bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1795: Small molecule SBI-601 inhibits Siah1/2 ubiquitin ligases, attenuates HIF1α expression and growth of melanoma and prostate cancer cells
Authors: Feng Yongmei , Varsano Tal , Sessions Hampton , Davies Michael , Roth Greg , Ronai Ze'ev 
Published: May 2015

Abstract
The ubiquitin ligases Siah1/2 have been implicated in the control of key cellular pathways, including hypoxia (through the control of prolyl hydroxylase 1/3 stability), mitochondrial fission (through the control of AKAP121 stability) and Ras/Raf signaling (through its control of Sprouty 2 stability). Expression or activity of Siah1/2 is upregulated in number of cancer types and correspondingly, inhibition of Siah1/2 effectively attenuates growth of prostate, melanoma, lung and pancreatic tumors. To identify possibly Siah1/2 inhibitors, we have performed a HTS screen using affinity selection-mass spectrometry (AS-MS). Using a select set of 32,000 drug-like molecules in mass-encoded mixtures of 400 compounds per assay well, we identified 36 distinct clusters of structurally related scaffolds that demonstrate high-binding affinity to full-length bacterially produced purified and active Siah2. Of those, 9 out of 21 closely related analogs were evaluated in functional assays. One compound, SBI-0640601, showed potent and reproducible inhibition of Siah2, as measured by the reduction in HIF1α levels and activity, measured by HRE-Luciferase assays in both melanoma and prostate cancer cultures. SBI-0640601 is a natural product known as betulonic acid (BA) and is one of a family of triterpenoid natural medicinal products derived from birch trees (genera Betula). Independent binding studies (differential scanning calorimetry) confirmed that SBI-0640601 binds to full-length bacterially produced Siah2 and to a RING domain-deleted version of Siah1. In vitro, SBI-0640601 attenuated the binding of PHD3 to Siah2, in keeping with the observation that ubiquitination of most substrates requires binding to the Siah2 substrate-binding domain. SBI-0640601 inhibited growth of melanoma and prostate cancer cells in 2D and 3D cultures. Further, SBI-0640601 effectively attenuated neuroendocrine differentiation phenotype in adenocarcinoma cells, consistent with the effect seen upon inhibition of Siah1/2 expression. RPPA analysis identified that SBI-0640601 effectively attenuates AMPK and mTOR signaling pathways, in addition to affecting MAPK signaling. Overall, SBI-0640601 appears to inhibit key processes previously shown to be regulated by Siah1/2, holding promise for further assessment in preclinical setting.
Note: This abstract was not presented at the meeting.
Citation Format: Yongmei Feng, Tal Varsano, Hampton Sessions, Michael Davies, Greg Roth, Ze'ev Ronai. Small molecule SBI-601 inhibits Siah1/2 ubiquitin ligases, attenuates HIF1α expression and growth of melanoma and prostate 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 1795. doi:10.1158/1538-7445.AM2014-1795
Abstract 1796: Novel triazole nucleoside inhibits heat shock factor 1 and androgen receptor to fight against prostate cancer
Authors: Xia Yi , Beraldi Eliana , Zoubeidi Amina , Peng Ling , Gleave Martin 
Published: May 2015

Abstract
Prostate cancer is one of the most commonly diagnosed cancers and leading cause of cancer-related mortality in men in developed countries. While most patients initially respond to first-line androgen deprivation therapy (ADT), many become refractory to hormonal and other conventional therapies and eventually develop castration-resistant prostate cancer (CRPC) with time. CRPC is often characterized by the reactivation of androgen receptor (AR) and constitutes the most important therapeutic target in CRPC.
It is known that AR is bound to heat shock protein (HSPs) complex to maintain its stable and mature conformation with high affinity to androgen. Targeting HSPs are therefore to result in perturbation of AR. Using a lead optimization process, we have recently identified a novel triazole nucleoside VM-1 which can down-regulate heat shock transcription factor 1 (HSF1), the dominant upstream transcriptional regulator for HSPs. The down-regulation of HSF1 by VM-1 leads to the simultaneous suppression of multiple HSPs and results in growth inhibition of various prostate cancer cells. Interestingly, VM-1 displays more potent antiproliferation activity in AR-positive LNCaP, C4-2 and 22RV-1 cells than AR-negative PC-3 cells. Our further studies have showed that VM-1 reduces the expression of AR and a panel of AR targeted genes as well as inhibits AR transactivation, which consequently leads to effective caspase-dependent apoptosis in LNCaP, C4-2 and 22RV-1 cells. Moreover, VM-1 arrests cell cycle of prostate cancer cells in AR-governed phase suggesting the potential functionality of this compound involved in the crosstalk between AR and cell cycle pathways. Taken together, the above data suggest the role of HSF1 in regulation of AR, and the inhibition on both HSF1 and AR contribute to the activity of VM-1 in prostate cancer cells. Therefore, VM-1 may serve as a novel structural motif in the search of anticancer candidates to fight against prostate cancer via inhibiting HSF1 and AR.
Citation Format: Yi Xia, Eliana Beraldi, Amina Zoubeidi, Ling Peng, Martin Gleave. Novel triazole nucleoside inhibits heat shock factor 1 and androgen receptor to fight against 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 1796. doi:10.1158/1538-7445.AM2014-1796
Abstract 1797: Discovery of NVP-CGM097, a highly potent and optimized small molecule inhibitor of Mdm2 under evaluation in a Phase I clinical trial
Authors: Jeay Sebastien , Berghausen Joerg , Buschmann Nicole , Chène Patrick , Cozens Robert , Erdmann Dirk , Ferretti Stéphane , Furet Pascal , Gabriel Tobias , Gessier François , Graus-Porta Diana , Hofmann Francesco , Holzer Philipp , Ito Moriko , Jacoby Edgar , Jensen Michael , Kallen Joerg , Lang Marc , Lisztwan Joanna , Murakami Masato , Pissot-Soldermann Carole , Ruetz Stephan , Rynn Caroline , Sterker Dario , Stutz Stefan , Valat Thérèse , Wiesmann Marion , Masuya Keiichi 
Published: May 2015

Abstract
Activation of p53 by blocking the p53-Mdm2 interaction using non-peptidic small-molecule inhibitors is being pursued as a promising cancer therapeutic strategy. In the present study, we show the identification of NVP-CGM097, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction. NVP-CGM097 binds to human Mdm2 protein with a Ki value of 1.3 nM, activates p53 in human cells and induces robust p53-dependent cell cycle arrest and apoptosis in human p53 wild-type tumor cells. Its activity and selectivity has been tested and confirmed across a large panel of cancer cell lines from the Cancer Cell Line Encyclopedia. Importantly, NVP-CGM097 displays desirable pharmacokinetic and pharmacodynamic profiles in animals together with excellent oral bioavailability, which triggers rapid and sustained activation of p53-dependent pharmacodynamic biomarkers resulting in tumor regression in multiple xenografted models of p53 wild-type human cancer. The validation and understanding of its mechanism of action, the overall favorable drug-like properties and the characterization of its on-target toxicological profile in preclinical species strongly supported the initiation of Phase I clinical trials with NVP-CGM097 in pre-selected patients with p53 wild-type tumors.
Citation Format: Sebastien Jeay, Joerg Berghausen, Nicole Buschmann, Patrick Chène, Robert Cozens, Dirk Erdmann, Stéphane Ferretti, Pascal Furet, Tobias Gabriel, François Gessier, Diana Graus-Porta, Francesco Hofmann, Philipp Holzer, Moriko Ito, Edgar Jacoby, Michael Jensen, Joerg Kallen, Marc Lang, Joanna Lisztwan, Masato Murakami, Carole Pissot-Soldermann, Stephan Ruetz, Caroline Rynn, Dario Sterker, Stefan Stutz, Thérèse Valat, Marion Wiesmann, Keiichi Masuya. Discovery of NVP-CGM097, a highly potent and optimized small molecule inhibitor of Mdm2 under evaluation in a Phase I clinical trial. [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 1797. doi:10.1158/1538-7445.AM2014-1797
Abstract 180: Interaction between bone marrow-derived mesenchymal stem cells and tumor cells induces expression of fibronectin in human colon cancer cells
Authors: Shinagawa Kei , Kitadai Yasuhiko , Tanaka Yuichiro , Yuge Ryo , Onoyama Mieko , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: May 2015

Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to contribute to the formation of tumor stroma. We reported recently that in an orthotopic nude mouse model of human colon cancer, MSCs migrated to tumor stroma, where they differentiated into carcinoma-associated fibroblast (CAF)-like cells and promoted tumor growth and metastasis. However, the molecular mechanisms of this phenomenon have not been elucidated. We performed microarray analysis of gene expression in KM12SM cells and found that expression of fibronectin (FN) mRNA was increased markedly by direct co-culture of KM12SM cells with MSCs. FN, a glycoprotein in extracellular matrix and also a maker of epithelial-mesenchymal transition (EMT), has been implicated in the development of several types of human cancer. Many reports indicate that EMT is an important step during the cascade of tumor progression. However, the potential role of FN in carcinogenesis is not fully elucidated. We examined FN expression in surgical specimens of human colon cancer and colon adenoma by immunohistochemistry. A total of 87 tumors were analyzed. Levels of FN expression in tumor cells correlated with disease stage, and FN immunoreactivity was detected in invasive cancers, especially at the invasive edge, but less in mucosal cancers or adenomas. Furthermore, in an orthotopic nude mouse model of colon cancer, mRNA expression levels of FN were shown to be higher in the tumors produced by KM12SM cells mixed with MSCs than in the tumors produced by KM12SM cells alone.These findings suggest that the interaction between cancer cells and MSCs recruited into tumor stroma may play a role in tumor growth and metastasis via induction of FN expression in invasive colon cancer.
Citation Format: Kei Shinagawa, Yasuhiko Kitadai, Yuichiro Tanaka, Ryo Yuge, Mieko Onoyama, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Interaction between bone marrow-derived mesenchymal stem cells and tumor cells induces expression of fibronectin in human colon 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 180. doi:10.1158/1538-7445.AM2014-180
Abstract 1811: Evaluation of anti-CXCR2 small molecule inhibitors as novel chemotherapy targeting the Interleukin-8 pathway in colorectal cancer
Authors: Huang Yinghui Jane E. , Gaffney Kevin J. , Gerdts Ethan , Petasis Nicos A. , Lenz Heinz-Josef , LaBonte Melissa J. 
Published: May 2015

Abstract
Despite new and improved chemotherapy treatments for colorectal cancer (CRC) contributing to enhanced treatment response rates and patient prognosis, it has been suggested that an overwhelming 90% of metastatic CRC patients encounter treatment failure due to drug resistance. The Interleukin-8/CXCR2 pathway has been validated as a promising target for novel chemotherapy due to its overarching effects on various cell types within the tumor microenvironment that ultimately drive tumor growth, proliferation, survival, chemoresistance, metastasis and angiogenesis. A series of homologous small molecule inhibitors, which competitively bind to the active site of CXCR2, was developed and evaluated in terms of their efficacy in inhibiting the various cellular responses induced by IL-8/CXCR2 signaling, utilizing MTS cell proliferation, angiogenesis tube formation, colony formation, Western blot, cell migration and invasion assays. The anti-CXCR2 compounds developed produce potent repression of proliferation and colony forming capacity in HCT116, HT29, SW620 and LoVo CRC cell lines, achieving IC50 values as low as 9.6 μM in HCT116 and 9.6 μM in HT29, along with colony formation fold changes as low as .163 in HCT116 and .255 in HT29. Additionally, the compounds demonstrated inhibition of angiogenesis, migration and invasion and induced significant down-regulation of pathways downstream of CXCR2, including NF-κB, MAPK and Akt. The proposed targeting of the IL-8 pathway offers an attractive and promising approach to CRC therapy. Based on the structure and functional relationship of these compounds, new inhibitors will be designed and validated in hopes of having improved drug properties by utilizing our in vitro and in vivo assay systems.
Citation Format: Yinghui Jane E. Huang, Kevin J. Gaffney, Ethan Gerdts, Nicos A. Petasis, Heinz-Josef Lenz, Melissa J. LaBonte. Evaluation of anti-CXCR2 small molecule inhibitors as novel chemotherapy targeting the Interleukin-8 pathway in colorectal 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 1811. doi:10.1158/1538-7445.AM2014-1811
Abstract 1818: ERBB3/HER2 signaling limits the effectiveness of EGFR blockade in head and neck and colorectal cancer models
Authors: Zhang Li , Castanaro Carla , Luan Bo , Yang Katie , Fan Amy , Rudge John , Papadopoulos Nicholas , Thurston Gavin , Daly Christopher 
Published: May 2015

Abstract
Introduction: EGFR blocking antibodies are approved for the treatment of colorectal cancer (CRC) and head and neck squamous cell carcinoma (HNSCC). However, responses to single agent EGFR blocking antibodies are relatively infrequent and transient. Thus, there is a clear need for agents that can enhance the benefit of EGFR blockade. While ERBB3 signaling has been proposed to limit the effectiveness of EGFR inhibitors, the underlying molecular mechanisms are not fully understood. In this report, we employ blocking antibodies against ERBB3 (REGN1400) and EGFR (REGN955), as well as a HER2 blocking antibody, to investigate the role of ERBB3 in modulating the response to EGFR inhibition.
Experimental procedures and results: We show that EGFR and ERBB3 are co-activated in multiple HNSCC cell lines and that combined blockade of EGFR and ERBB3 inhibits the growth of these cell lines more effectively than blockade of either receptor alone. Western blotting analysis shows that REGN955 strongly inhibits activation of ERK, but not Akt, while REGN1400 strongly inhibits activation of Akt, but not ERK, consistent with the more potent effect of the combination on cell growth. In addition, using a colorectal cancer cell line with low endogenous ERBB3 activity, we show that neuregulin 1 treatment significantly increases ERBB3 phosphorylation and reverses the inhibitory effect of REGN955 on cell growth. To further understand the mechanism of ERBB3 activation, we employed a HER2 blocking antibody to show that ERBB3 phosphorylation in HNSCC and CRC cells is strictly dependent on association with HER2, but not EGFR, and that neuregulin 1 activates ERBB3/HER2 signaling to reverse the effect of EGFR blockade on CRC cell growth. Finally, while REGN1400 and REGN955 as single agents slowed the growth of HNSCC and CRC xenografts, the combination of REGN1400 plus REGN955 caused significant tumor regression.
Summary and conclusion: Our findings demonstrate that ERBB3 partners with HER2 to activate the Akt survival pathway and to limit the effect of EGFR blockade on the growth of HNSCC and CRC cell lines and tumor xenografts. These findings suggest that REGN1400, which is currently in a Phase 1 clinical trial, could provide clinical benefit when combined with EGFR blocking antibodies.
Citation Format: Li Zhang, Carla Castanaro, Bo Luan, Katie Yang, Amy Fan, John Rudge, Nicholas Papadopoulos, Gavin Thurston, Christopher Daly. ERBB3/HER2 signaling limits the effectiveness of EGFR blockade in head and neck and colorectal cancer models. [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 1818. doi:10.1158/1538-7445.AM2014-1818
Abstract 1839: LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small cell lung cancer (NSCLC) cells
Authors: Whang Young M. , Park Serk I. , Trenary Irina A. , Lee Changki , Kaufman Jacob M. , Carbone David P. , Young Jamey D. 
Published: May 2015

Abstract
The tumor suppressor LKB1 is inactivated in 20-30% of non-small cell lung cancer (NSCLC) patient tumors. Because LKB1 is the master kinase phosphorylating the energy-sensing kinase AMPK, dysregulation of the LKB1-AMPK signaling axis causes loss of cellular homeostasis in response to metabolic inhibition or external stress-induced mitochondrial insults. Erlotinib is used clinically in NSCLC patients to target mutationally activated EGFR and is known to induce mitochondrial-mediated apoptosis. We investigated the metabolic response and mitochondrial function of LKB1-deficient NSCLC cells treated with erlotinib. LKB1-deficient cells exhibited enhanced sensitivity to erlotinib treatment in vitro and in vivo despite having wild-type EGFR. We found that this enhanced response was due to altered energetic metabolism and mitochondrial dysfunction in LKB1-deficient cells, which prevents homestatic maintenance of ATP and reactive oxygen species (ROS) levels in response to erlotinib treatment. Despite negative regulation of mTOR activity by LKB1-AMPK signaling, erlotinib effectively blocked mTOR signaling in LKB1-deficient cells, resulting in inhibition of cell growth, as well as activation of apoptosis. These findings will be important for designing targeted treatments for LKB1-deficient NSCLC patient tumors harboring wild-type EGFR, which disrupt metabolic and signaling pathways known to regulate energy metabolism in these cells.
Citation Format: Young Mi Whang, Serk In Park, Irina A. Trenary, Changki Lee, Jacob M. Kaufman, David P. Carbone, Jamey D. Young. LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small cell lung cancer (NSCLC) 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 1839. doi:10.1158/1538-7445.AM2014-1839
Abstract 1843: Primary and acquired resistance to HERs inhibition in colorectal cancer cells: All HERs go to RAS
Authors: Russo Mariangela , Riggio Alessandra , Cancelliere Carlotta , Nicolantonio Federica D. , Bardelli Alberto 
Published: May 2015

Abstract
The monoclonal antibodies cetuximab and panitumumab are approved for the treatment of metastatic colorectal cancers (mCRC). When used as monotherapy, the anti-EGFR antibodies are effective in approximately 15% of patients. It is now well established that colorectal tumors carrying KRAS and BRAF mutations (40%) are refractory to EGFR targeted therapies (primary resistance). Virtually all-responsive patients eventually become insensitive to anti-EGFR antibodies (secondary resistance) within 3 to 12 months of initiating therapy. Primary and acquired resistance therefore limits the clinical benefit of EGFR blockade in CRC patients.
We postulated that concomitant inhibition of multiple members of the HER (ErbB) receptors family might suppress the growth of CRC cells more effectively than selectively targeting only the EGFR with cetuximab or panitumumab.
Accordingly, we assessed the pharmacological activity of momelotinib and afatinib- two pan-HER tyrosine kinase inhibitors- in a collection of 40 CRC cell lines, which recapitulate the genetic profiles commonly detected in CRC patients. We report that primary resistance to pan-HER inhibition is associated with KRAS and BRAF mutations thus suggesting that this patients' population will unlikely benefit from momelotinib and afatinib treatments. Notably, however, pan-HER blockade was effective in a subset of KRAS/BRAF wild type CRC cell lines refractory to cetuximab and panitumumab indicating that a subgroup of patients, which do not benefit from EGFR blockade, may profit from pan-HER inhibition.
To define the molecular mechanisms of acquired resistance to ErbB inhibitors, three KRAS/BRAF/NRAS wild type CRC cell models were continuously treated with cetuximab, momelotinib and afatinib, until resistant derivatives emerged. Genetic characterization of such derivatives unveiled that, regardless of the drug used, the resistant populations were a mixture of clones carrying distinctive mutations in KRAS or NRAS. Detailed biochemical analyses of the ErbB signalling pathway revealed that resistant variants displayed high levels of MEK and ERK activation, which persisted upon ErbBs inhibition.
Collectively, these results identify KRAS, BRAF and NRAS mutations as major drivers of primary and/or acquired resistance to HERs inhibition in colorectal cancer cells and suggest that a molecularly defined subset of CRC patients might benefit from pan-HER blockade.
Citation Format: Mariangela Russo, Alessandra Riggio, Carlotta Cancelliere, Federica Di Nicolantonio, Alberto Bardelli. Primary and acquired resistance to HERs inhibition in colorectal cancer cells: All HERs go to RAS. [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 1843. doi:10.1158/1538-7445.AM2014-1843