bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-104: Targeting solid malignancies with TEGs: αβT cells

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ngineered to express a defined γδTCR in xenograft mice model
Authors: Johanna Inez , Straetemans Trudy , Heijhuurs Sabine , Jansen Koen , Rheenen Jacco van , Drost Jarno , Sebestyen Zsolt , Kuball Jurgen 
Published: August 2018

Abstract
γδT cells mediate cancer immune surveillance by sensing metabolic changes of malignant cells via their γδT cell receptor (TCR). Activation of γδTCR is independent of MHC molecules, making them a valuable addition to current treatment strategies. Moreover, γδTCR are able to differentiate between healthy and leukemic stem cells. This concept led to the development of next generation CAR T cells, so-called TEGs: αβT cells Engineered to express a defined γδTCR. A particular γ9δ2TCR, isolated from “clone 5”, has been selected as the candidate for clinical testing (TEG001). A purification strategy was introduced that combined maximal interference of γδTCR chains with endogenous TCR chains with a GMP-grade anti-αβTCR-bead-based depletion strategy to obtain a pure population of engineered immune cells (Straetemans et al. 2015). TEG001 cells showed a strong and broad recognition of hematological malignancies against both cell lines and primary AML (Marcu-Malina et al. 2011, Gründer et al. 2012). To further broaden the clinical implementation of this novel strategy we here investigated the in vivo efficacy profile against solid malignancies.
In this study, we evaluated clinical potency of TEG001 against human organoids engineered with most frequent mutations for colorectal cancer, including APC knockout (APCKO), constitutively active KRAS (KRASG12D), P53 knockout (P53KO), and SMAD4 knockout (SMAD4KO), also known as quadruple mutant organoids. These organoids are tumorigenic and can be successfully engrafted as solid tumor mass in immunodeficient mice (Fumagalli et al., 2017; Drost et al., 2015). Irradiated NSG mice received luciferase-positive quadruple mutant organoids subcutaneously and were subsequently infused with TEGs. Tumor growth was measured by bioluminescence imaging. TEG001 showed reduced tumor growth of quadruple mutant organoids compared to untreated and mock controls. Moreover, TEG001-treated mice showed increased overall survival relative to the control mice, followed up to 130 days after treatment.
Our current data shows that TEG001 mediates antitumor reactivity against quadruple mutant organoids as solid tumor model in vivo. This xenograft model allows further preclinical testing of next generation TEGs targeted to solid malignancies. Importantly, TEGs are a promising addition to the currently available immune therapeutic strategies as they target cancer as a metabolic disorder.
Citation Format: Inez Johanna, Trudy Straetemans, Sabine Heijhuurs, Koen Jansen, Jacco van Rheenen, Jarno Drost, Zsolt Sebestyen, Jurgen Kuball. Targeting solid malignancies with TEGs: αβT cells engineered to express a defined γδTCR in xenograft mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-104.
Abstract LB-120: Systematic association analysis of immune checkpoint blockade of PD-1 by RNA-seq data in advanced melanoma patients
Authors: Wang Shu 
Published: August 2018

Abstract
Immune checkpoint blockade with anti-programmed cell death protein-1 (PD-1) monoclonal antibodies (mAbs) provides long-term clinical benefits to 30-40% patients with advanced melanoma. In spite of this success, the majority of the melanoma patients (MPs) fail to respond to therapy. To further explore the mechanisms about how immunotherapy influences immune systems and cancers, we have developed a novel clinical trial with anti-PD-1 antibody (Pembrolizumab) and Peginterferon. In this trial, 43 melanoma patients were treated and had tumor biopsies pre- and post-treatment (week 12) that were used for transcriptomic studies using RNA-seq. Here, we report the data obtained from 21 MPs with lymph node metastases, including 10 responders and 10 non-responders. We found that lymph nodes and metastatic tumors show different gene expression pattern for response: besides immune signature which is expressed in lymph nodes also, metastatic tumors presents gene signature related to cell-ECM communication, vasculogenesis, etc. In addition, we found several pathways that favor response, such as IGF1/mTOR pathway. Our work gives a deeper insight into how anti-PD1 immunotherapy functions and how resistance against it occurs, which may predict clinical outcome in MPs treated with anti-PD-1 mAbs and Peginterferon.
Citation Format: Shu Wang. Systematic association analysis of immune checkpoint blockade of PD-1 by RNA-seq data in advanced melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-120.
Abstract LB-132: MOSPD2: A novel target for Bi-specific Ab mediated killing of tumor cells
Authors: Mendel Itzhak , Salem Yaniv , Yacov Niva , Prhopheta-Meiran Osharat , Kafri Pinhas , Breitbart Eyal 
Published: August 2018

Abstract
Introduction: We have previously described motile sperm domain-containing protein 2 (MOSPD2) as essential for breast cancer metastasis in vitro and in vivo. In this study, we detected high expression of MOSPD2 in different organ tumors and cancer cells, and subsequently developed CD3xMOSPD2 BiTE, a firstly generated bi-specific antibody that directs killing of MOSPD2 expressing cancer cells.
Experimental procedure: The prevalence of MOSPD2 was evaluated by IHC in tissue microarrays layered with cores, representing multiple organ tumors and normal tissue. MOSPD2 abundance was scored according to the staining intensity on a scale from 0 to 3. Human monoclonal antibody against the extracellular region of human MOSPD2 was generated. To determine the presence of cell surface MOSPD2 expression, FACS analysis was performed on cell lines derived from different tumor origins. BiTE was generated to comprise the scFv region of anti-human CD3 and the scFv region of a human anti-human MOSPD2. Cancer cell lines were co-cultured with freshly isolated T-cells or effector CD8 T-cells in the presence of CD3xMOSPD2 or a control BiTE. Cancer cell survival rate and T cell activation was determined after 2-3 days by FACS.
Results: MOSPD2 expression was evident in the majority of organ tumors, with high prevalence in tumors such as colon, liver and breast. Normal tissue was either devoid of MOSPD2, or had low expression relative to its parallel tumor tissue. Within normal or normal adjacent tissue (NAT), staining could be detected primarily in lymphoid tissues where myeloid cells abundantly reside. FACS staining using a human anti-MOSPD2 mAb demonstrated that MOSPD2 is expressed on the surface of different cancer cell lines. Employing CD3xMOSPD2 BiTE on myeloid or solid tumor-derived cell lines induced T-cell activation and yielded profound killing of cancer cells.
Conclusions: IHC staining demonstrates MOSPD2 expression profile supportive of targeting cancer cells. CD3xMOSPD2 BiTE directs T-cells to MOSPD2 expressing cancer cells and induces their destruction in-vitro. Therefore, we propose CD3xMOSPD2 bi-specific antibodies as a potential therapy for the treatment of cancer via a unique target, directed for the destruction of hematological cancers and solid tumors expressing MOSPD2.
Citation Format: Itzhak Mendel, Yaniv Salem, Niva Yacov, Osharat Prhopheta-Meiran, Pinhas Kafri, Eyal Breitbart. MOSPD2: A novel target for Bi-specific Ab mediated killing of tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-132.
Abstract LB-140: CAR T cells that target full-length MUC1 enrich for MUC1* and induce metastasis
Authors: Bamdad Cynthia C. , Stewart Andrew K. , Deary Luke T. , Smagghe Benoit J. , Huang Pengyu , Glennie Nelson D. , Swanson Tyler E. 
Published: August 2018

Abstract
Purpose: Investigate the rationale for CAR Ts that target full-length MUC1 (MUC1-FL) rather than the cleaved, growth factor receptor form, MUC1*. Over 75% of solid tumors aberrantly express MUC1. However, attempts to create an effective therapeutic by targeting MUC1-FL have all failed. No therapeutic that targets the cleavage product, MUC1*, has ever been tested in humans. On cancer cells, most of the MUC1-FL is enzymatically cleaved, releasing the bulk of the extra cellular domain and leaving a truncated transmembrane protein - MUC1*. There are currently two CAR T therapeutics (based on antibody 5E5 or SM3) being developed that target aberrant O-linked glycans. Importantly, MUC1* has no sites for O-linked glycans and is not recognized by 5E5 or SM3.
Experimental Procedures: Human ovarian cancer cells that express both MUC1-FL and MUC1* were implanted into the intraperitoneal (i.p.) space of female NSG mice. IVIS measurement verified engraftment. A cleavage enzyme that is overexpressed in most solid tumors and known to cleave MUC1-FL to MUC1* was injected into i.p. space to simulate the effect of a therapeutic that would eliminate cells expressing MUC1-FL. Human cancerous tissue specimens were probed with antibody VU4H5 that recognizes tandem repeats of MUC1-FL, 5E5 that recognizes aberrant O-linked glycans on tandem repeats of MUC1-FL, and anti-MUC1* antibody huMNC2.
Summary New Data: Elimination of cells expressing MUC1-FL, by cleaving MUC1-FL to MUC1*, caused tumors to grow dramatically (average 221-times in only 9 days) and metastasize. IHC studies showed that 30% of breast cancers do not express MUC1-FL but only express MUC1*. No tumor specimens were positive for MUC1-FL but negative for MUC1*. Our studies show that as tumor stage progresses, expression of MUC1* increases as MUC1-FL decreases. Over 95% of breast, 83% ovarian, 78% pancreatic and 71% lung cancers reacted with our anti-MUC1* antibody huMNC2-scFv (n&gt;3,000). huMNC2-CAR44 T cells inhibited growth of MUC1* positive and MUC1-FL/MUC1* positive tumors, even after metastasis.
Conclusions: CAR T cells that target full-length MUC1 will enrich the tumor for MUC1*, increasing tumor growth and inducing metastasis.
Citation Format: Cynthia C. Bamdad, Andrew K. Stewart, Luke T. Deary, Benoit J. Smagghe, Pengyu Huang, Nelson D. Glennie, Tyler E. Swanson. CAR T cells that target full-length MUC1 enrich for MUC1* and induce metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-140.
Abstract LB-158: Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number
Authors: Hang Dong , Nan Hongmei , Kværner Ane Sørlie , Vivo Immaculata De , Chan Andrew T. , Hu Zhibin , Shen Hongbing , Giovannucci Edward , Song Mingyang 
Published: August 2018

Abstract
Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses' Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60 years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility loci. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR = 1.18, 95% CI: 1.04, 1.35; P = 0.01), and the medium-marked increase group had higher odds of having below-median mtCN (OR = 1.28, 95% CI:1.00,1.64; P = 0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend = 0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria.
Citation Format: Dong Hang, Hongmei Nan, Ane Sørlie Kværner, Immaculata De Vivo, Andrew T. Chan, Zhibin Hu, Hongbing Shen, Edward Giovannucci, Mingyang Song. Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-158.
Abstract LB-159: A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer
Authors: Shen Sipeng , Su Li , Zhang Ruyang , Loehrer Elizabeth , Lanuti Michael , Diao Nancy , Christiani David 
Published: August 2018

Abstract
Background B-cell translocation gene 2 (BTG2), which functions as a tumor suppress gene, has been reported to be involved in several cancers. However, no study has focused on its role in lung cancer progression or prognosis. We aimed to investigate the role of BTG2 in early-stage non-small cell lung cancer (NSCLC) survival.
Patients and methods This study included 1,230 early-stage (1-2) surgically treated NSCLC patients with methylation and expression data from five international cohorts. We built a prognostic model based on methylation. Then, we explored BTG2 expression and NSCLC survival in 3,038 cases, including the above-mentioned cohorts as well as 17 extended public datasets by meta-analysis. Further, we integrated the clinical information, expression, and methylation to build an integration model and evaluated its prediction ability for 5-year survival.
Results Three risk CpG probes (cg01798157, cg06373167, cg23371584) were associated with overall survival. The prognostic model could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51 to 2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 acted as a tumor-suppress gene in each cohort (HR range, 0.28 to 0.68). A meta-analysis showed high BTG2 expression was associated with better survival (HR = 0.61, 95%CI: 0.54-0.68). The three CpG probes were all negatively correlated with BTG2 expression. Additionally, the integration model showed a better prediction ability in the training set [area under the curve (AUC) = 0.78] and the validation set (AUC = 0.77). The integrated signature showed a better predictive ability among cases with adjuvant therapy (AUC = 0.85). In addition, 17 miRNAs including miR-21 and miR-23a were associated with BTG2 expression and survival.
Conclusions: methylation and integrated prognostic signatures of BTG2 are stable and reliable biomarkers for early-stage NSCLC. These markers may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.
Citation Format: Sipeng Shen, Li Su, Ruyang Zhang, Elizabeth Loehrer, Michael Lanuti, Nancy Diao, David Christiani. A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-159.
Abstract LB-168: Inhibitory activities of Sesamum indicum L. leaf extract against the growth, invasion, migration, and adhesion of human colon cancer cells
Authors: Kim Seoyun , Ju Jihyeung 
Published: August 2018

Abstract
Colorectal cancer is one of the most common cancers in both incidence and mortality among men and women worldwide. Sesame (Sesamum indicum L.) leaves (SL) are used as vegetables and traditional medicines in Asian and African countries. In the current study, we aimed to investigate the effects of ethanol extract of sesame leaves (SLE) against key characteristics of cancer cells, including unrestricted growth, resisted apoptosis, and activated metastasis, and to evaluate whether thermal treatment of SL alter the inhibitory effects. Two human colon cancer cell lines were used in this study, HT29 colon adenocarcinoma cells and HCT116 colorectal carcinoma cells. In 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, treatment with SLE at the concentrations of 50-500 µg/mL for 24-72h resulted in dose-dependent and time-dependent growth inhibition in HT29 and HCT116 cells. In cell cycle analyses, SLE caused significantly increased cell population at sub-G1 (in HT29 and HCT116) and G2/M (in HCT116) phases, suggesting that the observed growth inhibition is associated with induction of apoptosis and cell cycle arrest. SLE at non-cytotoxic concentrations was effective in inhibiting critical events during metastasis in HT29 and HCT116, such as invasion (determined by matrigel-coated transwell assay), migration (determined by wound-healing assay), and adhesion (determined using fibronectin-coated plates). Thermal treatment of SL (at 150°C for 15 min) resulted in significantly enhanced inhibitory activities of SLE against the invasion, migration and adhesion in HCT116 cells, but did not change the growth-inhibitory and apoptosis-inducing activities. These results suggest that SLE possesses in vitro anti-cancer activities against colon cancers and that thermal treatment of SL enhances the anti-metastatic activities of SLE. Further studies are needed to verify whether similar effects are reproduced in vivo and to identify active ingredients of SLE responsible for the inhibitory activities.
Citation Format: Seoyun Kim, Jihyeung Ju. Inhibitory activities of Sesamum indicum L. leaf extract against the growth, invasion, migration, and adhesion of human colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-168.
Abstract LB-170: 9cis-retinoid UAB30 manifests potent chemopreventive effects in a murine model of UVB-induced basal cell and squamous cell carcinoma
Authors: Chaudhary Sandeep C. , Kashyap Mahendra P. , Nguyen Gloria , Elmets Craig A. , Athar Mohammad 
Published: August 2018

Abstract
Vitamin A derivatives such as retinoids are known to inhibit cell proliferation and induce cellular differentiation/apoptosis in various tumor cells. Although many retinoids have been limited due to their severe adverse effects, but 9cUAB30, a highly selective novel retinoid X receptors (RXR)-agonist has been shown an effective anti-carcinogenic activity. Here, we demonstrated the chemopreventive and chemotherapeutic efficacy of 9cUAB30 in UVB-induced photocarcinogenesis in Ptch+/-/SKH-1 murine model, which develops both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Both topical and systemic application to 9cUAB30 significantly reduced UVB-induced skin photocarcinogenesis in terms of tumor number and tumor volume. 9cUAB30 reduced UVB-induced skin hyperplasia, proliferation, and enhanced differentiation of suprabasal epidermal keratinocytes. Induction of apoptosis was also noted in these neoplastic lesions treated with this retinoid. 9cUAB30 was almost equally potent in the inhibition of either UVB-induced skin BCCs or SCCs in Ptch+/-/SKH-1 mice. 9cUAB30-treated residual tumors were manifesting reduced epithelial-mesenchymal transition (EMT) progression with a less aggressive tumor phenotype, which was associated with the enhanced expression of E-cadherin and reduced expression of N-cadherin, Fibronectin, Snail and Twist. 9cUAB30-mediated therapeutic intervention against these tumors was also involved induction of extensive DNA double strand breaks (DSBs) characterized by the enhanced phosphorylation of H2AX. This DNA damage response was unique to 9cUAB30 compare to other known RXR inhibitors such as Bexarotene. It was also independent of reactive oxygen species (ROS) production as ROS scavenger namely, N-acetyl cysteine did not effectively block it. However, 9cUAB30 provoked DNA damage response signaling was associated with the enhanced phosphorylation and activation of ATM, Rad50, ATR, Chk1, and Chk2. In summary, these data demonstrate that 9cUAB30 is a novel cancer chemopreventive agent for UVB-induced skin neoplasm and acts by invoking extensive DDSBs similar to those caused by chemotherapeutic drug like cisplatin.
Citation Format: Sandeep C. Chaudhary, Mahendra P. Kashyap, Gloria Nguyen, Craig A. Elmets, Mohammad Athar. 9cis-retinoid UAB30 manifests potent chemopreventive effects in a murine model of UVB-induced basal cell and squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-170.
Abstract LB-184: Core circadian clock component, PERIOD2, regulates adaptive radioprotection via PER2-β-Catenin controlled mitochondrial bioenergetics
Authors: Alexandrou Aris , Fan Ming , Juma Shuaib , Perks Julian , Vaughan Andrew , Tepper Clifford , Fu Loning , Woloschak Gayle , Grdina David 
Published: August 2018

Abstract
Circadian clocks are intimately involved in the homeostatic maintenance of metabolic and physiological processes that may have increasingly important roles to enhance bone marrow transplantation success in cancer patients; to protect normal tissue surrounding tumors from the harmful effects of radio/chemotherapy; and to enhance the quality of diet and sleep for astronauts during space exploration. Herein, we report that expression of PERIOD2 (PER2; a core circadian clock component and “the inherent driver” of radioprotection) is required for adaptive protection against environmental radiation stress. PER2 expression is induced by exposure to low dose radiation (LDR; 10cGy) and siRNA blockade of PER2 ablates LDR-induced adaptive radioprotection. In addition, melatonin (N-acetyl-5-methoxytryptamine), a natural anti-oxidant and hypothalamic circadian synchronizer, stimulates PER2 expression and confers mice radioprotection through weight maintenance and increased survival. LDR-induced PER2 transcription is regulated by NF-κB and β-catenin and is released from phospho-glycogen synthase kinase-3ß (p-GSK3ß) in the WNT/β-catenin pathway. Unbound β-catenin interacts with the TCF/LEF domain on the Per2 promoter to promote feed-forward PER2-pGSK3β complex formation. Mitochondrial bioenergetics measured by oxygen consumption and ATP generation was attenuated in bone marrow isolated from PER2 mutant (Per2m/m) mice. Furthermore, RNA-seq profiling of bone marrow-derive progenitor hematopoietic stem cells (BM-pHSCs; Lin-/Sca1+/cKit+; LSK) cells isolated form LDR-treated wild-type (WT) versus Per2m/m mice showed a cluster of genes involved in mitochondrial bioenergetics and DNA repair capacity. These results demonstrate that a core circadian regulator plays an indispensable role in defending mammalian cells against environmental genotoxic stress through the PER2/β-catenin pathway, a potential therapeutic target to enhance cell survival under radiation.
Citation Format: Aris Alexandrou, Ming Fan, Shuaib Juma, Julian Perks, Andrew Vaughan, Clifford Tepper, Loning Fu, Gayle Woloschak, David Grdina. Core circadian clock component, PERIOD2, regulates adaptive radioprotection via PER2-β-Catenin controlled mitochondrial bioenergetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-184.