bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1773: Phosphodiesterase 10A: A novel target for selective inhibition of colon tumor cell growth and Wnt/β-catenin signaling
Authors: Li Nan , Lee Kevin , Xi Yaguang , Zhu Bing , Gary Bernary D. , Ramírez-Alcántara Verónica , Gurpinar Evrim , Canzoneri Joshua C. , Fajardo Alexandra , Sigler Sara , Piazza John T. , Chen Xi , Andrews Joel , Lu Wenyan , Li Yonghe , Russo Suzanne , Yet Larry , Keeton Adam B. , Grizzle William E. , Piazza Gary A. 
Published: May 2015

Abstract
The cyclic nucleotide phosphodiesterase10A (PDE10) has been studied as a therapeutic target for certain psychiatric and neurological conditions, although a potential role in tumorigenesis has not been reported. Here we report that PDE10 is elevated in human colon tumor cell lines compared with normal colonocytes. Similarly, PDE10 is elevated in colon tumors from human clinical specimens as well as intestinal tumors from the ApcMin/+ mouse model compared with non-involved tissue or normal intestinal mucosa, respectively. An isozyme and tumor-selective role of PDE10 was evident by the ability of specific inhibitors and siRNA knockdown to suppress colon tumor cell growth without significantly affecting the growth of normal colonocytes. Stable knockdown of PDE10 by shRNA also inhibits colony formation and increases doubling time of colon tumor cells. Inhibition of PDE10 results in the selective activation of cGMP/PKG signaling in colon tumor cells to suppress β-catenin levels and T-cell factor (TCF) transcriptional activity. Conversely, ectopic expression of PDE10 in normal and precancerous colonocytes increases proliferation and activates TCF transcriptional activity. These observations demonstrate that PDE10 is essential for colon tumor cell growth and suggest that inhibitors may have therapeutic potential for the treatment or prevention of colorectal cancer.
Citation Format: Nan Li, Kevin Lee, Yaguang Xi, Bing Zhu, Bernary D. Gary, Verónica Ramírez-Alcántara, Evrim Gurpinar, Joshua C. Canzoneri, Alexandra Fajardo, Sara Sigler, John T. Piazza, Xi Chen, Joel Andrews, Wenyan Lu, Yonghe Li, Suzanne Russo, Larry Yet, Adam B. Keeton, William E. Grizzle, Gary A. Piazza. Phosphodiesterase 10A: A novel target for selective inhibition of colon tumor cell growth and Wnt/β-catenin signaling. [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 1773. doi:10.1158/1538-7445.AM2014-1773
Abstract 1775: Identification of small molecule inhibitors of HSF1 stress pathway activation in cancer cells
Authors: Billy Emmanuel de , Chessum Nicola , Poele Robert Te , Smith Jennifer , Zani Lorenzo , Sharp Swee , Stubbs Mark , Aherne Wynne , Jones Keith , Workman Paul 
Published: May 2015

Abstract
Heat Shock Factor 1 (HSF1) is a key transcription factor involved in proteostasis and response to stress, as well as being implicated in many diseases including cancer. Up-regulation of its activity by environmental stress or oncogenesis leads to transcriptional induction of genes involved in diverse cellular processes supporting the cancer state, including proteostasis, proliferation, survival and metastasis. Inhibition of HSF1 is therefore potentially beneficial for cancer treatment, but HSF1 is not technically druggable. We developed a high-throughput cell-based reporter gene assay to screen a library of small-molecule kinase inhibitors and identified 3 compound series as validated inhibitors of HSF1 activation by the HSP90 inhibitor 17-AAG. Further characterization of imidazo[1,2-b]pyridazine compounds showed inhibition of HSF1 target gene expression and the ability to mimic other features of the HSF1 knockdown phenotype. Using these tool compounds and by siRNA knockdown of HSF1 expression we demonstrate that HSF1 inhibition leads to cell cycle arrest and enhances the antiproliferative effect of 17-AAG. In addition, we show that HSP90 inhibition induces HSF1 phosphorylation at two serine residues, Ser326 and Ser320, highlighting the importance of Ser320 phosphorylation in HSP72 up-regulation by 17-AAG-induced HSF1 activation, and show that this activation is inhibited by our tool compounds. Our findings support the optimization and development of small-molecule inhibitors of the HSF1 pathway for cancer treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Emmanuel de Billy, Nicola Chessum, Robert Te Poele, Jennifer Smith, Lorenzo Zani, Swee Sharp, Mark Stubbs, Wynne Aherne, Keith Jones, Paul Workman. Identification of small molecule inhibitors of HSF1 stress pathway activation in 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 1775. doi:10.1158/1538-7445.AM2014-1775
Abstract 1788: 19-Substituted benzoquinone ansamycins. Hsp90 inhibitors with decreased off-target toxicity
Authors: Chang Chuan-Hsin , Drechsel Derek A. , Kitson Russell R.A. , Siegel David , You Qiang , Backos Donald S. , Ju Cynthia , Moody Christopher J. , Ross David 
Published: May 2015

Abstract
Benzoquinone ansamycin (BQA) Hsp90 inhibitors such as 17-DMAG and 17-AAG have off-target toxicities in clinical trials including hepatotoxicity. Mechanisms underlying the toxicity of quinones are a function of their ability to redox cycle and/or arylate cellular nucleophiles at the unsubstituted 19-position of the molecule. Therefore, we designed 19-substituted BQAs to prevent glutathione conjugation and non-specific interactions with protein thiols as an approach to reduce the hepatotoxicity and minimize off-target effects of the BQA class of Hsp90 inhibitors. In this study, the results showed that 19-substituted BQAs did not react with glutathione at the 19-position, while marked reactivity was observed using parent BQAs. Importantly, while parent 17-DMAG induced cell death in primary and cultured mouse hepatocytes, 19-phenyl and 19-methyl 17-DMAG showed reduced toxicity, validating the overall approach. There was no significant difference between the redox cycling ability of either 19-phenyl or 19-methyl 17-DMAG with their parental BQAs in both mouse and human liver microsomes. Accordingly, this suggests that arylation reactions at the unsubstituted 19-position are predominantly responsible for hepatotoxicity. 19-substituted17-DMAG inhibited purified Hsp90 ATPase activity in an NQO1-dependent manner that demonstrated increased inhibitory efficacy of the hydroquinone ansamycin relative to its parent quinone. In human breast cancer cells, 19-phenyl BQAs induced growth inhibition in an NQO1-dependent manner with molecular signatures of Hsp90 inhibition, including decreases in client proteins and compensatory induction of Hsp70. These data indicate that 19-substituted BQAs may be useful Hsp90 inhibitors with decreased off target toxicity (Supported by NCI grant CA51210)
Citation Format: Chuan-Hsin Chang, Derek A. Drechsel, Russell R.A. Kitson, David Siegel, Qiang You, Donald S. Backos, Cynthia Ju, Christopher J. Moody, David Ross. 19-Substituted benzoquinone ansamycins. Hsp90 inhibitors with decreased off-target toxicity. [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 1788. doi:10.1158/1538-7445.AM2014-1788
Abstract 1789: Profiling HSP90 inhibitors in cellular extracts on a mass spectrometry chemoproteomics platform
Authors: Nomanbhoy Tyzoon K. , Nordin Brian E. , Rosenblum Jonathan , Liu Yongsheng 
Published: May 2015

Abstract
HSP90 is a ubiquitous molecular chaperone that couples ATP hydrolysis to the folding and maturation of numerous client proteins. Because many of these client proteins are essential to cancer cell growth and survival, HSP90 inhibitors have undergone clinical investigation in numerous oncology indications. Here, using an LC-MS/MS platform previously developed to characterize ATP-competitive inhibitors of protein kinases, several HSP90 inhibitors were profiled in native cell lysates. This method utilizes an ATP derivative that covalently labels lysine residues in the ATP-binding site of any amenable enzyme. The specificity of inhibitors for all four paralogs of HSP90 (HSP90α, HSP90β, Grp94 and Trap-1) found in human cells was simultaneously monitored at their endogenous relative abundances. Interestingly, the concentration of HSP90 paralogs in human cell lysates was significantly higher than reported inhibitor binding constants, therefore complete inhibition was only observed at much higher concentrations than would have been predicted. In addition to the four HSP90 paralogs, inhibition data was collected on over 400 protein kinases and other nucleotide-binding proteins. This led to the discovery that NVP-AUY922 has off-target activity toward PMS2, an enzyme, like HSP90 itself, belonging to the GHKL ATPase superfamily. In addition to directly profiling compound targets in lysates, downstream effects of HSP90 inhibition were monitored by treating live cells and analyzing the resulting cell lysates at defined time points. Many proteins were found to be much less abundant in the compound-treated cells, including known HSP90 client proteins and novel, putative client proteins.
Citation Format: Tyzoon K. Nomanbhoy, Brian E. Nordin, Jonathan Rosenblum, Yongsheng Liu. Profiling HSP90 inhibitors in cellular extracts on a mass spectrometry chemoproteomics platform. [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 1789. doi:10.1158/1538-7445.AM2014-1789
Abstract 1790: Small molecule inhibitors of QSOX1 suppress tumor cell growth and invasion
Authors: Hanavan Paul D. , Faigel Douglas O. , Ma Chen-Ting , Sergienko Eduard , Meurice Nathalie , Petit Joachim L. , Ruiz Yvette W. , Katchman Benjamin A. , Lake Douglas F. 
Published: May 2015

Abstract
Introduction:
QSOX1 is a flavin-dependent sulfhydryl oxidase and the only known human enzyme with both disulfide generating and transferring activities. Using tissue microarrays, we previously demonstrated that QSOX1 is over-expressed in multiple tumor types including breast, pancreas, prostate and myeloma. Loss of QSOX1 leads to a significant decrease in tumor cell proliferation and invasion. The over-expression of QSOX1 in tumor cells compared to non-malignant cells combined with its role in tumor cell proliferation and invasion make it an attractive target for potential anti-neoplastic agents.
Methods:
Using a high throughput screening assay to detect sulfhydryl oxidase activity, we screened a library of compounds for inhibition of the QSOX1 enzyme. We used ROS-GloTM, a luciferase-based assay that detects H2O2, to determine if any compounds in the library inhibited QSOX1-mediated disulfide bond formation using reduced RNAse A as a substrate. QSOX1 generates H2O2 as a by-product of disulfide bond formation. To determine if compounds that showed activity in the enzymatic assay were also active against tumor cells, we treated pancreatic, breast, and myeloma cells with the compounds in a dose-dependent fashion, using non-malignant cells as controls. We assayed growth/viability by MTT and CellTiter-Glo assays. Invasive activity of tumor cells was assessed using matrigel-coated inserts in a modified Boyden chamber assay.
Results:
High throughput library screening identified 4 compounds that specifically inhibited QSOX1 activity (designated A-D) compared to a glucose oxidase counter-screen. Growth/viability assays showed that compound D suppressed the growth of tumor cells with IC50s between 300nM-750nM, depending on tumor cell line. In non-malignant cells the IC50s for compound D were more than 10-fold higher than in tumor cells. Compounds A and D also inhibited invasion of breast and pancreatic tumor cells through Matrigel.
Conclusion:
This is the first report of chemical compounds that inhibit QSOX1 enzymatic activity. The discovery of QSOX1 inhibitors with cellular efficacy establishes the chemical tractability of the target. Our data demonstrate that these First-In-Class compounds have potential as anti-neoplastic therapeutics via inhibition of QSOX1.
Citation Format: Paul D. Hanavan, Douglas O. Faigel, Chen-Ting Ma, Eduard Sergienko, Nathalie Meurice, Joachim L. Petit, Yvette W. Ruiz, Benjamin A. Katchman, Douglas F. Lake. Small molecule inhibitors of QSOX1 suppress tumor cell growth and invasion. [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 1790. doi:10.1158/1538-7445.AM2014-1790
Abstract 1791: 19-Substituted benzoquinone ansamycin Hsp90 inhibitors: Effects on Hsp90 co-chaperones and Hsp90-Hsf1 complexes in cellular systems
Authors: Drechsel Derek A. , Chang Chuan-Hsin , Kitson Russell , Siegel David , Moody Christopher J. , Ross David 
Published: May 2015

Abstract
The 19-substituted benzoquinone ansamycin (BQA) class of Hsp90 inhibitors were developed to decrease the off-target toxicity of their parent unsubstituted BQAs, geldanamcyin, 17-AAG, and 17-DMAG. We have shown that 19-BQAs do not react with thiols and show decreased toxicity to liver cell systems relative to parent BQAs. As a class, Hsp90 inhibitors exhibit anti-cancer activity by decreasing the levels of Hsp90 client proteins critical to cell growth and survival. Some Hsp90 inhibitors also disrupt interaction with Hsp90 co-chaperones, including cdc37, contributing to inhibited growth. Upon inhibition, the transcription factor heat shock factor 1 (Hsf1) dissociates from Hsp90 leading to a compensatory induction of other heat shock proteins, including Hsp70 which is commonly used as a molecular biomarker of cellular Hsp90 inhibition. We undertook a detailed study of the mechanism of action of 19-BQAs in HER2-positive breast cancer cells (BT474) using 19-phenyl- and 19-methyl-DMAG as model compounds. Their ability to disrupt association of Hsp90 with the co-chaperones p23 and cdc37, the kinetics of decreased Hsp90-Hsf1 levels, nuclear Hsf1 accumulation and increases in Hsp70 levels were defined. Both 19-phenyl- and 19-methyl -DMAG disrupted Hsp90-p23 association, confirming binding of the compounds at the N-terminal ATPase site of Hsp90. 19-Phenyl-DMAG and 19-methyl-DMAG also disrupted association of Hsp90 with cdc37, although 19-phenyl-DMAG was more potent. A detailed time course of decreased levels of Hsp90 client proteins and Hsp induction showed that increased Hsp70 was a more sensitive cellular marker as it could be detected at lower drug concentrations. Increases in Hsp70 did not appear to be a generalized stress response, since 19-substituted-BQAs caused dissociation of the Hsp90-Hsf1 dimer, nuclear translocation of Hsf-1, and subsequent increases in Hsp70 levels in a temporal manner. These data indicate that 19-substituted BQAs may exhibit their growth inhibitory effects in breast cancer cells through disruption of Hsp90 and its co-chaperones, particularly cdc37. The N-terminal ATPase site binding and Hsp90 inhibitory activity of these compounds was confirmed through disruption of Hsp90-p23 and Hsp90-Hsf1 associations, respectively (Supported by NCI grant CA51210).
Citation Format: Derek A. Drechsel, Chuan-Hsin Chang, Russell Kitson, David Siegel, Christopher J. Moody, David Ross. 19-Substituted benzoquinone ansamycin Hsp90 inhibitors: Effects on Hsp90 co-chaperones and Hsp90-Hsf1 complexes in cellular systems. [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 1791. doi:10.1158/1538-7445.AM2014-1791
Abstract 1794: The HSP90 inhibitor, AT13387, combined with erlotinib improves response in EGFR-driven xenograft models of NSCLC
Authors: Smyth Tomoko , Lewis Jon , Hearn Keisha , Thompson Neil , Lyons John , Wallis Nicola G. 
Published: May 2015

Abstract
Background: Although Epidermal Growth Factor Receptor (EGFR)-driven non-small cell lung cancer (NSCLC) can be successfully treated with EGFR inhibitors such as erlotinib, relapse is common due to the development of resistance. Methods to improve response and delay resistance are therefore of value. Inhibition of the chaperone, HSP90, leads to the depletion of many client proteins, including EGFR, and has the capacity to simultaneously affect many signalling pathways, offering an alternative strategy for targeting EGFR-driven disease. AT13387 is a potent, second generation HSP90 inhibitor currently being tested in Phase II clinical trials. Here we investigated the effects of combining AT13387 and erlotinib in models of EGFR-driven NSCLC.
Results: AT13387 single-agent treatment was effective in EGFR-driven NSCLC xenograft models, significantly inhibiting tumor growth of both HCC827 and NCI-H1650 xenograft tumors when dosed once weekly (see table). As expected, treatment with erlotinib caused significant tumor regression in all HCC827 tumors, but was less effective in the NCI-H1650 model; its PTEN status conferring a reduction in sensitivity. However, combination of AT13387 with erlotinib led to a further enhancement of tumor growth inhibition over either of the monotherapies in both of these models. All HCC827 tumors treated with the combination regressed further (by at least 80%), and regression was also now observed in all NCI-H1650 tumors. These data demonstrate that combination with AT13387 has the potential to increase response, despite the differing initial sensitivities to erlotinib of these models. The combination was well tolerated.
Effects of AT13387 and erlotinib on EGFR-driven xenograftsCell lineGenetic BackgroundT/C(Median RTV, treated / control)AT1338755 mg/kg ip 1qwErlotinib12.5 mg/kg po qdCombinationHCC827(Day 32)EGFR Del E746_A75026%17%(47% regression)6%(84% regression)NCI-H1650(Day 31)EGFR Del E746_A750/PTEN del35%36%6%(50% regression)
Conclusions: AT13387 was shown to improve response when combined with erlotinib in EGFR-driven xenograft models. These data suggest that there is therapeutic potential in an upfront combination of an HSP90 inhibitor, such as AT13387, with erlotinib and support clinical investigation of such a combination.
Citation Format: Tomoko Smyth, Jon Lewis, Keisha Hearn, Neil Thompson, John Lyons, Nicola G. Wallis. The HSP90 inhibitor, AT13387, combined with erlotinib improves response in EGFR-driven xenograft models of NSCLC. [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 1794. doi:10.1158/1538-7445.AM2014-1794
Abstract 18: MicroRNA-103 induces DNA damage and radiosensitizes the tumor vasculature
Authors: Anand Sudarshan , Advani Sunil J. , Cheresh David A. 
Published: May 2015

Abstract
While it is well known that tumor vasculature is a key determinant of resistance to radiotherapy, there remains a paucity of agents that sensitize this compartment to clinical doses of radiation. Using an expression screen for ‘apoptomiRs’ induced by high dose radiation, we have identified microRNA-103 as a potent, genotoxic stress responsive apoptomiR in endothelial cells. Functionally, ectopic expression of miR-103 mimics genotoxic stress causing DNA double strand breaks leading to cell death and decreased retinal angiogenesis in mice . Mechanistically, we show that miR-103 targets DNA repair pathway components - the exonuclease TREX1 and the adaptor FANCF. Finally, miR-103 injection in mice decreased tumor burden in a human colorectal cancer xenograft model where it enhanced the effects of low dose radiation. Our data uncovers a microRNA mediated pathway of DNA damage unique to proliferating endothelium that can be exploited for radiosensitization of tumor vasculature.
Citation Format: Sudarshan Anand, Sunil J. Advani, David A. Cheresh. MicroRNA-103 induces DNA damage and radiosensitizes the tumor vasculature. [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 18. doi:10.1158/1538-7445.AM2014-18
Abstract 1810: PI-1840, a novel non-covalent and rapidly reversible proteasome inhibitor with anti-tumor activity
Authors: Sebti Said M. , Kazi Aslamuzzaman , Ozcan Sevil , Tecleab Awet G. , Sun Ying , Lawrence Harshani 
Published: May 2015

Abstract
Non-covalent proteasome inhibitors that are less toxic and more effective against solid tumors than currently used proteasome inhibitors are desirable. Through HTS and hit-to-lead optimization efforts we have identified PI-1840, a potent and selective inhibitor for chymotrypsin-like (CT-L) (IC50 value = 27 ± 0.14 nM) over T-L and PGPH (IC50 values &gt;100 µM) activities of the proteasome. Furthermore, PI-1840 is over 100-fold more selective for the constitutive proteasome over the immunoproteasome. Dialysis and mass spectrometry studies demonstrate that PI-1840 is a non-covalent and rapidly reversible CT-L inhibitor. PI-1840 inhibits CT-L activity, induces the accumulation of proteasome substrates p27, Bax and IκB-α, inhibits survival pathways and proliferation, and induces apoptosis in human cancer cells. The mdm2/p53 disruptor, nutlin, sensitizes cancer cells to PI-1840 in a p53-dependent manner. Furthermore, the pan Bcl-2 antagonist BH3-M6 also sensitizes cancer cells to PI-1840. Finally, in vivo, PI-1840 but not Bortezomib (clinically used proteasome inhibitor) suppresses the growth in nude mice of human breast xenografts. These results warrant further evaluation of non-covalent and rapidly reversible proteasome inhibitor as potential anticancer agents against solid tumors.
Citation Format: Said M. Sebti, Aslamuzzaman Kazi, Sevil Ozcan, Awet G. Tecleab, Ying Sun, Harshani Lawrence. PI-1840, a novel non-covalent and rapidly reversible proteasome inhibitor with anti-tumor activity. [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 1810. doi:10.1158/1538-7445.AM2014-1810