bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 251: Luteolin-mediated increase in miR-26a inhibits prostate cancer cell growth and induces cell cycle arrest targeting EZH2
Authors: Kanwal Rajnee , Moreton Stephen , Franco Daniel , Gupta Sanjay 
Published: August 2018

Abstract
Luteolin (3',4',5,7-tetrahydroxyflavone), a flavonoid found in several vegetables and fruits, has been reported to possess anticancer and apoptosis inducing properties. However, the molecular targets of luteolin action are presently unknown. The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of polycomb repressive complex 2 (PRC2), which catalyzes the trimethylation of histone H3 on Lysine 27 (H3K27) and is involved in chromatin remodeling and gene silencing. EZH2-mediated epigenetic gene silencing plays an important role in several human cancers including prostate neoplasm. Emerging studies demonstrate that miR-26a, a non-coding microRNA, regulates EZH2 expression and is frequently lost during cancer progression. Here we investigated the potential involvement of luteolin-mediated miR-26a upregulation and EZH2 suppression leading to cell cycle arrest and apoptosis in cancer cells. Human prostate cancer DU145 and PC-3 cells, which possess high constitutive EZH2 expression, were treated with 5-20 µM luteolin at various times significantly inhibited EZH2 and H3K27 trimethylation in dose and time dependent manner. Luteolin treatment further resulted in increased expression of miR-26a in both cell lines, as exhibited by EZH2 inhibitor GSK126. Mechanistic investigations revealed that miR-26a overexpression suppressed cell cycle regulatory molecules such as cyclin D and E, cyclin dependent kinases CDK4 and CDK6, and CDK inhibitors p14/ARF, p16/INK4A and p21/WAF1 in EZH2-dependent manner. Interestingly, similar observations were noted in prostate cancer cells with a marked decrease in cyclins and CDKs along with concomitant increase in CDK inhibitors after luteolin treatment resulting in G0/G1 phase cell cycle arrest. In plasma specimens, obtained from healthy individuals, high-risk subjects and prostate cancer patients exhibit a progressive decrease in miR-26a expression. Taken together, our results indicate that miR-26a functions as a growth suppressive miRNA lost in prostate cancer, whereas luteolin is a promising agent which demonstrate anti-proliferative effects mediated by upregulation of miR-26 repressing EZH2 in prostate cancer cells.
Citation Format: Rajnee Kanwal, Stephen Moreton, Daniel Franco, Sanjay Gupta. Luteolin-mediated increase in miR-26a inhibits prostate cancer cell growth and induces cell cycle arrest targeting EZH2 [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 251.
Abstract 2518: Folate hydrolase-1 is a novel target for J591-brachytherapy in Merkel cell carcinoma
Authors: Meier Barbara , Ramirez-Fort Marigdalia K. , Lachance Kristina , Church Candice D. , Mahase Sean S. , Jenrette Joseph M. , Lange Christopher S. , French Lars E. , Nghiem Paul , Bander Neil H. 
Published: August 2018

Abstract
Folate hydrolase-1 (FOLH1) is a type II transmembrane protein. Oncologically, FOLH1 is upregulated throughout prostate cancer cells; it is also luminally expressed by the neovasculature of most solid tumors but not by normal vessels. J591, a monoclonal antibody (AB), is specific to, and is effectively endocytosed after extracellular binding to, FOLH1. J591 is presently being developed in clinical trials as a vehicle for AB-based brachytherapy in FOLH1+ cancers. Merkel cell carcinoma (MCC) is a rare, neuroendocrine tumor; metastatic (m) MCC is associated with poor survival. We characterized FOLH1 expression in MCC to determine its target potential for J591-brachytherapy. Paraffin sections from primary (p) and mMCC were deparaffinized and rehydrated. Samples were stained with 3E6 (DAKO), a mouse IgG1 monoclonal anti-human FOLH1. Mouse IgG1 (10 ug/mL in 1% bovine serum albumin) was used as an isotype-matched negative control. Anti-CD31 (IgG1) was used as a positive control. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression. 81 MCC tumors were evaluated. 67% (54/81) of all cases with 77% (24/31) of pMCC and 60% (30/50) of mMCC tumors demonstrated FOLH1+ neovessels. No cellular staining of tumor cells was identified. 34 patients with FOLH1 +/- MCC were demographically homogeneous in terms of sex, age, immunosuppression status, prior therapies, stage at diagnosis, and local or distant recurrences. No significant differences were detected based on FOLH1 status, in regards to MCC specific survival (P=0.905), or overall survival (P=0.687), as measured from time of diagnosis. FOLH1 is expressed in the majority of pMCC and mMCC cases and is nonprognostic. Our findings support further investigation of targeted therapy with J591-brachytherapy for the management of MCC.
Citation Format: Barbara Meier, Marigdalia K. Ramirez-Fort, Kristina Lachance, Candice D. Church, Sean S. Mahase, Joseph M. Jenrette, Christopher S. Lange, Lars E. French, Paul Nghiem, Neil H. Bander. Folate hydrolase-1 is a novel target for J591-brachytherapy in Merkel 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 2518.
Abstract 2521: Patient GBM cell originated secretome analysis identifies cytokine A, as a potent therapeutic target
Authors: Han Suji , Shin Kayoung , Lee Kyoungmin , Kim Sungsoo , Kang Hyunju , Lee Jin-Ku , Nam Hyun , Joo Kyeung Min , Nam Do-Hyun 
Published: August 2018

Abstract
GBM is the most aggressive human primary brain tumor and leads to poor clinical outcomes. According to previous studies, exogenous factors secreted from primary brain tumor cells can change the growth pattern of normal cells. We analyzed the ingredients of cell culture media from two patient glioblastoma cells which can grow without growth factors. As a result, we selected a significant factor for tumor cell growth which is called cytokine A, the Heparin-binding growth factor. Because of the cell viability maintenance ability of cytokine A, we tried to investigate detailed mechanism of cytokine A and applied the result to the combination therapy. Cytokine A is critical for tumorigenesis of GBM by modulating DNA damage signaling and cell cycle through ROS. For that reason, cytokine A is effective therapeutic target and can be used in combination therapy.
Citation Format: Suji Han, Kayoung Shin, Kyoungmin Lee, Sungsoo Kim, Hyunju Kang, Jin-Ku Lee, Hyun Nam, Kyeung Min Joo, Do-Hyun Nam. Patient GBM cell originated secretome analysis identifies cytokine A, as a potent therapeutic target [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 2521.
Abstract 2522: Luminal epithelial cell expression of amphiregulin is required for mammary gland development and facilitates mutant p53-driven tumorigenesis
Authors: Lofgren Kristopher A. , Meier David R. , Girtman Megan A. , Peterson Esther A. , Jenkins E. Charles , Kenny Paraic A. 
Published: August 2018

Abstract
Amphiregulin (AREG) is an estrogen-responsive ligand of the epidermal growth factor receptor. Mice with germline deletion of AREG are defective in pubertal mammary expansion. Using shRNA, we have previously reported that the estrogen-responsive growth of MCF7 xenograft tumors in immunocompromised mice is also AREG-dependent. Here we use a series of genetically engineered mouse AREG models (lacZ-knock-in, conditional knockout and germline knockout) to address two outstanding questions: (1) Among the numerous AREG-expressing cell types in the mammary gland and stroma, does the requirement for AREG in mammary gland development reside specifically in the luminal epithelial cells? (2) Is AREG required for mammary tumorigenesis in immunologically-intact mice? An initial characterization of mammary gland development using an AREG-lacZ knock-in allele identified AREG promoter activity in the luminal epithelial but not the myoepithelial compartment. We generated AREGfl/fl mice and achieved luminal epithelial cell specific AREG deletion using MMTV-Cre. Mice lacking AREG in the luminal epithelial compartment (but otherwise proficient in AREG expression) phenocopied the deficit in outgrowth seen in the AREG germline deletion, indicating that luminal epithelial AREG expression is essential for mammary gland development. To determine the extent to which AREG deletion affects mammary tumor latency and multiplicity in immune-intact animals, we used a Cre-regulated model of p53 mutation in mammary tissue (MMTV-Cre x p53LSL-R172H). We used this p53-dependent model to generate at-risk cohorts with AREG deficient (AREG-/-) and AREG proficient (AREG+/+ & AREG+/-) genotypes. Although the cohorts are still maturing, the median age of mammary tumors observed in AREG proficient mice is 258 days (median tumor multiplicity is 2 per animal), while only a single tumor has been detected in the AREG deficient cohort (at 415 days). Together, these data point to two temporally distinct roles for amphiregulin–an essential function in mammary ductal expansion during puberty and a subversion of this developmental role during tumorigenesis later in life.
Citation Format: Kristopher A. Lofgren, David R. Meier, Megan A. Girtman, Esther A. Peterson, E. Charles Jenkins, Paraic A. Kenny. Luminal epithelial cell expression of amphiregulin is required for mammary gland development and facilitates mutant p53-driven tumorigenesis [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 2522.
Abstract 2526: Modulation of metastatic factors in prostate cancer cells by DAX-1 (NR0B1), an androgen-induced orphan nuclear receptor
Authors: Valencia Roxxana Valeria Beltran , Tzagarakis-Foster Christina 
Published: August 2018

Abstract
DAX-1, a member of the nuclear hormone receptor superfamily, has a pivotal role in adrenal and gonadal development. However, recent studies have shown that DAX-1 acts as a transcriptional repressor influencing the progression of many types of cancers. We hypothesize that DAX-1 has key roles in regulating metastatic genes during prostate cancer progression. We found that introducing DAX-1 into prostate cancer cells lacking endogenous expression of DAX-1 leads to a decrease in metastatic rates. Consequently, we analyzed DAX-1 transcriptional regulation over different markers associated with metastasis. Since the androgen receptor is a key regulator of prostate cancer progression, we used CRISPR to knockout DAX-1 expression in hormone-dependent prostate cancer cells, allowing us to understand the role DAX-1 has as a negative regulator of metastatic genes after androgen receptor activation. We have shown that treatment of hormone-dependent prostate cancer cells with a non-aromatizable androgen leads to upregulation of DAX-1 expression. Here we use the same mechanism to induce DAX-1 expression and analyze the effects on metastatic markers. Results have shown that DAX-1 is sufficient to decrease the expression of metastatic markers and inhibit metastatic rates in prostate cancer cells. These results further explain some of the intrinsic mechanisms involved in prostate cancer metastasis and could reveal new therapeutic routes in the treatment of metastatic prostate cancer.
Citation Format: Roxxana Valeria Beltran Valencia, Christina Tzagarakis-Foster. Modulation of metastatic factors in prostate cancer cells by DAX-1 (NR0B1), an androgen-induced orphan nuclear receptor [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 2526.
Abstract 2529: GENT 2.0, a newly updated database: Gene expression across normal and tumor tissues
Authors: Park Seung-Jin 
Published: August 2018

Abstract
We previously developed GENT1.0 (Gene Expression Database of Normal and Tumor tissues), a web-accessible database that provides gene expression patterns across diverse human cancer and normal tissues. GENT shows gene expression patterns in various tissues easily and has more than 40,000 samples for 25 normal-cancer paired tissues. Here, we made updated database called GENT2.0 based on 60,000 microarray data for 36 normal-cancer paired tissues with various functions. GENT2.0 1) has collected over 60,000 amounts of data for 36 normal cancer paired tissues; 2) can analyze histologic or molecular subtypes or tumor stages for 19 tissues; 3) provides all sorts of plots in svg (Scalable Vector Graphics) format with a high-resolution figure; 4) has twice the amount of data compared to GENT1.0, and the web page loading speed is almost the same as GENT1.0; and 5) data will be accessible on the web. We hope GENT2.0 will be a useful resource for cancer researchers in many stages from target discovery to target validation.
Citation Format: Seung-Jin Park. GENT 2.0, a newly updated database: Gene expression across normal and tumor tissues [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 2529.
Abstract 2543: Concurrent chemotherapy and temozolomide-resistant CAR-T immunotherapy enhances glioblastoma clearance in experimental animals
Authors: Sengupta Sadhak , Gergi Mansour , Guha Prajna , Sengupta Sudarshana , Junghans Richard P. , Sampath Prakash 
Published: August 2018

Abstract
Dismal long-term progression-free survival of glioblastoma (GBM) patients, who are concurrently treated with radiation and chemotherapy, demands development of alternative strategies for management of this disease. Recent clinical success of chimeric antigen receptors expressing T cells (CAR-T) in GBM patients, interest in tumor-directed immunotherapy has been reinvigorated. However as per standard care, immunotherapy must be concurrent with or following the standard care protocol for glioma therapy, which includes Temozolomide (TMZ) chemotherapy. Concurrent chemotherapy with TMZ reduces the efficacy of adoptive T cell immunotherapy by inducing severe lymphopenia, while post-chemotherapy treatment minimizes the window of opportunity for effective immunotherapy, because of inherent tumor heterogeneity resulting in an altered antigenic profile in recurrent GBMs. To address this, we have created a TMZ-resistant CAR-T cell directed against IL13Rα2+ GBM tumors by introducing a mutated O6-methylguanine-DNA methyltransferase (MGMT) moiety in the existing IL13CAR backbone. This specific mutation in MGMT (P140KMGMT) blocks the interaction of TMZ to MGMT and therefore protects the rapidly proliferating anti-GBM CAR-T cells from TMZ-induced lymphopenia. Activated P140KMGMT-IL13CAR-T cells were protected from TMZ-induced cytotoxicity in vitro without any loss of anti-tumor effects of these modified CAR-T cells. Experimental xenograft animals treated with P140KMGMT-IL13CAR-T cells and concurrent TMZ therapy showed 2-fold increase in median survival over groups that were treated with TMZ alone, and 2.8-fold increase in overall survival over groups that were treated with TMZ-sensitive second generation IL13CAR-T cells and concurrent TMZ. These encouraging results point us strongly in the direction of developing this CAR-T technology towards a promising future of concurrent chemotherapy and immunotherapy of GBM.
Citation Format: Sadhak Sengupta, Mansour Gergi, Prajna Guha, Sudarshana Sengupta, Richard P. Junghans, Prakash Sampath. Concurrent chemotherapy and temozolomide-resistant CAR-T immunotherapy enhances glioblastoma clearance in experimental animals [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 2543.
Abstract 2548: An image-based method to detect and quantify T cell mediated cytotoxicity of 2D and 3D target cell models
Authors: Larson Brad , Kambach Diane , Luty Wini , Souza Glauco 
Published: August 2018

Abstract
T cell-mediated cytotoxicity plays an important role in a suite of new methods being developed with the goal of incorporating a patient's immune system to combat cancer. The purpose of this study was to develop a sensitive, image-based in vitro method to evaluate and optimize adoptive T cell immunotherapies. Experiments were performed using MDA-MB-231 and fibroblast target cells co-cultured in 2D and 3D models, along with T cell to target cell ratios of 20:1, 10:1 and 5:1. T cell activation procedures were also tested where T cells were activated in the presence of anti-CD3 and anti-CD28 antibodies plus an IL-2 superkine only, or in a directed fashion with antibodies, superkine, and varying concentrations of target breast cancer cells. Experimental data show that directing the activation of T cells to recognize surface antigens on specific target cancer cells enhances the killing ability of the cells when compared to results from nondirected cells. In addition, increased T cell to target cell ratios induce higher levels of target cell cytotoxicity. Finally, it was evident that assay performance using 2D cultured target cells could be reliably carried out through a 72-hour incubation period. However, it exhibited limited utility beyond this point due to increasing numbers of uninduced necrotic cells within wells, negating the effect of test conditions. This phenomenon was unseen from 3D cultured target cells, indicating their ability to maintain a higher level of viability when cultured in this manner. Necrotic induction can then be reliably attributed to cell treatments using multiday incubations. The combination confirms the ability of the image-based method to deliver dependable results to assess T cell-mediated cytotoxicity using 2D and 3D target cell models.
Citation Format: Brad Larson, Diane Kambach, Wini Luty, Glauco Souza. An image-based method to detect and quantify T cell mediated cytotoxicity of 2D and 3D target cell models [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 2548.
Abstract 2551: Allogeneic CRISPR engineered anti CD70 CAR T cells demonstrate potent preclinical activity against both solid and hematological cancer cells
Authors: Padalia Zinkal , Porras Ashley , Dequeant Mary Lee , Sagert Jason , Nguyen Thao , John Matthias , Allen Melanie , Dar Henia , Henderson Daniel , Police Seshidar , Mu Dakai , Maeng Kelly , Huang Elaine , Spencer Sarah , Lorson Nickolaus , Gonzales Paul , Holmquist Chelsea , Hirschfeld Gregg , Terrett Jonathan A. , Kalaitzidis Demetrios 
Published: August 2018

Abstract
Autologous CAR T therapeutics have recently been approved for use in B-cell malignancies. While responses have been impressive using CD19 directed CAR T cells there has been a lack of comparable success for CAR T cells directed at solid tumor antigens. In an effort to address the need for effective and durable off-the shelf therapies for both hematologic and solid tumors we have developed allogeneic CAR T cells targeting the CD70 antigen. CD70 is expressed in both hematologic malignancies as well as in solid cancers such as renal cell carcinoma (RCC), while its expression in normal tissues is restricted to a subset of lymphoid cell types. CAR-T cells expressing a CD70 targeting CAR were generated by CRISPR Cas9 genome editing. T cells from healthy donors were edited to express a CD70 CAR by knocking this construct into the concurrently knocked out TCR alpha constant region (TRAC). Loss of the TCR reduces the risk of graft versus host disease enabling an allogeneic therapeutic. CD70 CAR T cells displayed potent cell killing function in vitro against CD70 expressing lymphoid and renal cancer derived cell lines across a broad range of antigen expression levels. CD70 CAR T cells also secreted IFNg, released granzyme B and proliferated in a CD70 specific manner. Furthermore, the CD70 targeting CAR T cells were able to eliminate established ccRCC tumor xenografts in mice
Citation Format: Zinkal Padalia, Ashley Porras, Mary Lee Dequeant, Jason Sagert, Thao Nguyen, Matthias John, Melanie Allen, Henia Dar, Daniel Henderson, Seshidar Police, Dakai Mu, Kelly Maeng, Elaine Huang, Sarah Spencer, Nickolaus Lorson, Paul Gonzales, Chelsea Holmquist, Gregg Hirschfeld, Jonathan A. Terrett, Demetrios Kalaitzidis. Allogeneic CRISPR engineered anti CD70 CAR T cells demonstrate potent preclinical activity against both solid and hematological 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 2551.
Abstract 2561: Fully human immunoglobulin heavy chain only-derived CD33 CAR for the treatment of acute myeloid leukemia
Authors: Schneider Dina , Xiong Ying , Chen Weizao , Zhu Zhongyu , Wu Darong , Hwang Jennifer , Dimitrov Dimiter S. , Dropulic Boro , Orentas Rimas J. 
Published: August 2018

Abstract
CD33 antigen is a promising target expressed on non-solid cancers, including acute myeloid leukemia (AML). Present investigative approaches to treatment of CD33-positive AML include antibody drug conjugates (My96, Mylotarg®) and CART cells incorporating CD33-targeting domains derived from a humanized scFv. Here, we designed a chimeric antigen receptor utilizing targeting domain derived from a fully human CD33 fragment variable heavy chain sequence, termed CAR33VH, and examined its in vitro and in vivo potency against AML.
Primary human CD4+ CD8+ T cells derived from three healthy donors were transduced with lentiviral constructs (LV) encoding CAR33VH, or control CAR construct based on scFv My96 (My96CAR). Flow cytometric analysis revealed expression of CAR33VH at 32%-45%, and expression of My96CAR at 77% - 86%. When challenged with CD33+ AML tumor lines HL60 and MOLM-14 in vitro, both constructs demonstrated efficient target killing. CD33- tumor lines K562 and Reh were not sensitive to CAR killing, underscoring CAR specificity to CD33 antigen. Pro-inflammatory cytokines IFN gamma, TNF alpha and IL-2 in culture supernatants of CART cells incubated with CD33+ HL-60 and MOLM-14 tumors, but not with CD33- K562 cells overnight, were induced, as measured by ELISA. Long-term co-incubation assay of CART cells with HL-60 leukemia at E:T ratios 1:5 to 1: 0.04, suggested similar killing potency and persistence of CAR33VH to the positive control scFv-based CAR. In in vivo AML model, NSG mice engrafted with MOLM-14 cells stably expressing firefly luciferase, both CAR33VH, and My96CAR control were equally efficient in tumor elimination.
In conclusion, CAR33VH, comprised of a fully human heavy-chain variable fragment only antigen binding domain, was efficient in tumor killing in vitro and in vivo, and may be used clinically for treatment of CD33+ hematologic malignancies. To our knowledge, this is one of the first instances demonstrating the feasibility of employing heavy chain only binder sequence in CART design.
Citation Format: Dina Schneider, Ying Xiong, Weizao Chen, Zhongyu Zhu, Darong Wu, Jennifer Hwang, Dimiter S. Dimitrov, Boro Dropulic, Rimas J. Orentas. Fully human immunoglobulin heavy chain only-derived CD33 CAR for the treatment of acute myeloid leukemia [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 2561.