bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 41: An Antibody Drug Conjugate targeting HER-3 demonstrates promising antitumor efficacy in a wide range of human cancer
Authors: Sala Gianluca , Iezzi Manuela , Lamolinara Alessia , Capone Emily , Iacobelli Stefano , Sauniere Jean-Fred , Ponziani Sara , Giansanti Francesco , Ippoliti Rodolfo 
Published: July 2017

Abstract
The HER-3 receptor is emerging as an attractive molecule in therapeutics because of its overexpression across many human cancers and because of its role in in several compensatory processes that underlay emergence of resistance to certain cancer drugs. In this study, we present evidence of the preclinical efficacy of a novel Antibody-Drug Conjugate (ADC) targeting HER-3. It consists of a humanized HER-3 monoclonal antibody (mAb EV20), which recognizes the HER-3 extracellular domain, conjugated to different payloads (HER-3-ADC)s. In HER-3 expressing cancer cell lines, these HER-3-ADCs demonstrated a powerful, specific and target-dependent killing activity. High expression levels of HER-3 in tumor cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro. Efficacy studies demonstrated that HER-3-ADCs treatment leads to a long lasting tumor growth inhibition of cell line-based models of human head and neck, breast, pancreatic, prostatic, lung, stomach cancers and melanoma. Overall, these findings validate HER-3 as an attractive therapeutic target in multiple solid tumors and support further clinical development and application of HER-3 targeting ADCs.
Citation Format: Gianluca Sala, Manuela Iezzi, Alessia Lamolinara, Emily Capone, Stefano Iacobelli, Jean-Fred Sauniere, Sara Ponziani, Francesco Giansanti, Rodolfo Ippoliti. An Antibody Drug Conjugate targeting HER-3 demonstrates promising antitumor efficacy in a wide range of human 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 41. doi:10.1158/1538-7445.AM2017-41
Abstract 4113: Acquired resistance to cetuximab is mediated by HER3 activation in head and neck squamous cell carcinoma
Authors: Yang Yeon Ju , Cho Min Hee , Oh Yoo Jung , Kim Da Hee , Kim Jung Min , Byeon Hyung Kwon , Ban Myung Jin , Kim Ji Hoon , Kim Jae Wook , Ku Min Hee , Yang Jae Moon , Choi Eun Chang , Koh Yoon Woo , Lee Jeong Yeon 
Published: July 2017

Abstract
Cetuximab, an EGFR monocloanal antibody, is commonly known to be an effective treatment agent in head and neck squamous cell carcinoma (HNSCC). However, despite the clinical efficacy of cetuximab, a majority of patients with good initial response still suffer from side effects as the acquired resistance to cetuximab. To understand the mechanisms of acquired resistance to cetuximab, we developed a model by exposing a head and neck cancer cell line Cal27 to increasing concentrations of cetuximab and established cetuximab-resistant clones (CETr) derived from the cetuximab sensitive (CETp). We examined how the acquired resistance in the CETr influenced the signaling pathway compared to the CETp. We investigated the effect of lapatinib, a tyrosine kinase inhibitor inhibiting HER3, with or without cetuximab combination on CETr clones and in a xenograft mouse model. Cetuximab-resistant(CETr) clones showed robust overexpression on the HER family receptors HER3. CETr clones also expressed upregulated EGFR, HER2, and HER3 activation resulting in activation of PI3K/ATK and ERK signaling. We also showed that CETr clones exhibited increased EGFR/HER3 dimerization. Treatment of cetuximab and siHER3 RNA together reduced EGFR activation in CETr clones to re-sensitize cells against cetuximab and robustly decreased cell proliferation. Combined treatment of CETr clones with cetuximab and lapatinib led to potent anti-proliferative effects. Co-treatment with cetuximab and lapatinib blocked EGFR, HER2 and HER3 activities and inhibited downstream signaling pathways. Co-treatment resulted in suppression of cell growth more effectively than each drug alone and induced apoptotic cell death through mitochondrial ROS. Furthermore, Co-treatment with cetuximab and lapatinib also led to suppression of tumor growth in orthotopic xenograft mouse model of oral tongue cancer. Our results suggested the upregulation of HER3 as a mechanism underlying resistance to cetuximab in HNSCC, supporting further clinical treatment strategy for tumors displaying acquired resistance to cetuximab.
Citation Format: Yeon Ju Yang, Min Hee Cho, Yoo Jung Oh, Da Hee Kim, Jung Min Kim, Hyung Kwon Byeon, Myung Jin Ban, Ji Hoon Kim, Jae Wook Kim, Min Hee Ku, Jae Moon Yang, Eun Chang Choi, Yoon Woo Koh, Jeong Yeon Lee. Acquired resistance to cetuximab is mediated by HER3 activation in head and neck squamous cell carcinoma [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 4113. doi:10.1158/1538-7445.AM2017-4113
Abstract 4115: Combination of FTY720 and tamoxifen inhibits drug-resistant ovarian cancer cell proliferation
Authors: Kreitzburg Kelly Marie , Landen Charles N. , Gamblin Tracy , Arend Rebecca , Alvarez Ronald , Yoon Karina 
Published: July 2017

Abstract
Despite satisfactory initial responses to frontline therapies that combine surgical debulking with platinum based chemotherapy, virtually all women with advanced ovarian cancer relapse with drug resistant disease. There is a critical need to identify alternative, effective therapies.
Previously, we used patient derived xenograft (PDX) models of ovarian cancer in mice to identify the sphingosine1 phosphate (S1P) pathway as one of the pathways most affected by two agents frequently used to treat ovarian cancer, carboplatin and paclitaxel. The S1P pathway contributes to multiple biological processes recognized as essential for tumor development, and aberrations in sphingolipid metabolism have been directly correlated with advanced disease and with resistance to chemotherapy and radiation. Further, recent studies indicate that tamoxifen may counteract drug resistance mechanisms through modulation of sphingolipid metabolism, specifically through inhibition of the ceramide converting enyzmes acid ceramidase and glucosylceramide synthase. Therefore, we evaluated the efficacy of modulating S1P metabolism using the sphingosine analog FTY720 and tamoxifen as an approach to inhibit the proliferation of drug-resistant ovarian tumor cells.
We used alamarBlue cell proliferation assays to compare the anti-proliferative effect of FTY720 and tamoxifen with the effect of each drug as a single agent. FTY720 + tamoxifen synergistically decreased the cell viability of 3/3 ovarian cancer cell lines: estrogen receptor alpha (ERα) positive SKOV3.TR (taxane resistant), ERα negative A280.cp20 (platinum resistant) and HeyA8.MDR (taxane-platinum resistant). The combination also increased levels of apoptosis as reflected by Annexin V staining and cleaved caspase 3 levels. Further, administration of 5mg/kg i.p. FTY720 + 20mg/kg p.o. tamoxifen daily for 21 days to PDX-bearing mice demonstrated that FTY720 + tamoxifen suppressed tumor growth by ~60% compared to vehicle controls. Notably, immunohistochemical staining of tumors harvested from treated mice showed that the combination decreased expression of the proliferation marker Ki-67 and increased expression of apoptosis indicators ceramide and cleaved caspase 3 to a greater degree than in tumors exposed to either drug alone. We conclude that FTY720 + tamoxifen merit further investigation as potentially effective agents for the treatment of drug-resistant ovarian cancer.
Citation Format: Kelly Marie Kreitzburg, Charles N. Landen, Tracy Gamblin, Rebecca Arend, Ronald Alvarez, Karina Yoon. Combination of FTY720 and tamoxifen inhibits drug-resistant ovarian cancer cell proliferation [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 4115. doi:10.1158/1538-7445.AM2017-4115
Abstract 4131: ERRβ: Validating a novel target for triple negative breast cancer
Authors: Fernandez Aileen I. , Graham Garrett , Győrffy Balázs , Cavalli Luciane , Riggins Rebecca B. 
Published: July 2017

Abstract
Triple negative breast cancer (TNBC) - defined as estrogen receptor- (ER), progesterone receptor- (PR), and human epidermal growth factor receptor 2- (HER2) negative - is a highly aggressive form of breast cancer prevalent in African-American (AA) women. Because ER- and HER2-targeted therapies are ineffective in TNBC, current treatment strategies rely on cytotoxic chemotherapy. There is a tremendous need for new approaches that can identify effective therapies with less toxicity for this devastating form of breast cancer.
Nuclear receptors are highly druggable targets. Classical examples include ligand-regulated receptors like ER, but orphan nuclear receptors are also emerging as targets for cancer therapy. We recently published that increased mRNA expression of estrogen-related receptor beta (ERRβ, gene symbol ESRRB) correlates with better recurrence- and distant metastasis-free survival in women with TNBC, and that a small molecule agonist ligand for ERRβ (DY131, DY) has growth inhibitory and anti-mitotic activity in TNBC cell lines of multiple molecular subtypes. The goal of our current work is to validate ERRβ as a novel therapeutic target for TNBC in two distinct ways.
First, we sought to determine whether ERRβ is correlated with survival outcome specifically in African-American (AA) women. Analysis of The Cancer Genome Atlas (TCGA) Breast Cancer RNAseq data shows that low ERRβ mRNA expression is specifically associated with poor overall survival in AA women with TNBC. This association is not observed in AA women with ER- or HER2-positive disease. We further find that while ERRβ mRNA expression is decreased in tumor vs. normal breast tissue regardless of race, this decrease is more pronounced in AA women. Ongoing studies in an independent cohort of AA and white women will determine whether this is due, in part, to copy number changes at the ERRβ locus (chromosome 14q24.3).
Second, we sought to determine whether ERRβ expression could predict response to current treatment strategies commonly used in breast cancer, particularly TNBC. Using multiple combined datasets, we find that high ERRβ expression is associated with improved recurrence-free survival (RFS) in women with TNBC who received adjuvant or neoadjuvant therapy with anthracycline (e.g. doxorubicin, Adriamycin). No association between ERRβ and RFS is observed in patients treated with taxanes. Ongoing studies in TNBC cell lines seek to determine if activating ERRβ with its agonist ligand DY can enhance doxorubicin-mediated growth inhibition and cell death.
Citation Format: Aileen I. Fernandez, Garrett Graham, Balázs Győrffy, Luciane Cavalli, Rebecca B. Riggins. ERRβ: Validating a novel target for triple negative breast 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 4131. doi:10.1158/1538-7445.AM2017-4131
Abstract 4142: Regulation of tumor suppressor decorin by APE1 in head and neck squamous cell carcinoma
Authors: Wicker Christina A. , Scott Timothy L. , Suganya Rangaswamy , Arnold Susan M. , Brill Yolanda M. , Horbinski Craig M. , Napier Dana , Valentino Joseph , Kudrimoti Mahesh R. , Yu Guoqiang , Izumi Tadahide 
Published: July 2017

Abstract
Oral cancers have a high rate of recurrence, and a tendency to develop treatment resistance. From 2009 to 2013, Kentucky had a disproportionately higher incidence of invasive oral cancers and resultant higher mortality compared to the national average (SEER & NPCR, Kentucky Cancer Registry).
Apurinic/Apyrimidinic endonuclease (APE1) is a key protein in DNA repair, and an important transcriptional regulator. Gene array analysis in pMEFs expressing wild-type APE1 and extremely low levels of APE1 showed an eight-fold reduction of tumor suppressor decorin (DCN), with wild-type APE1.
Decorin is a known tumor suppressor and extracellular matrix protein, which can suppress tumor proliferation, migration and angiogenesis. Tumors with decreased decorin are associated with increased mortality.
These studies aim to elucidate APE1’s role in decorin regulation in oral cancer and identify biomarkers, which may aid in diagnosis, treatment, or predicting prognosis.
Immunohistochemistry studies of head and neck squamous cell carcinoma from Kentuckians were analyzed aided by Aperio’s high resolution scanning capabilities, and software. Analysis showed a significant decrease in decorin in both tumor and carcinoma in situ compared to benign tissue. Whereas, APE1 was significantly increased in tumors. Additionally there was a significant negative correlation between APE1 and decorin total protein in carcinoma in situ. This data supports that increased APE1 may deplete decorin. Superoxide Dismutase 3, which is important in detoxifying extracellular ROS, was also significantly decreased in tumor and in carcinoma in situ. This along with previous research showing increased ROS in the tumor microenvironment and APE1 activation by ROS may explain the origination of decorin suppression.
We hypothesize that the overexpression of APE1 in early stages of oral cancer leads to diminished decorin translation, which may drive cancer progression and increase mortality. Better understanding how APE1 influences tumor suppressors may eventually aid in development of therapeutics that would increase patient survival.
Citation Format: Christina A. Wicker, Timothy L. Scott, Rangaswamy Suganya, Susan M. Arnold, Yolanda M. Brill, Craig M. Horbinski, Dana Napier, Joseph Valentino, Mahesh R. Kudrimoti, Guoqiang Yu, Tadahide Izumi. Regulation of tumor suppressor decorin by APE1 in head and neck squamous cell carcinoma [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 4142. doi:10.1158/1538-7445.AM2017-4142
Abstract 4154: Resistance to BET inhibitors involves the β-catenin pathway in uveal melanoma
Authors: Ambrosini Grazia , Tycko Benjamin , Do Chaterine , Schwartz Gary K. 
Published: July 2017

Abstract
Uveal melanoma (UM) is an aggressive intraocular malignancy with high tendency to metastasize to the liver. Currently available drugs have shown limited clinical activity in patients with UM and there is an urgent need for new effective therapies. Recent findings from our laboratory demonstrated that UM cells are sensitive to BET inhibitors (BETi) through the induction of cell cycle arrest and apoptosis. However, despite the initial inhibitory effects, UM cells acquire resistance to this class of drugs following chronic drug exposure. In order to understand the mechanistic basis for BETi resistance in UM, we assessed genome-wide CpG methylation patterns in UM cell lines that had been rendered resistant to the clinical BET inhibitor PLX51107 (Plexxikon, Berkeley, CA) following chronic drug exposure. The comparison between BET inhibitor-resistant versus sensitive cell lines revealed differential methylation of 1700 genes, including several involved in Wnt/β-catenin signaling, as well as other signaling pathways. Immunoblotting analysis confirmed that β-catenin protein was induced and activated in the resistant cells, while depletion of β-catenin by siRNA re-sensitized the resistant cells to the BET inhibitor. We then explored several combinations of PLX51107 with drugs that block β-catenin transcriptional activity through inhibition of its phosphorylation by PAK4 or through the inhibition of binding partners like Cdk8 and CBP. All these combinations increased the activity of the BET inhibitor in both sensitive and resistant cells, and these effects were synergistic, with combination indexes (CI) &lt;1. These observations support the evidence that acquired resistant to BET inhibitors is mediated, at least in part, by activation of the Wnt/β-catenin pathway, and inhibitors of this pathway may provide a means to overcome acquired BET inhibitor resistance in UM patients treated with this class of drugs.
Citation Format: Grazia Ambrosini, Benjamin Tycko, Chaterine Do, Gary K. Schwartz. Resistance to BET inhibitors involves the β-catenin pathway in uveal 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 4154. doi:10.1158/1538-7445.AM2017-4154
Abstract 4161: Increased expression of ABCB1 could be associated with osimertinib resistance in non-small cell lung cancer cell line PC9 cell
Authors: Nomizo Takashi , Ozasa Hiroaki , Tsuji Takahiro , Yasuda Yuto , Funazo Tomoko , Yoshida Hironori , Sakamori Yuichi , Nagai Hiroki , Kim Young Hak 
Published: July 2017

Abstract
Osimertinib, a third-generation EGFR Tyrosine kinase inhibitor, has shown promising activity in EGFR mutation positive non-small cell lung cancer (NSCLC) which harboring T790M mutation. The mechanisms of resistance to osimertinib have been still unclear. To investigate the mechanisms of acquired resistance to osimertinib, we established the osimertinib-resistant cell line (PC9/osimertinib) from the NSCLC cell lines PC9, and measured the expression levels of ATP-binding cassette (ABC) transporters using quantitative real-time polymerase chain reaction. Expression profiling of ABC transporters revealed that the levels of ABCB1 gene expression were significantly increased in the PC9/osimertinib cells compared with the parental cells, but not other ABC transporters. Knockdown of ABCB1 expression using short hairpin RNA enhanced osimertinib cytotoxicity in PC9/osimertinib cells. These data suggest that increased expression of ABCB1 may have an important role in the acquired resistance to osimertinib.
Citation Format: Takashi Nomizo, Hiroaki Ozasa, Takahiro Tsuji, Yuto Yasuda, Tomoko Funazo, Hironori Yoshida, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim. Increased expression of ABCB1 could be associated with osimertinib resistance in non-small cell lung cancer cell line PC9 cell [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 4161. doi:10.1158/1538-7445.AM2017-4161
Abstract 4163: Blockade of the interleukin-1 signaling pathway overcomes erlotinib resistance in head and neck cancer cells
Authors: Simons Andrean L. , Stanam Aditya , Gibson-Corley Katherine N. 
Published: July 2017

Abstract
The EGFR tyrosine kinase inhibitor erlotinib has demonstrated poor clinical response rates for head and neck squamous cell carcinoma (HNSCC) to date and the majority of respondents acquire resistance to erlotinib relatively quickly. Our previous data has shown that erlotinib activated interleukin-1 (IL-1) expression and signaling in HNSCC cells in vitro. We therefore investigated if upregulation of IL-1 signaling is involved in erlotinib resistance in HNSCC cells. We compared gene expression profiles of erlotinib-resistant (ER) and the parental erlotinib-sensitive (ES) HNSCC cell lines and observed a deregulation of the IL-1 signaling pathway in ER versus ES-HNSCC cells using microarray enrichment analysis. Secretion of IL-1 alpha (IL-1α) and IL-1 beta (IL-1β) were not significantly different in ER-SQ20B and ER-CAL 27 cells compared to their respective ES-cells, however secretion of the IL-1 receptor antagonist (IL-1RA) was significantly reduced in ER-cells compared to ES-cells. Blockade of IL-1 signaling using a recombinant IL-1R antagonist (anakinra) was able to significantly suppress the growth of ER-SQ20B but not ES-SQ20B xenografts as a single agent and in combination with erlotinib. ER-SQ20B xenografts treated with anakinra with or without erlotinib were found to be less vascularized (as determined by CD31 staining) than ER-SQ20B xenografts treated with water or erlotinib. Altogether, blockade of the IL-1 pathway using anakinra overcame erlotinib resistance in HNSCC xenografts and may represent a novel strategy to overcome EGFR inhibitor resistance for the treatment of HNSCC patients.
Citation Format: Andrean L. Simons, Aditya Stanam, Katherine N. Gibson-Corley. Blockade of the interleukin-1 signaling pathway overcomes erlotinib resistance in head and neck 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 4163. doi:10.1158/1538-7445.AM2017-4163
Abstract 4165: SOX2 promotes lineage plasticity and antiandrogen resistance in TP53 and RB1 deficient prostate cancer
Authors: Mu Ping , Zhang Zeda , Benelli Matteo , Karthaus Wouter , Hoover Elizebeth , Chen Chi-Chao , Wongvipat John , Ku Sheng-Yu , Gao Dong , Cao Zhen , Shah Neel , Adams Elizabeth , Abida Wassim , Watson Philip , Prandi Davide , Huang Chun-Hao , Stanchina Elisa de , Lowe Scott , Ellis Leigh , Beltran Himisha , Rubin Mark , Goodrich David , Demichelis Francesca , Sawyers Charles L. 
Published: July 2017

Abstract
Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. Here we show, using in vitro and in vivo prostate cancer models, that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR) dependent luminal epithelial cells to AR independent basal-like cells. This lineage plasticity is enabled by loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2 and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.
Citation Format: Ping Mu, Zeda Zhang, Matteo Benelli, Wouter Karthaus, Elizebeth Hoover, Chi-Chao Chen, John Wongvipat, Sheng-Yu Ku, Dong Gao, Zhen Cao, Neel Shah, Elizabeth Adams, Wassim Abida, Philip Watson, Davide Prandi, Chun-Hao Huang, Elisa de Stanchina, Scott Lowe, Leigh Ellis, Himisha Beltran, Mark Rubin, David Goodrich, Francesca Demichelis, Charles L. Sawyers. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53 and RB1 deficient prostate 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 4165. doi:10.1158/1538-7445.AM2017-4165