bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT133: Association of programmed death-ligand 1 (PD-L1) and 2 (PD-L2) expression with nivolumab (NIVO) efficacy in advanced melanoma (MEL)
Authors: Rodig Scott J. , Gjini Evisa , Desai Kaushal , Jin Chelsea , Horak Christine , Ruisi Mary , Weber Jeffrey , Freeman Gordon J. , Hodi F. Stephen 
Published: July 2016

Abstract
Background: NIVO inhibits the interaction of the PD-1 receptor with its ligands, PD-L1 and PD-L2. While high tumor PD-L1 expression results in greater clinical benefit with NIVO, MEL patients (pts) with low-to-no PD-L1 expression also benefit from NIVO. This may be partially attributed to PD-L2. Here, we analyzed the association between PD-L1/PD-L2 expression and efficacy from a phase II study (CheckMate 064) evaluating NIVO followed by ipilimumab (IPI) vs IPI followed by NIVO in MEL.
Methods: Pts were randomized 1:1 to receive sequential treatment with NIVO (3 mg/kg IV Q2W x 6) then IPI (3 mg/kg IV Q3W x 4) (cohort A) or IPI then NIVO (cohort B). Pts were biopsied prior to treatment and at Wk 13; pts had only received one agent at Wk 13. PD-L1 and PD-L2 expression were assessed by immunohistochemistry on formalin-fixed, paraffin-embedded tumor samples with the Dako PD-L1 28-8 pharmDx assay and a novel PD-L2 assay (antibody clone 9E5). Dichotomization of the percent expression of PD-L1 and PD-L2 was optimized by ROC analyses.
Results: In pre-treatment samples, 32/97 (33%) pts had PD-L1 expression ?5% and 38/83 (46%) pts had PD-L2 expression ?70%. No consistent change from baseline in PD-L1 or PD-L2 was observed in either cohort with treatment. The frequency of pts with PD-L2 expression ?70% was higher among pts with PD-L1 ?5% vs PD-L1 &lt;5%: 63% (19/30) vs 36% (17/47). In cohort A, there was a greater mean tumor burden reduction and higher response rates at Wk 13 among pts with high vs low PD-L2 expression, even in pts with low-to-no PD-L1 (Table). No association between PD-L2 and efficacy was observed in cohort B.
Conclusions: Similar to PD-L1, PD-L2 expression may enrich response to NIVO in MEL. PD-L2 expression may partially explain the efficacy of NIVO in pts with low-to-no PD-L1. However, NIVO is still active in pts with low-to-no expression of both ligands, suggesting other factors may explain the activity of NIVO. Further analysis is required to delineate these factors. ExpressionStatus, %NCheckMateCheckMate064064Cohort ACohort BPD-L1PD-L2Tumor response, n/N (%)Reduction in tumor burden, %Tumor response, n/N (%)Reduction in tumor burden, %≥5≥70197/13 (54)-26.62/6 (33)4.9≥5&lt;70112/7 (29)-13.30/4 (0)49.8&lt;5≥70174/10 (40)-28.40/7 (0)58.0&lt;5&lt;70304/18 (22)-2.80/12 (0)31.3
Citation Format: Scott J. Rodig, Evisa Gjini, Kaushal Desai, Chelsea Jin, Christine Horak, Mary Ruisi, Jeffrey Weber, Gordon J. Freeman, F. Stephen Hodi. Association of programmed death-ligand 1 (PD-L1) and 2 (PD-L2) expression with nivolumab (NIVO) efficacy in advanced melanoma (MEL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT133.
Abstract LB-015: XIAP induction by the MAPK-eIF4G1 pathway drives NFκB activation in inflammatory breast cancer growth and therapeutic resistance
Authors: Evans Myron K. , Geradts Joseph , Edwards Courtney , Price Arianna , Arora Arjun J. , Aldrich Amy J. , Ramirez Adrian , Robinson Timothy J. , Vermeulen Peter B. , van Laere Steven , Devi Gayathri R. 
Published: July 2016

Abstract
Inflammatory breast cancer (IBC) is the most lethal, distinct form of breast cancer, however, the basis for its aggressiveness and rapid acquisition of drug resistance is not fully understood. Using immunohistochemical analysis, we identified a strong correlation between high grade, high stage, and triple-negative status and elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) in IBC. Molecular profiling of multiple IBC cell lines revealed that modulating XIAP expression can significantly alter the expression pattern of a 79-gene, characteristic IBC profile that was previously obtained from clinical samples. Using specific antagonists and RNAi, we determined that the mitogen activated protein kinase (MAPK) pathway and its interaction with the protein synthesis initiation factor eIF4G1, both of which are elevated in IBC, cooperate to drive XIAP induction and resistance to therapeutic apoptosis. Further, we found that XIAP expression directly correlates with activation of the transcription factor NFκB, a molecular component defining IBC. Mutational analysis revealed that the BIR1 domain of XIAP is essential for subsequent TAB1:IKKβ-dependent NFκB activation. After determining this association between XIAP and TAB1, we tested a peptide-mediated strategy used to block the BIR1:TAB1 interaction antagonized NFκB activity which led to decreased anchorage independent growth and reversed resistance to an EGFR tyrosine kinase inhibitor. Most significantly, orthotopic implantation of XIAP silenced IBC cells revealed the necessity of expression for IBC tumor growth, while overexpression of XIAP enhanced tumor growth. Our findings establish that XIAP augments the malignant properties in IBC by enhancing NFκB function, identify a druggable pathway with multiple targets, and provide feasibility for the development of novel therapeutics targeting the BIR1 domain of XIAP in IBC.
Grant Support: Supported by American Cancer Society, the Duke Cancer Institute as part of the P30 Cancer Center Support Grant NIH CA014236, the Duke Department of Surgery, and DOD grant W81XWH-13-1-0047.
Citation Format: Myron K. Evans, Joseph Geradts, Courtney Edwards, Arianna Price, Arjun J. Arora, Amy J. Aldrich, Adrian Ramirez, Timothy J. Robinson, Peter B. Vermeulen, Steven van Laere, Gayathri R. Devi. XIAP induction by the MAPK-eIF4G1 pathway drives NFκB activation in inflammatory breast cancer growth and therapeutic resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-015.
Abstract LB-039: Genetic dissection of mechanisms underlying epidermal growth factor receptor-independent colorectal cancer development
Authors: Mantilla-Rojas Carolina , Yu Ming , Threadgill David 
Published: July 2016

Abstract
Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the United States. Substantial effort has gone into understanding molecular mechanisms governing CRC progression with the goal of developing potent targeted therapies. Epidermal growth factor receptor (EGFR) was one of the first molecular targeted therapies. However clinical trials using EGFR inhibitors are not as efficient, suggesting an alternative and independent EGFR-CRC progression mechanism. In this study, we also evaluated the importance of ERBB3, a related EGF receptor, in EGFR-independent colorectal cancer progression. Using intestine-specific genetic ablation of Egfr in the ApcMin/+ (genetic) and axozymethane (carcinogenic) CRC mouse models, we show that 10% of colonic tumors arise independent of EGFR activity. Molecular analysis confirmed the lack of Egfr in these tumors and the formal proof for the existence of an EGFR-independent pathway. Tumors developing in absence of EGFR are larger in size than those developing under normal EGFR activity suggesting that EGFR independent tumors may have a faster growth rate. We also have evidence that ERBB3 may mediate compensatory pathways. Using intestinal specific ablation of Erbb3 (Erbb3f/f) we previously showed that the number of intestinal tumors in the ApcMin/+ model is greatly reduced. Importantly, polyps forming in absence of ERBB3 are significantly smaller than controls, suggesting that normal levels of ERBB3 signaling is essential for tumor growth in the ApcMin/+ model. More recently, we have generated a combinatorial model that conditionally inactivates both Erbb3 and Egfr in the intestinal epithelia. These models will provide powerful tools to genetically dissect molecular pathways contributing to CRC, and aid in identifying molecular biomarkers that can differentiate EGFR-independent from EGFR-dependent CRC. These studies may advance understanding of ERBB biology during colonic tumorigenesis and help design better therapies in combination with EGFR-targeted agents.
Citation Format: Carolina Mantilla-Rojas, Ming Yu, David Threadgill. Genetic dissection of mechanisms underlying epidermal growth factor receptor-independent colorectal cancer development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-039.
Abstract LB-063: A high-resolution, quantitative proteomic map of human prostate cancer cells
Authors: Zhou Bo , Freeman Michael R. , Yang Wei 
Published: July 2016

Abstract
Prostate cancer is the second leading cause of cancer death in American men. Despite remarkable progress in the past decade, the molecular basis of prostate cancer development and progression remains incompletely understood. Owing to the rapid advancement of next generation sequencing technologies, whole-genome and -transcriptome sequencing have been increasingly applied to analyze prostate cancer. In comparison, whole-proteome sequencing of prostate cancer remains very challenging. Here, by applying three different endoproteinases (i.e., trypsin, Glu-C and Asp-N) and two-dimensional liquid chromatography-tandem mass spectrometry, we generated a high-resolution and quantitative proteomic map for DU145, a widely used human prostate cancer cell line. A total of 11,759 non-redundant protein groups were identified with a false discovery rate of 1%, corresponding to 10,561 genes. The absolute abundance of each identified protein was computed, ranging from 110 million to several copies (median = 35,700 copies). In addition, a recent RNA-Seq analysis of DU145 cells suggested that only 10,964 genes have FPKM values of ? 1, indicating that our proteomic profiling covers almost the entire proteome. Among the 10,561 identified genes, at least 904 (e.g., BRAF, BRCA1, EZH2, FGFR1, HNF1B, and STAT3) express two to eight different protein isoforms, some of which have not been characterized before. In addition, proteogenomic analysis identified over 40 aberrant proteins derived from alternative splicing and site mutation as well as translation from 5’UTR, long non-coding RNAs, and pseudogenes. In conclusion, we generated the first near-complete quantitative proteomic map for prostate cancer cells, which may guide the discovery of prostate cancer-specific protein biomarkers.
Citation Format: Bo Zhou, Michael R. Freeman, Wei Yang. A high-resolution, quantitative proteomic map of human prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-063.
Abstract LB-088: Heterodimeric IL-15 enhances tumor infiltration, persistence and effector functions of adoptively transferred tumor-specific T cells in the absence of lymphodepletion
Authors: Ng Sinnie , Bergamaschi Cristina , Nagy Bethany , Alicea Candido , Jensen Shawn M. , Fox Bernard A. , Felber Barbara K. , Pavlakis George N. 
Published: July 2016

Abstract
Adoptive cell transfer (ACT) is a promising immunotherapeutic approach for cancer. Lymphodepletion of the host is associated with favorable ACT outcomes but it may cause detrimental effects in humans. Lymphodepletion results in high level of homeostatic cytokines including Interleukin-15 (IL-15) that support survival and proliferation of the transferred lymphocytes. We tested the hypothesis that exogenous IL-15 enhances ACT in the absence of lymphodepletion. We have previously shown that bioactive IL-15 in vivo comprises a stable complex of the IL-15 chain with the IL-15 Receptor alpha chain, termed heterodimeric IL-15 (hetIL-15). We therefore evaluated the effects of the combination regimen ACT+hetIL-15 in absence of lymphodepletion by transferring melanoma-specific Pmel-1 T cells into B16 melanoma-bearing mice. hetIL-15 promoted infiltration and persistence of both adoptively transferred Pmel-1 cells and endogenous CD8+ T cells in the tumor. Following lymphodepletion by irradiation, Pmel-1 cells also localized to tumor sites efficiently, but their persistence was severely reduced in comparison to mice treated with hetIL-15. Importantly, we found that hetIL-15 preferentially enriched Pmel-1 cells in the tumor sites. hetIL-15 treatment also supported proliferation and cytotoxic function of tumor-infiltrating Pmel-1 cells, while reducing their expression level of PD-1, and resulted in improved tumor control and survival benefit. Thus, hetIL-15 administration improves the outcome of ACT in non-lymphodepleted hosts, and can be a valuable addition to strategies for cancer immunotherapy.
Citation Format: Sinnie Ng, Cristina Bergamaschi, Bethany Nagy, Candido Alicea, Shawn M. Jensen, Bernard A. Fox, Barbara K. Felber, George N. Pavlakis. Heterodimeric IL-15 enhances tumor infiltration, persistence and effector functions of adoptively transferred tumor-specific T cells in the absence of lymphodepletion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-088.
Abstract LB-093: Vaccine based immunotherapy regimen (VBIR) for the treatment of prostate cancer
Authors: Cho Helen , Cockle Paul , Joe Binder , Risini Weeratna , White Phil , Jooss Karin 
Published: July 2016

Abstract
A successful cancer vaccine will activate the host immune system to induce a balanced T- and B-cell response to tumor-specific antigens that can lead to tumor regression. Effective cancer vaccines will need to overcome several challenges to accomplish this goal, such as to break tolerance to the tumor associated antigens which are mostly self antigens, induce and maintain high tumor-specific T-cell titers to keep the immune pressure on the tumor as well as to overcome the immune suppressive tumor microenvironment to keep the T-cells active at the tumor site. We have applied the lessons learned in the field to the development of a multi-component cancer immunotherapy regimen that has entered clinical testing at the beginning of 2016 for the treatment of patients with prostate cancer. The vaccine regimen consists of a chimpanzee adenovirus prime vaccination administered intramuscularly followed by DNA boost vaccinations delivered with an electroporation device and with each vaccination low dose of an anti-CTLA4 antibody is administered locally, in close proximity of the vaccine draining lymph nodes. The adenovirus and DNA express the three prostate cancer antigens PSA, PSMA and PSCA. Lastly, sutent or anti-PD-1 is added to the regimen to counter the immune suppressive tumor microenvironment by lowering myeloid derived suppressor cells (by sutent doses that are lower than the approved clinical dose) or interfering with the PD-L1/PD-1 signaling pathway (by anti-PD-1). Data will be presented in tumor-bearing mice and non human primates (NHPs) demonstrating the attributes of the heterologous prime/boost vaccine with local anti-CTLA4 that induces potent, polyclonal and functional tumor-antigen specific T- and B cell responses that are maintained at high levels for up to a year in NHPs. We could also demonstrate that low dose of sutent is highly effective at lowering MDSCs in tumors and the periphery of tumor bearing mice, resulting in significantly enhanced potency of a heterologous prime/boost cancer vaccine. Lastly, our data suggest that - in the context of active vaccination - local delivery of anti-CTLA4 is superior to systemic delivery of the immune modulator at enhancing vaccine induced T-cell responses, thereby broadening the therapeutic window of the immune modulator.
Citation Format: Helen Cho, Paul Cockle, Binder Joe, Weeratna Risini, Phil White, Karin Jooss. Vaccine based immunotherapy regimen (VBIR) for the treatment of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-093.
Abstract LB-119: Single-cell live imaging of paclitaxel-resistant cancer cell generation
Authors: Niu Na , Zhang Jie , Zhang Ning , Mercado-Uribe Imelda , Tao Fangfang , Han Zhenbo , Pathak Sen , Multani Asha , Kuang Jian , Yao Jun , Bast Robert , Sood Anil , Hung Mien-Chie , Liu Jinsong 
Published: July 2016

Abstract
Polyploid giant cancer cells (PGCCs) are abundant in cancers after chemotherapy. PGCCs have generally been considered nonviable because of their inability to execute mitosis. However, our recently reported studies challenged this paradigm by showing that PGCCs were capable of tumor initiation. To understand the role of PGCCs in chemoresistance, we monitored paclitaxel-induced PGCCs by conventional and live-cell fluorescence time-lapse recording. We found that paclitaxel induced massive cell death but also initiated endoreplication to form PGCCs. These PGCCs continued to grow via endoreplication, endomitosis, or cytofission before generating new mononuclear or multinucleated daughter cells via nuclear fragmentation or budding. These daughter cells resumed mitosis with a new stable karyotype and exhibited drug resistance. Budding from PGCCs was also observed in chemotherapy-treated ovarian cancer specimens from patients. On the basis of our findings, we propose the existence of an amitotic giant cell cycle composed of four phases: initiation, maintenance, termination, and speciation. We believe this is the first report of fluorescent live-cell imaging of the birth of resistant cancer cells at the single-cell level in response to paclitaxel treatment. Our findings provide strong evidence that a stress-induced amitotic giant cell cycle may be a programmed event underlying chemotherapy resistance and cancer relapse.
Citation Format: Na Niu, Jie Zhang, Ning Zhang, Imelda Mercado-Uribe, Fangfang Tao, Zhenbo Han, Sen Pathak, Asha Multani, Jian Kuang, Jun Yao, Robert Bast, Anil Sood, Mien-Chie Hung, Jinsong Liu. Single-cell live imaging of paclitaxel-resistant cancer cell generation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-119.
Abstract LB-128: High prevalence of elevated TRPV6 mRNA in pancreatic ductal adenocarcinoma
Authors: Lutes Tyler , Dugourd Dominique , Davey Michelle , Rice Christopher , St-Pierre Stephanie , Stewart Jack M. 
Published: July 2016

Abstract
SOR-C13, a 13-mer peptide derived from soricidin, the paralytic protein component of saliva of the Northern Short-tailed shrew, just completed an open-label, all comers phase I clinical trial for the treatment of epithelial-derived cancers. SOR-C13 is a first-in-class drug candidate that specifically targets and inhibits the TRPV6 calcium channel - a recognized oncochannel over-expressed in a number of epithelial cancers (e.g. breast, ovarian, prostate). TRPV6 over-expression is associated with a poor prognosis particularly with breast and prostate cancers. SOR-C13 is the first TRPV6-targeting drug to enter clinical development. Pancreatic patients were enrolled in the phase I clinical trial for SOR-C13 and for this reason the TRPV6 gene expression in pancreatic tumour biopsies was assessed. Association of TRPV6 oncochannel expression with aggressive pancreatic adenocarcinoma compared to neuroendocrine tumours has never been investigated. Pancreatic adenocarcinoma represents 90% of the pancreatic tumours and is associated with a poor prognosis compared to neuroendocrine tumours. TRPV6 gene expression was assessed in 19 pancreatic tumor biopsies including five adenocarcinoma (Grade I to III), one acinar cell (exocrine), and 13 neuroendocrine (Islet cell) tumors by two-step RT-qPCR. TRPV6 and β-actin (reference gene) mRNA expression was evaluated in duplicate in a reproducible TRPV6 plus β-actin duplex two-step RT-qPCR assay. The acinar cell, and 69% (9/13) of the neuroendocrine tumors had no detectable TRPV6 mRNA expression with &gt;90% of neuroendocrine tumors (12/13) having very little TRPV6 mRNA expression (&lt;30 copies/ng RNA). Of the five pancreatic adenocarcinoma biopsies 4/5 (80%) had 67-285 copies of TRPV6 mRNA/ng RNA, indicating a high level of TRPV6 expression in this type of aggressive pancreatic cancer. The β-actin CT was between 24 and 30 for all tumours (mean 28.5 ± 1.2) indicating that the lack TRPV6 amplification in a majority of the neuroendocrine tumors was not due to RT-qPCR failure or a lack of quality of the biopsy cDNA. Results indicate that drugs specifically targeting TRPV6 oncochannel, like SOR-C13, have the potential to be used to treat the high medical need in pancreatic ductal adenocarcinoma.
Citation Format: Tyler Lutes, Dominique Dugourd, Michelle Davey, Christopher Rice, Stephanie St-Pierre, Jack M. Stewart. High prevalence of elevated TRPV6 mRNA in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-128.