tbuckley/cabot-search huggingface dataset:
Abstract 124: Imipridone ONC201 promotes intra-tumoral accumulation of CD3+/NK+ cells that contribute to its anti-tumor efficacy
Authors: Jessica Wagner, C. Leah Kline, Lanlan Zhou, Andrew Zloza, Charles Chesson, Jenna Newman, Howard Kaufman, Joseph Bertino, Mark Stein, Wafik El-Deiry
Journal: Cancer Research (2017)

Abstract ONC201, a first-in-class oral anti-tumor agent, upregulates the pro-apoptotic immune cytokine TRAIL and activates the integrated stress response leading to upregulation of death receptor 5 in bulk tumor and cancer stem cells. We previously demonstrated that ONC201 exerts a dose- and schedule-dependent effect on tumor progression in vivo while suppressing Akt/ERK signaling in tumors in a dose/frequency-dependent manner (Wagner et al., AACR, 2016). We also provided evidence that ONC201 exhibits a potent anti-metastatic effect (Wagner et al., AACR, 2016). We observe accumulation and activation of TRAIL-secreting NK+ cells within ONC201-treated tumors in C57/BL6, Balb/c, and athymic nude tumor-bearing mice. Importantly, ONC201 exerts in vivo anti-tumor efficacy on tumor cell lines that are ONC201-resistant in vitro, including acquired stable resistance. Using the NK-depleting antibody GM1, we demonstrate that the activation and TRAIL secretion of NK cells by ONC201 significantly contributes to in vivo anti-tumor efficacy, including TRAIL/ONC201-resistant tumors. We are currently investigating how ONC201 recruits NK cells to the tumor by examining NK-recruiting chemokine factors within the tumor site. We have also demonstrated upregulation of CD3+ T cells by ONC201 in syngeneic mice. Finally, we observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients upon ONC201 administration in the clinic. Our results demonstrate novel and potentially significant increases in cytotoxic NK cell recruitment to tumors. The results offer a unique pathway of immune stimulation for cancer therapy that may be combined with immune checkpoint or targeted cancer therapy strategies. We are currently investigating the role of NK cells and CD3+ cells in ONC201’s ability to inhibit metastasis by using a metastatic model that involves surgically removing the primary tumor and allowing metastases to grow in vivo before treatment. These findings indicate that ONC201 possess immunomodulatory activity and provide a rationale for combining ONC201 with PD-1/PDL-1 inhibitors, a combination we are currently testing in syngeneic immunocompetent mouse models. Citation Format: Jessica Wagner, C. Leah Kline, Lanlan Zhou, Andrew Zloza, Charles Chesson, Jenna Newman, Howard Kaufman, Joseph Bertino, Mark Stein, Wafik El-Deiry. Imipridone ONC201 promotes intra-tumoral accumulation of CD3+/NK+ cells that contribute to its anti-tumor efficacy [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 124. doi:10.1158/1538-7445.AM2017-124
Abstract 2263: Neonatal hormone levels and risk of testicular germ cell tumors (TGCT)
Authors: Libby Morimoto, David Zava, Katherine McGlynn, Frank Stanczyk, Joseph Wiemels, Xiaomei Ma, Catherine Metayer
Journal: Cancer Research (2017)

Abstract Testicular germ cell tumors (TGCT) are the most commonly occurring cancers in adolescent and young adult males in the U.S. Steroid sex hormones play a central role in the development of the testis. As proposed by the testicular dysgenesis syndrome hypothesis, the origins of TGCT are likely to be in utero or early in life, and to be a manifestation of disturbed prenatal testis development. However, no studies have provided direct, empirical evidence to date. Using an innovative linkage between the California birth records and cancer registry data, we conducted a population-based case-control study of neonatal hormones levels and risk of TGCT diagnosed at 0-19 year of age. We obtained archived neonatal dried blood spot (DBS) specimens from 370 TGCT cases (276 adolescent and young adults [AYA] aged 15-19 yrs at diagnosis; 94 0-4 yrs at diagnosis), and 344 age- and race/ethnicity-matched controls, born between 1982 and 2009. Liquid chromatography with tandem mass spectrometry was used to measure a panel of 17 sex steroids, glucocorticoids, and mineralcorticoids; 12 were present at detectable levels in the newborn DBS samples, including estrone (E1), estradiol (E2), estriol (E3), testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for matching factors and age (in hours) of child at blood spot collection. A4, a precursor for T and E1, was positively associated with TGCT (OR: 1.71, 95% CI: 1.09-2.69). Analyses stratified by age group showed that this association was limited to AYA, and was of stronger magnitude in this group (OR: 2.33, 95% CI: 1.37-3.97). A similar, though weaker, trend was observed for T (ORoverall: 1.37, 95% CI: 0.86-2.19; ORAYA: 1.73. 95% CI: 1.00-3.00). There was no significant association of the other measured hormones with risk. In the first case-control study of TGCT with direct measures of neonatal hormone levels, we found that higher levels of T and A4 were associated with increased risk of TCGT, particularly among males diagnosed at 15-19 years of age. These results oppose the dominant theory in TGCT etiology, that TGCT is related to androgen insufficiency in utero, and provides an important link in the etiologic pathway of this increasingly common cancer. Citation Format: Libby Morimoto, David Zava, Katherine McGlynn, Frank Stanczyk, Joseph Wiemels, Xiaomei Ma, Catherine Metayer. Neonatal hormone levels and risk of testicular germ cell tumors (TGCT) [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 2263. doi:10.1158/1538-7445.AM2017-2263
Abstract 5866: t-Darpp chemoresistence protein: insights into its structure, oligomerization status, calcium-binding properties and phosphorylation sites
Authors: Patrycja Magdziarz, You Feng, Dianlu Jiang, Elizabeth Parga, Arianna Celis, Erin Denny, Xiaoying Wang, Martin Phillips, Feimeng Zhou, Susan E. Kane, Jamil Momand
Journal: Cancer Research (2017)

Abstract t-Darpp, one of two protein isoforms encoded by the PPP1R1B gene, is overexpressed in gastric, esophageal, colon, prostate, and breast cancers; and confers resistance to trastuzumab in Her2+ breast cancer cells. To gain insight into the trastuzumab-resistance mechanism of t-Darpp, we studied its structure, oligomerization status, metal-binding properties, and sites of phosphorylation. Circular dichroism spectroscopy analysis showed that recombinant t-Darpp exhibits 12% alpha helix, 29% beta strand, 24% beta turn and 35% random coil character at 25°C. Upon mild heat treatment (50°C for five min) the secondary structure does not appreciably change. Metal ion-binding analyses through inductively coupled plasma-mass spectrometry and graphite furnace-atomic absorption indicated that t-Darpp co-purifies with calcium, but not other metals commonly found in biological systems. The T75 site, critical for t-Darpp activation of the Akt signaling pathway, is a substrate for phosphorylation by cyclin-dependent kinase 1 (CDK1) and cyclin-dependent kinase 5 (CDK5). Gel filtration chromatography, sedimentation equilibrium analysis, native blue gel electrophoresis, and glutaraldehyde-mediated crosslinking experiments showed that the majority of t-Darpp (calculated mass = 19 kDa) exists as a monomer, but forms low levels (&amp;lt; 3%) of hetero-oligomers with its longer isoform Darpp-32. t-Darpp has a relatively large Stokes radius of 4.4 nm, suggesting an elongated structure. In summary, this study indicates that t-Darpp is an elongated, mild-heat-stable, and monomeric calcium-binding protein that is capable of being phosphorylated at T75 by CDK1 and CDK5. Blockage of t-Darpp calcium binding capacity or T75 phosphorylation may therefore help sustain Her2+ breast cancer sensitivity to trastuzumab therapy. Citation Format: Patrycja Magdziarz, You Feng, Dianlu Jiang, Elizabeth Parga, Arianna Celis, Erin Denny, Xiaoying Wang, Martin Phillips, Feimeng Zhou, Susan E. Kane, Jamil Momand. t-Darpp chemoresistence protein: insights into its structure, oligomerization status, calcium-binding properties and phosphorylation sites [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 5866. doi:10.1158/1538-7445.AM2017-5866
Abstract 4659: Detection of autoantibodies against tumor-associated antigens (TAAs) improving immunodiagnosis in human osteosarcoma by serological proteome analysis
Authors: Jitian Li, Manyu Huang, Manli Luo, Liping Dai, Wen Xie, Xiaofei Qin, Zongchang Han, Wuyin Li, Jianying Zhang
Journal: Cancer Research (2017)

Abstract Osteosarcoma (OS) is the most common malignant primary solid bone-tumor. Despite its relatively low incidence rate among overall cancers, it remains one of the most harmful primary malignant tumors in childhood and adolescence. Thus, a critical need in the diagnosis and management of OS is to determine an optimal combination of clinical biomarkers that could detect tumors early with high specificity/sensitivity and with limited invasiveness. The objective of this study is to identify and characterize the targeted tumor-associated antigens (TAAs) as biomarkers in OS by serological proteome analysis (SERPA) approach, and further to analyze the frequency and specificity of anti-TAA antibodies in OS patients. In this initial study, autoantibodies to 29 TAAs were detected by ELISA and Western blotting in 90 sera from patients with OS, Osteochondroma (OC), and age matched normal individuals. Only 8 protein antigens including DSF70, HMGB1, HCC1, RalA, c-myc, AnnexinA1, IMP1, PBP, can induce significantly higher antibody responses in OS patients compared to normal individuals, achieving the highest sensitivity and specificity, 66% and 95%, respectively. The cumulative positive rate of autoantibodies against these eight selected TAAs in OS reached 70.7% with an observed AUC of 0.972 (95% CI: 0.867-0.988), significantly higher than that in normal control sera. Positive results were also confirmed by Western blotting. These preliminary data extensively evidence that not all proteins identified in cancer can be used as TAA biomarkers in OS, and only some of these proteins can induce immune responses, which could be potential TAAs in OS immunodiagnosis or prognosis, and further studies of novel targeted proteins in OS are currently in progress by SERPA approach. In addition, it supports the hypothesis that a customized TAA array can be used for enhancing anti-TAA antibodies detection, and it may constitute a promising and powerful tool for immunodiagnosis of OS. Citation Format: Jitian Li, Manyu Huang, Manli Luo, Liping Dai, Wen Xie, Xiaofei Qin, Zongchang Han, Wuyin Li, Jianying Zhang. Detection of autoantibodies against tumor-associated antigens (TAAs) improving immunodiagnosis in human osteosarcoma by serological proteome analysis [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 4659. doi:10.1158/1538-7445.AM2017-4659
Abstract 5024: Unmasking heterogeneity within the adult mammary stem cell compartment
Authors: Nai Yang Fu, Anne Rios, Bhupinder Pal, Charity Law, Paul Jamieson, Francois Vaillant, Gordon K. Smyth, Matthew E. Ritchie, Geoffrey J. Lindeman, Jane E. Visvader
Journal: Cancer Research (2017)

Abstract Breast cancer is a highly heterogeneous disease at both the molecular and pathological levels. To understand this heterogeneity and ‘cells of origin’ of breast cancer, it is important to dissect the normal mammary epithelial hierarchy. Despite accumulating evidence for a mammary differentiation hierarchy, the basal compartment comprising stem cells remains poorly characterized. Through gene expression profiling of Lgr5+ versus Lgr5– basal epithelial cells, we identify a novel marker that led to the fractionation of three distinct mammary stem cell (MaSC) subsets in the adult gland. These exist in a largely quiescent state but differ in their repopulating ability, spatial localisation, and their molecular signatures. Interestingly, the dormant MaSC subset localises to the proximal region of the gland throughout life. These cells appear to originate from the embryonic mammary primordia before switching to a quiescent state post-natally but can be recruited into the cell cycle in response to hormones. Single cell gene expression analyses have also revealed unexpected complexity within the basal and luminal compartments. Moreover, analyses at different stages of development have provided insights into the earliest ‘lineage priming’ events. Citation Format: Nai Yang Fu, Anne Rios, Bhupinder Pal, Charity Law, Paul Jamieson, Francois Vaillant, Gordon K. Smyth, Matthew E. Ritchie, Geoffrey J. Lindeman, Jane E. Visvader. Unmasking heterogeneity within the adult mammary stem cell compartment [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 5024. doi:10.1158/1538-7445.AM2017-5024
Abstract 3458: Role of zyxin in mitosis and colon cancer
Authors: JIULI ZHOU, Jixin Dong, YUANHONG CHEN, XINGCHENG CHEN, Seth Stauffer, Yongji Zeng
Journal: Cancer Research (2017)

Abstract Zyxin is a LIM domain protein that is concentrated at sites of cell-cell adhesion, where it is proposed to dock proteins involved in cytoskeletal dynamics and signaling. Recently, Zyxin has been shown to promote LATS degradation and YAP activation in Hippo Pathway. Here, We have identified a novel mechanism for phospho-regulation of Zyxin in mitosis and its biological significance in colon cancer. We found that the mitotic kinase cyclin-dependent kinase 1 (CDK1) phosphorylates Zyxin in vitro and in vivo at serine 281, serine 308 and serine 344 during antimitotic drug-induced G2/M phase arrest and unperturbed mitosis. Moreover, Zyxin mitotic phosphorylation-deficient mutant (Zyxin3A, harboring S281A/S308A/S344A) was sufficient to suppress colon cancer cell proliferation and migration. We further demonstrated that depletion of Zyxin resulted in impaired colon cancer tumorigenesis in vitro and in vivo through inhibiting F-actin cytoskeleton and YAP activity. Importantly, these observations could be fully rescued by re-expression of wild type Zyxin, but not Zyxin-3A mutant. Expression profile analysis revealed CDK8 (cyclin-dependent kinase 8) as a mediator downstream Zyxin/YAP. Inhibition of CDK8 phenocopied knockdown of Zyxin in colon cancer cells. Ectopic expression of CDK8 substantially restored the tumorigenic ability of Zyxin depletion cells in vitro and in vivo. Expression levels of Zyxin and CDK8 are both elevated in colon tumors and are negatively correlated with survival. Together, our findings reveal a novel layer of regulation for Zyxin in mitosis and define the Zyxin-YAP-CDK8 axis as a novel oncogenic regulator in colon cancer. Citation Format: JIULI ZHOU, Jixin Dong, YUANHONG CHEN, XINGCHENG CHEN, Seth Stauffer, Yongji Zeng. Role of zyxin in mitosis and colon 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 3458. doi:10.1158/1538-7445.AM2017-3458
Abstract 339: Identification of a novel isoform of WNT/planar cell polarity VANGL2 in breast cancer
Authors: Jean-Paul Borg, Alexandra Walton, Eric Bailly, Sylvie Marchetto, Stéphane Audebert
Journal: Cancer Research (2017)

Abstract The WNT/PCP pathway is an evolutionarily conserved developmental process which is essential in embryogenesis and development of polarized structures in metazoans. Its importance in human diseases is best demonstrated in neural tube closure defects and cancer. WNT/PCP signaling involves a set of evolutionarily conserved WNT/PCP genes encoding WNT ligands, transmembrane (vangl2, frizzled, fat, dachsous) and cytoplasmic (scribble, prickle, dishevelled, diego) molecules triggering a genetically well-defined non-canonical WNT-JNK pathway. Recent work has linked defects of this pathway to breast cancer aggressiveness. We have shown that the non-canonical WNT/PCP transmembrane receptor VANGL2 is overexpressed in poor prognosis basal breast cancers and implicated in tumor growth. We also found that VANGL2 binds through its C-terminal sequence to Scribble and p62/SQSTM1 which are involved in cancer cell migration and growth. A recent in silico study has suggested the existence of an N-terminally extended VANGL2 isoform (VANGL2-Long), owing to the occurrence of an alternative non-AUG translation initiation site, upstream of the conventional start site. Translation initiation from this alternative site is expected to add an N-terminal extension of 48 amino acids. Accordingly, by analyzing VANGL2 immunoprecipitates by mass spectrometry, we identified a peptide mapping upstream of the first methionine supporting the existence of a longer isoform of VANGL2. While missing in Drosophila, this N-terminal extension is found in all vertebrate VANGL2 sequences that have been examined, suggesting a function for VANGL2-Long. We provide further experimental evidence in favor of the VANGL2-Long isoform, using polyclonal antibodies that have been raised against the predicted VANGL2 N-terminal extension. Using these tools, we characterized VANGL2-Long and showed that it dimerizes with VANGL2 and VANGL1, a close homologue, at the endogenous level in living cells. Our data depict a complex organization of VANGL1/VANGL2 molecules at the plasma membrane and improve the mechanistic understanding of VANGL2 in normal and cancer cells. Citation Format: Jean-Paul Borg, Alexandra Walton, Eric Bailly, Sylvie Marchetto, Stéphane Audebert. Identification of a novel isoform of WNT/planar cell polarity VANGL2 in 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 339. doi:10.1158/1538-7445.AM2017-339
Abstract 5401: Assessment of whole genome amplification for whole exome sequencing in detecting genetic mutation
Authors: Crystal Xue, Laura Gardner, Guanglong Jiang, Fei Shen, Bryan Schneider
Journal: Cancer Research (2017)

Abstract Whole exome sequencing (WES) has been widely used for studying genetic mutations in DNA coding regions to elucidate cancer etiology and for identifying biomarkers to optimize chemotherapy. However, these studies can be limited when only small amount of DNA is available. Whole genome amplification (WGA) technology can be combined with WES to make these studies technically possible. Here, we evaluated WGA using a phi 29 polymerase prior to library preparation for WES in samples with various DNA concentrations. WES was performed by targeted exon amplification followed by massively parallel sequencing. We compared the base calls of single nucleotide variants for individual same samples with or without WGA prior to library construction to determine the concordance rate of variant calls. We also assessed genetic variant call rate in the same samples with or without WGA. The number of variants obtained ranged from 159,851,999 to 390,784 in the non-amplified samples and from 353,215 to 384,118 in the same amplified samples. The average concordance rate of identical variants in the samples with or without WGA was 96.5%. Our results indicate that WGA in prior to WES can increase detection efficiency of single nucleotide variants in samples with relatively small amount of DNA and/or low DNA concentration. Citation Format: Crystal Xue, Laura Gardner, Guanglong Jiang, Fei Shen, Bryan Schneider. Assessment of whole genome amplification for whole exome sequencing in detecting genetic 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 5401. doi:10.1158/1538-7445.AM2017-5401
Spider Toxin Peptide Lycosin-I Functionalized Gold Nanoparticles for <i>in vivo</i> Tumor Targeting and Therapy
Authors: Huaxin Tan, Yazhou Huang, Jianghong Xu, Bo Chen, Peng Zhang, Zhongju Ye, Songping Liang, Lehui Xiao, Zhonghua Liu
Journal: Theranostics (2017)

Cell penetrating peptides (CPPs) are commonly utilized for intracellular delivery of functional materials to circumvent biomembrane barrier.However, further application of CPPs is hindered by lacking selectivity toward targeted cells.The spider venom peptide, lycosin-I, is a CPP with potent cytotoxicity to cancer cells, which might enable lycosin-I to deliver functional materials into cancer cells selectively.In this study, we demonstrated that the lycosin-I-conjugated spherical gold nanoparticles (LGNPs) not only exhibited efficient cellular internalization efficiency toward cancer cells but also displayed unprecedented selectivity over noncancerous cells.Although LGNPs were removed from the living circulatory system via reticuloendothelial system-dominant clearance modes without noticeable adverse effects to animals, they actually displayed active tumor-targeting effects and efficient accumulation in tumors in vivo.Furthermore, the potential application of this platform for cancer therapy was explored by lycosin-I-conjugated gold nanorods (LGNRs).LGNRs exhibited selective intracellular translocation towards cancer cells and efficient photothermal effect under near infrared (NIR, 808 nm) irradiation, which consequently killed cancer cells in vitro and in vivo effectively.Therefore, the established LGNPs and LGNRs possessed great potential in cancer-targeting delivery and photothermal therapy.