bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3122: Pharmacogenomic profiling to identify novel therapeutic strategies in colorectal cancer
Authors: Bruun Jarle , Eide Peter W. , Kryeziu Kushtrim , Sveen Anita , Murumägi Astrid , Kolberg Matthias , Arjama Mariliina , Kallioniemi Olli , Lothe Ragnhild A. 
Published: July 2017

Abstract
Colorectal cancer (CRC) is amongst the most frequent cancers worldwide and the fourth most common cause of cancer mortality. Surgery is the standard treatment of care, while chemotherapy and/or radiotherapy are offered to subgroups of patients according to disease stage. Current guidelines do not have sufficient accuracy to identify chemotherapy responders, resulting in under- or overtreatment of many patients.To discover novel therapeutic strategies for CRC we performed a high-throughput drug screen containing 461 approved and preclinical drugs on a representative panel of 42 CRC cell lines. Integrative pharmacogenomic profiles were explored by matching data from gene expression, exome sequencing, copy number and reverse-phase protein arrays. These analyses identified defined molecular subgroups sensitive to targeted drugs like Inhibitors of EGFR, IGF-1R and downstream signaling mediators like B-Raf, MEK, PI3K/AKT, as well as inhibitors of aurora mitotic kinases, heat shock protein 90 and p53. Additionally, a correlation between microsatellite instability and sensitivity against topoisomerase-I inhibitors was found. Comparison of the most sensitive and the most resistant cell models against HSP90 inhibitors indicated that drug sensitivity does not depend on target expression but is likely attributed to the cell line-specific expression of client proteins. Real-time cell analyses measured with the xCELLigence system demonstrated a strong impact on cell proliferation but not on the migration of HSP90-sensitive cells treated with HSP90 inhibitors as compared to resistant cells. These integrative analyses have unraveled pharmacogenomic relationships that if validated in in vivo model systems, might be used to stratify patients for therapeutic intervention in biomarker guided clinical trials.
Citation Format: Jarle Bruun, Peter W. Eide, Kushtrim Kryeziu, Anita Sveen, Astrid Murumägi, Matthias Kolberg, Mariliina Arjama, Olli Kallioniemi, Ragnhild A. Lothe. Pharmacogenomic profiling to identify novel therapeutic strategies in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3122. doi:10.1158/1538-7445.AM2017-3122
Abstract 3149: Identification of genes associated with the cisplatin resistance in cervical cancer cells expressing E545K mutation
Authors: Arjumand Wani , Jette Nicholas , McIntyre Jb , Ghatage Prafull , Doll Corinne M. , Lees-Miller Susan P. 
Published: July 2017

Abstract
The phosphatidylinositol-3 kinase (PI3K)/AKT/ mTOR signaling pathway is activated in several human cancers and activation is frequently mediated by “hotspot” mutations including E542K, E545K and H1047R in the PIK3CA gene. Approximately 30% of cervical cancer patients have the PIK3CA-E545K mutation. Cisplatin with radiotherapy (RT) is the standard treatment of cervical cancer world-wide, used in both the radical and post-operative adjuvant settings. However, details of the molecular mechanisms responsible for cisplatin resistance remain unclear. We previously reported PIK3CA mutation in patients with earlier stage (IB/II) cervical cancer was associated with poor survival (McIntyre et al. Gynecol Oncol. 2013, PMID:23266353), and in our recent study we observed that PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin or cisplatin plus RT and results in a more migratory phenotype than isogenic cell lines with wild type-PIK3CA. Moreover, these phenotypes are reversed by the PI3K inhibitor GDC-0941/Pictilisib (Wani et al. Oncotarget. 2016, PMID:27489350). The aim of the present study is to identify the expression of genes related to cisplatin resistance in cervical cancer cells engineered to express PIK3CA-E545K. Microarray analysis identified 161 genes that were up-regulated and 189 that were down-regulated in the cervical cancer cells stably expressing PIK3CA-E545K, some of which are involved in well-characterized mechanisms that could be relevant to cisplatin resistance. We are currently validating some of those genes by Real-time PCR that will help us to determine the mechanism of PIK3CA-E545K induced cisplatin resistance and enhanced migration in cervical cancer cells expressing PIK3CA-E545K and extending our in vitro findings to animal models. Together, our data will provide a useful basis for screening candidate targets for risk stratification and provide valuable information for potential targeted intervention in patients whose tumors harbor cisplatin-resistant molecular characteristics.
Citation Format: Wani Arjumand, Nicholas Jette, Jb McIntyre, Prafull Ghatage, Corinne M. Doll, Susan P. Lees-Miller. Identification of genes associated with the cisplatin resistance in cervical cancer cells expressing E545K mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3149. doi:10.1158/1538-7445.AM2017-3149
Abstract 315: S100B regulates IL-6 signaling via the p90 ribosomal S6 kinase (RSK) in malignant melanoma
Authors: Alasady Milad J. , Adipietro Kaylin A. , Pierce Adam D. , Wilder Paul T. , Hartman Kira G. , Weber David J. , Hay Nissim 
Published: July 2017

Abstract
S100B is a tumor marker that is highly elevated during the progression of malignant melanoma. However, the function of S100B in the progression of melanoma is not well understood. Here we propose a regulatory mechanism that defines interplay between S100B, Interleukin-6 (IL-6), STAT3, and CREB. First, we show that S100B inhibits IL-6 mRNA and protein levels, and that silencing S100B in melanoma cell lines induces the expression and secretion of IL-6. Consistent with this result, STAT3 phosphorylation and its activation occur upon S100B ablation and IL-6 production. Our data suggest that S100B exerts its effect on the IL-6 pathway via p90 ribosomal S6 kinase (RSK), leading to activation of transcription factor CREB. Elevated S100B in melanoma cells were shown to bind directly to RSK, sterically block its phosphorylation (at Thr573) and sequester RSK in the cytoplasm (Hartman et al., 2014). Silencing of S100B enables RSK nuclear translocation, which in turn elevates CREB phosphorylation and its transcriptional activity in the nucleus to induce IL-6 expression, which is consistent with these newer observations. Because IL-6 can inhibit the proliferation of melanocytes and early stage melanoma cells, we propose that the suppression of IL-6 by elevated S100B may be a mechanism for cancer cells to circumvent the inhibitory effect of IL-6 at early stages of melanoma. Additionally, the suppression of IL-6 by elevated S100B may also curb local immune response(s), which otherwise would be elevated by the secreted IL-6.
Note: This abstract was not presented at the meeting.
Citation Format: Milad J. Alasady, Kaylin A. Adipietro, Adam D. Pierce, Paul T. Wilder, Kira G. Hartman, David J. Weber, Nissim Hay. S100B regulates IL-6 signaling via the p90 ribosomal S6 kinase (RSK) in malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 315. doi:10.1158/1538-7445.AM2017-315
Abstract 3151: Loss of Axin1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions
Authors: Picco Gabriele , Petti Consalvo , Centonze Alessia , Torchiaro Erica , Bardelli Alberto , Medico Enzo 
Published: July 2017

Abstract
In colorectal cancer (CRC), WNT pathway activation by genetic rearrangements of RSPO3 is emerging as a promising target. However, its low prevalence severely limits availability of preclinical models for in-depth characterization. Using a pipeline designed to suppress stroma-derived signal, we find that RSPO3 “outlier” expression in CRC samples highlights translocation and fusion transcript expression. Outlier search in 151 CRC cell lines identified VACO6 and SNU1411cells as carriers of, respectively, a canonical PTPRK(e1)-RSPO3(e2) fusion and a novel PTPRK(e13)-RSPO3(e2) fusion. Both lines displayed marked in vitro and in vivo sensitivity to WNT blockade by the porcupine inhibitor LGK974, associated with transcriptional and morphological evidences of WNT pathway suppression. Long-term treatment of VACO6 cells with LGK974 led to the emergence of a resistant population carrying two frameshift deletions of the WNT pathway inhibitor AXIN1, with consequent protein loss. Suppression of AXIN1 in parental VACO6 cells by RNA interference conferred marked resistance to LGK974. These results provide the first mechanism of secondary resistance to WNT pathway inhibition.
Citation Format: Gabriele Picco, Consalvo Petti, Alessia Centonze, Erica Torchiaro, Alberto Bardelli, Enzo Medico. Loss of Axin1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3151. doi:10.1158/1538-7445.AM2017-3151
Abstract 3158: In vivo acquired resistance to an emibetuzumab analogue in MET-amplified gastric xenografts can be overcome by a MET-targeting antibody mixture or PIK3CA/AKT/mTOR inhibition
Authors: Pollmann Sofie Ellebæk , Petricoin Emanuel Frank , Calvert Valerie , Rao Shruti , Boca Simina , Madhavan Subha , Horak Ivan David , Kjær Andreas , Kragh Michael , Poulsen Thomas Tuxen 
Published: July 2017

Abstract
Aberrant over-activation of MET receptor tyrosine kinase is involved in driving malignancies such as gastric and non-small cell lung cancer (NSCLC), and in the development of resistance to EGFR-targeting therapeutics. This has led to the development of several MET-targeting agents in the form of tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs), many of which are in clinical development. However, resistance to MET-targeted agents is an emerging problem. This study aims to understand mechanisms underlying resistance development to an analogue of emibetuzumab, a mAb targeting MET. Upon long term in vivo treatment, emibetuzumab-resistant tumors and cell lines were generated, isolated, and characterized to investigate their acquired resistance mechanisms. Extensive reverse phase protein array and network analysis were used to characterize the proteomic profiles of three resistant cell lines, revealing three distinct resistance profiles, one involving activation of the PI3Kinase/AKT/mTOR pathway. We further show, how these resistance mechanisms can be overcome by treatment with other targeting therapeutics both in vitro and in vivo. Two of the models demonstrated in vivo sensitivity to Sym015, a novel mixture of two mAbs targeting non-overlapping epitopes of MET, partly due to ADCC, indicating that Sym015 can overcome acquired resistance to emibetuzumab. The third model demonstrated a marked increase in PI3Kinase/AKT/mTOR pathway activation. This activation translated into induced cancer cell and tumor growth, which could be inhibited by agents targeting PI3Kinase, AKT, or mTOR. This study thus points to treatment of patients with acquired resistance to single targeting MET mAbs with PI3Kinase/AKT/mTOR-targeting agents or a MET-targeting antibody mixture such as Sym015.
Citation Format: Sofie Ellebæk Pollmann, Emanuel Frank Petricoin, Valerie Calvert, Shruti Rao, Simina Boca, Subha Madhavan, Ivan David Horak, Andreas Kjær, Michael Kragh, Thomas Tuxen Poulsen. In vivo acquired resistance to an emibetuzumab analogue in MET-amplified gastric xenografts can be overcome by a MET-targeting antibody mixture or PIK3CA/AKT/mTOR inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3158. doi:10.1158/1538-7445.AM2017-3158
Abstract 3159: Lysosomal membrane permeabilization as potential mediator of resistance in pancreatic neuroendocrine tumors
Authors: Wiedmer Tabea , Frank Rasmus M. , Tschan Mario P. , Perren Aurel , Marinoni Ilaria 
Published: July 2017

Abstract
Sunitinib, an anti-angiogenic tyrosine kinase inhibitor, is approved for treatment of pancreatic neuroendocrine tumors (pNETs). However, its efficacy is greatly limited due to resistance. Sunitinib is a lysosomotropic drug, thus accumulates in lysosomes, leading to their destabilization and to lysosomal membrane permeabilization (LMP), which in turn can lead to cell death. Autophagy might be activated for clearance of damaged lysosomes, thus promote survival and act as a mechanism of resistance. We found that the autophagy inhibitor chloroquine increases sunitinib efficacy in pNET cell lines and in a transgenic mouse model of pNETs. Interestingly, chloroquine is a lysosomotropic drug as well and the response towards sunitinib and chloroquine in pNET cell lines correlated with lysosome-associated membrane protein 2 (LAMP2) levels, which influence lysosome stability. We hypothesized that sunitinib and the combination with chloroquine induce LMP in pNETs and that LMP leads to activation of the transcription factor EB (TFEB), master regulator of genes involved in lysosomal biogenesis and autophagy, leading to therapy resistance. We found that LMP increased upon combined treatment of sunitinib and chloroquine compared to single treatment in pNET cell lines. Treatment of pNET cell lines with sunitinib or chloroquine led to activation of TFEB as assessed by nuclear/cytoplasmic fractionation and western blotting. Additionally, sunitinib significantly increased the expression of TFEB target genes, which were further upregulated upon combination with chloroquine. Interestingly, activation of TFEB and upregulation of TFEB target genes was more pronounced in the more resistant pNET cell line with respect to reduced viability and increased apoptosis. Our data indicate that sunitinib and chloroquine activate TFEB in pNET cell lines, leading to autophagy as a survival mechanism. Upon massive LMP or if autophagy is dysfunctional, cell death is induced. Based on our data, we suggest the combination of sunitinib and chloroquine as a treatment option for pNET patients and that TFEB could be an interesting therapeutic target in combination with lysosomotropic drugs.
Citation Format: Tabea Wiedmer, Rasmus M. Frank, Mario P. Tschan, Aurel Perren, Ilaria Marinoni. Lysosomal membrane permeabilization as potential mediator of resistance in pancreatic neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3159. doi:10.1158/1538-7445.AM2017-3159
Abstract 3180: Chemotherapeutical agent triggers transient resistance of cancer cells by promoting ABCB1 intercellular transfer
Authors: Wang Xiaokun , Qiao Dongjuan , Chen Likun , Huang Liyan , Xu Meng , Chen Zhen , Wang Fang , Chen Zhesheng , Zeng Musheng , Fu Li-Wu 
Published: July 2017

Abstract
Multidrug resistance remains a major impediment to successful chemotherapy. In clinical chemotherapy, some patients often develop chemoresistance quite rapidly, the underlying mechanism remains elusive. Herein, we report that a transient exposure to chemotherapeutic agents can acutely promote the intercellular transfer of ABCB1 through stimulating Rab8B-mediated secretion of microvesicles (MVs) containing ABCB1 in drug-resistant donor cells, and promoting parallelly the endocytic recycling of ABCB1 in recipient tumor cells via the downregulation of Rab5. Sensitive recipient cells take up these ABCB1-incorporated MVs by a clathrin- and dynamin 2- dependent endocytic pathway, thereby acquiring a transient resistance to chemotherapeutic agents which are ABCB1 substrates. More fascinatingly, ABCB1 molecules can locally or distantly transfer to recipient tumor cells and respond to chemotherapeutical drug in the xenograft tumor models. In some cases of patients with NSCLC, a variable increase of ABCB1 surface expression was also detected in the peripheral blood monocyte subpopulations after they received the first chemotherapy. Our findings proposed a novel molecular mechanism of how sensitive cancer cells rapidly acquire the emergency resistance to chemotherapeutic agents by stimulating intercellular transfer of ABCB1. The precise modulation of this process may provide a valid therapeutic strategy to alleviate the MDR phenotype for successful treatment.
Citation Format: Xiaokun Wang, Dongjuan Qiao, Likun Chen, Liyan Huang, Meng Xu, Zhen Chen, Fang Wang, Zhesheng Chen, Musheng Zeng, Li-Wu Fu. Chemotherapeutical agent triggers transient resistance of cancer cells by promoting ABCB1 intercellular transfer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3180. doi:10.1158/1538-7445.AM2017-3180
Abstract 3185: Adipocyte-derived hydrogen peroxide promotes chemoresistance to daunorubicin in leukemia cells
Authors: Parmentier Jean-Hugues , Dieli-Conwright Christina M. , Mittelman Steven D. 
Published: July 2017

Abstract
Background: Adipocytes protect acute lymphoblastic leukemia (ALL) cells from several chemotherapeutic drugs. This protection is associated with an oxidative stress response in adipocytes. Since adipocytes are known to release reactive oxygen species, and anthracyclines are sensitive to inactivation mediated by hydrogen peroxide (H2O2), we investigated whether adipocyte release of H2O2 into the micro-environment might contribute to drug resistance of ALL cells.
Methods: Pre-B lymphoblast/myeloblast BV173 cells in complete media (CM) were co-cultured for 3 days in transwells over 3T3-L1 fibroblasts or adipocytes. Viable cells were determined by Trypan blue exclusion for BV173 cells. Leukemia Conditioned Media (LCM) was prepared from BV173 cultured for 48 hrs. Total antioxidant capacity was measured by ABTS-based assay. H2O2 released in the extracellular compartment of adipocytes was monitored with Amplex Red and ROS-Glo.
Results: BV173 cells were protected from DNR in presence of 1 mM H2O2 (9.34±2.15x104 vs. 3.33±1.01x104 viable cells with and without H2O2, p=0.03). Interestingly, this protection was only observed when pyruvate was present in the culture media at equimolar concentrations with H2O2 (DNR: 4.14±2.14x104; DNR+pyruvate: 4.17±1.53x104; DNR+H2O2: 3.77±2.74x103; DNR+pyruvate+H2O2: 3.21±0.59x105, p=0.02). Adipocytes released H2O2 into the media measured with Amplex Red fluorescence in a time-dependent manner significantly more than fibroblasts (1.96-fold, p=0.001). LCM potentiated adipocyte H2O2 released (1.5-fold over CM, p=0.05). Human adipose tissue biopsies from breast cancer survivors also released H2O2 (4.37x103 RFU for biopsies vs. 0.65x103 RFU for HBSS, 90 min, n=5). Co-culture of adipocytes and BV173 cells increases the survival of BV173 to DNR treatment (1.55±0.34x105 vs. 6.88±2.91x103 viable cells with and without adipocytes, p=0.006). Adipocyte-mediated protection of BV173 cells was reversed in a dose-dependent manner by adding the H2O2-inactivating enzyme catalase to the extracellular media (7.28±1.44x104 vs. 15.58±3.48x104 viable cells with and without 500 U/ml catalase, p=0.01).
Conclusion: These data show that adipocytes release H2O2, which in the presence of pyruvate, protects ALL cells from DNR. Further work is needed to determine whether adipocytes secrete significant amounts of H2O2 in the bone marrow micro-environment to contribute to anthracycline resistance.
Citation Format: Jean-Hugues Parmentier, Christina M. Dieli-Conwright, Steven D. Mittelman. Adipocyte-derived hydrogen peroxide promotes chemoresistance to daunorubicin in leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3185. doi:10.1158/1538-7445.AM2017-3185
Abstract 3202: Pharmacologic modulation of Sigma1 induces autophagic degradation of programmed death-ligand 1 in cancer cells
Authors: Maher Christina M. , Thomas Jeffrey D. , Longen Charles G. , Haas Derick A. , Oyer Halley M. , Tong Jane Y. , Kim Felix J. 
Published: July 2017

Abstract
Emerging evidence suggests that Sigma1 (also known as sigma1 receptor) is a unique ligand-operated integral membrane chaperone or scaffolding protein that contributes to cellular protein homeostasis. Previously, we found that treatment of various cancer cell lines with some prototypic small molecule modulators of Sigma1 can engage endoplasmic reticulum (ER) associated protein homeostasis pathways including the unfolded protein response and autophagy. Programmed death-ligand 1 (PD-L1) is a type 1 integral membrane glycoprotein that is processed and transported through the ER and secretory pathway of tumor cells. PD-L1 expressed at the surface of tumor cells can act as a T-cell inhibitory checkpoint molecule that inactivates tumor infiltrating immune cells that express PD-1, its cognate receptor. Here, we show that Sigma1 physically associates with PD-L1. In triple negative breast and androgen-independent prostate cancer cells, PD-L1 protein levels are suppressed by both RNAi mediated knockdown of Sigma1 and pharmacological modulation of Sigma1. We observe decreased cell surface and intracellular levels of PD-L1 by flow cytometry and biochemical subcellular fractionation respectively, which corresponds with a dose-responsive decrease in functional PD-L1/PD-1 interaction in a co-culture of cancer cells and T-cells. Inhibitors of autophagy block this suppression of PD-L1 protein levels, suggesting PD-L1 is degraded away by autophagy after Sigma1 modulation. Through confocal microscopy, we show that Sigma1 modulation results in colocalization of PD-L1 and GFP-LC3, a marker of autophagosomes. From these conclusions, we hypothesize that autophagic degradation of nascent PD-L1 after Sigma1 modulation plays a key role in preventing the transport of functional PD-L1 to the plasma membrane. Together, these data demonstrate that Sigma1 modulators have the potential to act as novel therapeutic agents in PD-1/PD-L1 blockade strategies.
Citation Format: Christina M. Maher, Jeffrey D. Thomas, Charles G. Longen, Derick A. Haas, Halley M. Oyer, Jane Y. Tong, Felix J. Kim. Pharmacologic modulation of Sigma1 induces autophagic degradation of programmed death-ligand 1 in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3202. doi:10.1158/1538-7445.AM2017-3202