tbuckley/cabot-search huggingface dataset:
Abstract 2501: Assessing metabolic activity of patient-derived models of non-small cell lung cancer using stable isotope resolved metabolomics (SIRM)
Authors: Connor J. Kinslow, Jinlian Tan, Yihua Cai, Jun Yan, Richard M. Higashi, Andrew N. Lane, Teresa W. Fan
Journal: Cancer Research (2017)

Abstract Stable Isotope-Resolved Metabolomics (SIRM) has been a useful tool in interrogating metabolic reprogramming in cancer. We have recently published several protocols using SIRM in patient-derived models of non-small cell lung cancer (NSCLC)1. In this case study, we compared central metabolic activity in three different model systems, all derived from the same patient. Slices from the human tumor (Warburg slices 2,3), slices from an NSG mouse bearing the human tumor 4, and the patient-derived cell culture were incubated in [U-13C]-glucose or [U-13C,15N]-glutamine for 24 hours. Samples were then harvested and analyzed by gas-chromatography-mass spectrometry and NMR. All three models displayed similar levels of fractional enrichment after 24 hours, making metabolic comparison possible, despite their very different 3D architectures. Glucose metabolism in particular, showed consistent labeling patterns of metabolites in glycolysis and the Krebs cycle. Glutamine metabolism, however, was distinct in the cell culture, with a pattern that indicated upregulation of anaplerotic glutaminolysis. Activation of glutaminolysis may be an important transformative step in the establishment of a viable cell culture. We are also in the process of validating the present finding by comparing multiple patient-derived models of NSCLC and tracking the evolution of their metabolic activity. 1 Lane, A. N., Higashi, R. M. &amp; Fan, T. W.-M. Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM) Metabolomics 12, 1-15 (2016). 2 Fan, T. W.-M. et al. Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator β-glucan in a two-case ex vivo non-small cell lung cancer study. CSH Molec. Case Studies J. 2, a00083, (2016). 3 Fan, T. W.-M., Lane, A. N. &amp; Higashi, R. M. Stable Isotope Resolved Metabolomics Studies in ex vivo Tissue Slices. Bio-protocol 6, e1730 (2016). 4 Lane, A. N., Yan, J. &amp; Fan, T. W.-M. 13C Tracer Studies of Metabolism in Mouse Tumor Xenografts. Bio-protocol 5, e1650 (2015). Citation Format: Connor J. Kinslow, Jinlian Tan, Yihua Cai, Jun Yan, Richard M. Higashi, Andrew N. Lane, Teresa W. Fan. Assessing metabolic activity of patient-derived models of non-small cell lung cancer using stable isotope resolved metabolomics (SIRM) [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 2501. doi:10.1158/1538-7445.AM2017-2501
Abstract LB-322: <i>MicroRNA-130a suppresses breast cancer cell migration and invasion by targeting FOSL1 and upregulating ZO-1</i>
Authors: Xiaowei Chen, Min Zhao, Yuhuang Li, Mushui Dai
Journal: Cancer Research (2017)

Abstract FOSL1 is frequently overexpressed in multiple types of human cancers including invasive breast cancers and implicated in cancer invasion and metastasis. However, how FOSL1 is overexpressed in cancers remains to be elucidated. Several microRNAs (miRNAs) have been shown to target FOSL1 and are downregulated in human cancers. Here, we report that miR-130a is a novel FOSL1 targeting miRNA. Using gene expression microarray analysis, we found that FOSL1 is among the most up-regulated genes in cells transfected with miR-130a inhibitors. Transient transfection-immunoblot, RNA-immunoprecipitation (IP) and luciferase reporter assays revealed that miR-130a directly targets FOSL1 mRNA at its 3’-UTR. Overexpression of miR-130a significantly reduced the levels of FOSL1 in invasive breast cancer MDA-MB-231 and Hs578T cell lines and suppresses their migration and invasion. This inhibition can be rescued by ectopic expression of miR-130a-resistant FOSL1. Interestingly, we show that overexpression of miR-130a increased the levels of tight-junction protein ZO-1 while inhibition of miR-130a reduced the levels of ZO-1, via regulating the expression of FOSL1. We further show that miR-130a expression is significantly reduced in cancer tissues from triple-negative breast cancer (TNBC) patients, correlating significantly with the upregulation of FOSL1 expression, compared to non-TNBC tissues. Together, our results reveal that miR-130a directly targets FOSL1 and suppresses FOSL1-mediated inhibition of ZO-1, thus inhibiting cancer cell migration and invasion, in TNBCs. Note: This abstract was not presented at the meeting. Citation Format: Xiaowei Chen, Min Zhao, Yuhuang Li, Mushui Dai. MicroRNA-130a suppresses breast cancer cell migration and invasion by targeting FOSL1 and upregulating ZO-1 [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 LB-322. doi:10.1158/1538-7445.AM2017-LB-322
Abstract 2080: Polycomb-mediated disruption of an AR-feedback loop drives castration-resistant prostate cancer
Authors: Ka-Wing Fong, Jonathan Zhao, Jung Kim, Shangze Li, Angela Yang, Bing Song, Laure Rittié, Ming Hu, Ximing Yang, Bernard Perbal, Jindan Yu
Journal: Cancer Research (2017)

Abstract Androgen receptor (AR) is an androgen-stimulated transcription factor that critically promotes prostate cancer development and progression. In addition to its conventional role in transcriptional activation, AR also acts as a transcriptional repressor to directly inhibit target gene expression. Through meta-analysis of androgen-regulated expression microarray data, we nominated CCN3/NOV, a CCN family protein, as one of the top AR-repressed genes in prostate cancer, implicating that CCN3 may play a tumor suppressive role in prostate cancer development. Therefore, we sought to investigate the molecular functions of CCN3 and its roles in prostate cancer progression especially in castration-resistant prostate cancer (CRPC). We first showed that CCN3 protein physically interacts with AR. The CCN3 interaction domain was mapped in the N-terminal domain of AR which is also present in constitutively active AR variants. Using immunofluorescence microscopy as well as subcellular fractionation technique, we demonstrated that CCN3 sequesters AR or AR variants into the cytoplasm to inhibit AR nuclear translocation, which in turn suppresses AR chromatin targeting and transcriptional activation. However, this negative feedback loop between AR and AR-repressed gene CCN3is disrupted in CRPC through CCN3 persistent epigenetic silencing by the Polycomb group protein EZH2, rendering AR transcriptional activation and CRPC progression. Taking advantage of this repressive mechanism, we restored CCN3 in CRPC cell model, either through ectopic overexpression or treatment with EZH2 inhibitor, which results in strong suppression of CRPC cell proliferation and anchorage-independent cell growth. Consistently, application of EZH2 inhibitor remarkably reduced tumor size in a castrated mice model. Taken together, our data highlight CCN3 as a novel regulator of AR signaling and support the promise of EZH2-targeting agents in treating CRPC. Citation Format: Ka-Wing Fong, Jonathan Zhao, Jung Kim, Shangze Li, Angela Yang, Bing Song, Laure Rittié, Ming Hu, Ximing Yang, Bernard Perbal, Jindan Yu. Polycomb-mediated disruption of an AR-feedback loop drives castration-resistant 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 2080. doi:10.1158/1538-7445.AM2017-2080
Abstract 2683: The gastrointestinal microbiome and its composition are critical for antitumor efficacy of immune checkpoint inhibition by anti-PD-L1
Authors: Benjamin G. Cuiffo, Caitlin S. Parello, Chelsea Ritchie, Katie Pedrick, Alexandra Kury, Catarina Costa, Brett Van Dam, Jonathan Jung, Gregory D. Lyng, Stephen T. Sonis
Journal: Cancer Research (2017)

Abstract The intestinal microbiome has become increasingly appreciated as a significant mediator of systemic antitumor immunity/response in both naïve and treatment contexts. In naïve contexts, an intact intestinal microbiome has been demonstrated to enhance tumorigenesis, and its composition to mediate primary tumor growth kinetics. In the context of cancer treatment, antibiotic depletion of the intestinal microbiota has been reported to inhibit the efficacy of cyclophosphamide and that of the immune checkpoint inhibitor αCTLA4. Compositional modulation of the intestinal microbiota has been found to be sufficient to enhance the antitumor efficacy of αPD-L1. Here, we assessed the relative importance of the intestinal microbiota in mediating αPD-L1 antitumor efficacy in a B16.F10.SIY murine model of melanoma, by performing parallel efficacy studies in C57BL/6 germ-free (Taconic) or specific pathogen free (Taconic or Jackson) mice. We observed that αPD-L1 treatment provided significant antitumor efficacy of in Taconic mice carrying an intact microbiome; however, this efficacy was abolished in germ-free Taconic mice. Furthermore, we observed that tumors of Jackson mice carrying an intact but compositionally different microbiome did not respond to αPD-L1 treatment. Phenotyping of local tumor and systemic immune responses, as well as characterization of the intestinal microbiome in responder vs nonresponder animals provided mechanistic insights. Taken together, these observations suggest that rational modulation of the microbiome may enhance response to immune checkpoint inhibition, and indicate that the gastrointestinal microbiome and its composition are critical for the antitumor efficacy of αPD-L1. Citation Format: Benjamin G. Cuiffo, Caitlin S. Parello, Chelsea Ritchie, Katie Pedrick, Alexandra Kury, Catarina Costa, Brett Van Dam, Jonathan Jung, Gregory D. Lyng, Stephen T. Sonis. The gastrointestinal microbiome and its composition are critical for antitumor efficacy of immune checkpoint inhibition by anti-PD-L1 [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 2683. doi:10.1158/1538-7445.AM2017-2683
Abstract 5479: Redox stress as a therapeutic Achilles heel in castration-resistant prostate cancer
Authors: Clara I. Troccoli, Govindi J. Samaranayake, Mai Q. Huynh, Karen Kage, Deukwoo Kwon, Yuguang Ban, Xi S. Chen, Enrique R. Zarco, Merce Jorda, Kerry L. Burnstein, Priyamvada Rai
Journal: Cancer Research (2017)

Abstract Androgen deprivation therapy (ADT) initially suppresses prostate cancer (PC) progression. However, castration resistant PC (CRPC) cells inevitably emerge, resulting in incurable disease. We recently demonstrated that AD produces a form of cellular senescence leading to outgrowth of CRPC subpopulations from the AD-sensitive parental cells. Gene expression profiling studies comparing the parental LNCaP line to the senescence-resistant, early CRPC variant, LNCaP SB5, revealed an enrichment of thiol-based redox-protective proteins in the latter under AD conditions. This finding suggests that redox stress due to hyperactivated mitogenic/survival signaling or metabolic stresses may be an important and understudied Achilles heel in the progression to CRPC. Here we present the effects of inhibiting thioredoxin-1 (TRX1), a redox-protective protein that was identified as being elevated in our early CRPC LNCaP SB5 model. Suppression of TRX1 expression via shRNA led to profound growth suppression of CRPC cells, relative to their AD-sensitive counterparts, and significantly reduced CRPC xenograft tumor growth. Furthermore, under AD, TRX1 suppression promoted p53-induced cell death, which was accompanied by increased reactive oxygen species (ROS). These in vitro and in vivo results were recapitulated using a Phase II clinical trial-tested chemical TRX1 inhibitor. Thus our results point to TRX1 as a critical requirement for CRPC progression and provide a rationale for using TRX1 inhibitors in conjunction with ADT to limit CRPC. Citation Format: Clara I. Troccoli, Govindi J. Samaranayake, Mai Q. Huynh, Karen Kage, Deukwoo Kwon, Yuguang Ban, Xi S. Chen, Enrique R. Zarco, Merce Jorda, Kerry L. Burnstein, Priyamvada Rai. Redox stress as a therapeutic Achilles heel in castration-resistant 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 5479. doi:10.1158/1538-7445.AM2017-5479
Abstract 4643: Plasma thioredoxin reductase 1 as a diagnostic marker for non-small cell lung cancer
Authors: Xiaozheng Kang, Chaoran Dong, Bocun Shen, Wanpu Yan, Liang Dai, Yongbo Yang, Hanwei Yin, Guobing Xu, Huihui Zeng, Ke-Neng Chen
Journal: Cancer Research (2017)

Abstract Non-invasive diagnostic markers for patients with suspicious non-small cell lung cancer (NSCLC) may provide needed guidance on invasive diagnostic and therapeutic decisions. Thioredoxin reductase 1 (TrxR1) is a pivotal intracellular redox sensor and antioxidant enzyme, and plays an important part in tumor growth, progression, metastasis, and chemotherapy resistance. The goal of this study is to test the feasibility of developing plasma TrxR1 as a novel diagnostic marker for NSCLC. The plasma TrxR1 activity was determined spectrophotometrically by monitoring the NADPH-dependent production of 2-nitro-5-thiobenzoate at 412nm and at 37°C. All detection kits and automatic analyzer possess independent intellectual property rights, and have been widely used in breast cancer screening. In this study, the plasma levels of TrxR1 were measured in 45 treatment-naïve NSCLC patients and 10 individuals with benign tumor-like pulmonary diseases. Taking plasma TrxR1 activity of 4 as reference, the overall concordance rate was 73.3%, while those of CEA, CA199, CA125, NSE, CYFRA21-1 and SCC were 19.0%, 7.1%, 16.7%, 35.7%, 24.4% and 2.5%, respectively. Furthermore, using TNM staging (AJCC 7th ed.) as classifier, the concordance rates of TrxR1 in local, local regional and advanced stage subgroups were 66.7% (20/30), 77.8% (7/9) and 100% (4/4), respectively. A multipoint linear fitting correlation model was created, and the equation was TrxR1 = 5.821 + 0.396*Stage. Besides, the concordance rates of TrxR1 in benign tumor-like pulmonary diseases was 60% (6/10). Our data suggest that plasma TrxR1 activity is a useful non-invasive diagnostic marker for NSCLC, and there may be a linear correlation between TrxR1 activity and pathological stage. Citation Format: Xiaozheng Kang, Chaoran Dong, Bocun Shen, Wanpu Yan, Liang Dai, Yongbo Yang, Hanwei Yin, Guobing Xu, Huihui Zeng, Ke-Neng Chen. Plasma thioredoxin reductase 1 as a diagnostic marker for non-small cell lung 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 4643. doi:10.1158/1538-7445.AM2017-4643
Abstract 5614: Novel mRNA purification method with RNaseIII improves efficacy of RNA chimeric antigen receptor T cells
Authors: Jessica Foster, Namrata Choudhari, Adam Resnick, David Barrett
Journal: Cancer Research (2017)

Abstract Chimeric Antigen Receptor (CAR) T-cells made with mRNA offer a transient and safe alternative to viral CARs, mitigating the concern for persistent unwanted side effects from constitutively active T-cells. Previous studies have shown that mRNA CARs are transiently effective, but lack CAR persistence and have struggled to show success across tumor types. We hypothesized the efficacy of mRNA CARs could be improved by utilizing recent advancements in RNA technology including the use of modified uracil and a novel purification method with RNaseIII to prevent double stranding that induces toxicity. Using the established CD19 CAR model in B-cell acute lymphoblastic leukemia, we created mRNA CARs using previously described methods and compared them to mRNA CARs created using modification of uracil and/or purification to remove any aberrant double stranded mRNA. Comparing the modified and purified mRNA CAR T cells to those created using prior methods of making mRNA, both modified and purified mRNA CAR T cells showed a two-fold increase in expression of the CAR on their surface initially, as well as a two-fold improvement in cytotoxic killing of leukemia cells in vitro that persisted for up to five days. Both the modified and purified mRNA CAR T cells also showed reduced expression of negative checkpoint regulators compared to original RNA CAR T cells. However, in vivo studies using a patient-derived xenograft model with a single dose of CAR T cells revealed purified RNA CAR T cells offered the most robust 2-log enhanced suppression of leukemic burden. RNaseIII is a novel purification technique that has not yet been reported in the literature for RNA manufacturing. Our results provide a time efficient purification method that can be easily incorporated into RNA production for use in clinical trials, and poise RNA CARs for increased efficacy as new CAR targets emerge and are being tested. Additional studies are ongoing investigating if the observed improved efficacy will translate to improved cytotoxicity in solid tumor models. Citation Format: Jessica Foster, Namrata Choudhari, Adam Resnick, David Barrett. Novel mRNA purification method with RNaseIII improves efficacy of RNA chimeric antigen receptor T 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 5614. doi:10.1158/1538-7445.AM2017-5614
Abstract 3482: SNORD-X in glioblastoma: regulation and functional analysis
Authors: Shikha Gupta, Prerana Jha, Chitra Sarkar, Ritu Kulshreshtha
Journal: Cancer Research (2017)

Abstract Glioblastoma Multiforme (GBM) is a kind of brain tumor which arises from astrocytes present in the brain. It represents approximately 15% of all primary brain tumor and has been considered as one of the deadliest type of cancer with very poor prognosis. Thus, there is an urgent need to identify novel targets for GBM therapy. Recently, non-coding RNAs (ncRNAs) such as miRNAs and lncRNAs have emerged as one of the promising tools as diagnostic or prognostic biomarkers and as novel targets for therapy. There are recent evidences that small nucleolar RNAs (snoRNAs), a subtype of ncRNAs might also play a key role in various cancers. In this context, we aimed at studying the role of snoRNAs in GBM. For this, we did snoRNA profiling in GBM patients and found that a particular cluster of snoRNA called SNORD-X was highly downregulated in adult as well as pediatric GBM patients. We also found SNORD-X promoter to be methylated and shows maternal imprinting. We next did functional analyses of SNORD-X by generation of an overexpression construct. Our preliminary data suggests that overexpression of SNORD-X in GBM cell lines (U87MG and A172) increases cell proliferation in vitro. It also enhances the colony forming capability of GBM cells. Further, its overexpression causes decrease in apoptosis in a caspase-dependent manner. A target analysis of SNORD-X was done using RNAhybrid software. We found EGR1, DCUN1D3 and BRCA1 to be the direct targets of SNORD-X using a combination of qRT-PCR and wild-type/mutated 3’UTR luciferase analyses. Overall, our work shows for the first time correlation and functional analysis of SNORD-X cluster in GBM. Citation Format: Shikha Gupta, Prerana Jha, Chitra Sarkar, Ritu Kulshreshtha. SNORD-X in glioblastoma: regulation and functional 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 3482. doi:10.1158/1538-7445.AM2017-3482
Abstract 788: Less is more: macrophage depletion via CSF1/CSF1R pathway improves anti-VEGF therapy after adaptive resistance
Authors: Yasmin A. Lyons, Sunila Pradeep, Jean M. Hansen, Michael J. Wagner, Robert L. Dood, Sherry Y. Wu, Rebecca A. Previs, Wei Hu, Robert L. Coleman, Anil K. Sood
Journal: Cancer Research (2017)

Abstract Objectives: Anti-angiogenesis therapy shows clinical benefit in patients with high-grade serous ovarian cancer (HGSC), but adaptive resistance typically occurs. Thus, approaches to overcome such resistance are needed. Here, we systematically assessed immune cell populations enriched during adaptive resistance and identify novel therapeutic avenues. Methods: A series of in vitro and in vivo (immune competent and nude mice) experiments were carried out. Animals were treated with anti-VEGF antibody continuously until resistance emerged, at which point full immune profiling was performed. Based on these results, efficacy of AC708 (CSF1R inhibitor to target tumor-associated macrophages) was tested in the adaptive-resistance models. F4/80 antibody was used as a macrophage marker. Results: On the basis of full immune profiling, we detected significantly increased macrophage infiltration in tumors with anti-VEGF antibody resistance compared to tumors from sensitive mice (p&amp;lt;0.0001). Given the dominant role of CSF1R in macrophage function and overexpression of CSF1R in HGSC, we added AC708 following emergence of adaptive resistance to anti-VEGF antibody. Mice treated with AC708 after anti-VEGF antibody resistance demonstrated complete response upon completion of the experiment, while those that did not receive AC708 still had abundant tumor. To mimic treatment with the AURELIA regimen, we next treated mice with anti-VEGF antibody and paclitaxel until resistance emerged, and then AC708 was added. The addition of AC708 restored response to anti-angiogenesis therapy, resulting in 82% lower tumor burden compared to treatment with anti-VEGF antibody and paclitaxel alone (p &amp;lt; 0.0001), and a substantial decrease in macrophages (p&amp;lt;0.0004). Conclusions: The addition of CSf1R inhibitor to anti-VEGF therapy and taxane chemotherapy results in robust anti-tumor effects. To confirm these findings, a clinical trial at our institution is nearing activation. The REDIRECT (RandomizEd Induction DIscontinuation TRial of EmaCTuzumab) trial will randomize patients to continue weekly paclitaxel and biweekly bevacizumab with or without a CSF1R inhibitor (emactuzumab) following an induction phase. Citation Format: Yasmin A. Lyons, Sunila Pradeep, Jean M. Hansen, Michael J. Wagner, Robert L. Dood, Sherry Y. Wu, Rebecca A. Previs, Wei Hu, Robert L. Coleman, Anil K. Sood. Less is more: macrophage depletion via CSF1/CSF1R pathway improves anti-VEGF therapy after adaptive resistance [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 788. doi:10.1158/1538-7445.AM2017-788