a result of its binding with MEK1 far from the C121S point mutation so the mutation is unable influence the MAPK pathway inhibitory activity. We conclude that E6201 is a potential therapeutic choice for improving the clinical outcome of vemurafenib-based therapy. However, further validation is needed.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A289.
Citation Format: Yusuke Narita, Kiyoshi Okamoto, Megumi Ikemori Kawada, Kazuma Takase, Yukinori Minoshima, Kotaro Kodama, Masao Iwata. Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A289.