bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CN06-02: Regulation of AR variants by BET bromodomains in prostate cancer
Authors: Dehm Scott M. 
Published: May 2016

Abstract
Expression of androgen receptor (AR) variants (AR-Vs) lacking the AR ligand binding domain (LBD) in prostate cancer tissues or circulating tumor cells is associated with poor clinical outcomes. AR-Vs function as constitutively active transcription factors and represent a resistance mechanism whereby the growth of prostate cancer cells can remain AR-dependent, yet uncoupled from endocrine regulation. Tumors that have developed this mechanism of resistance are unlikely to respond to successive generations of endocrine therapies. The absence of a LBD presents a formidable challenge for direct inhibition of AR-Vs because alternative sites on the AR protein appropriate for specific and high-affinity drug targeting are not evident. An indirect approach may be through inhibition of AR-V expression and/or transcriptional activation mechanisms. To this end, we have found that treatment of prostate cancer cell lines with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR and AR-V chromatin binding and impaired AR and AR-V driven prostate cancer cell growth in vitro and in vivo. These anti-AR activities were associated with JQ1-mediated reduction in binding of the BET family member BRD2 to a region near the AR transcription start-site featuring broad enrichment of histone H3 acetylated at lysine 27. Consistent with these chromatin effects at the AR locus, JQ1 treatment down-regulated AR and AR-V transcript and protein expression. Overall, these findings highlight regulation of AR and AR-V expression by BRD2, and provide pre-clinical rationale for BET inhibition as a strategy for overcoming resistance mediated by constitutively active AR-Vs in prostate cancer.
Citation Format: Scott M. Dehm. Regulation of AR variants by BET bromodomains in prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN06-02.
Abstract CN08-01: Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies
Authors: Levine Ross L. , Shih Alan , Guryanova Olga , Maydan Cem , Melnick Ari 
Published: May 2016

Abstract
Clinical, cytogenetic, and gene-based studies have been used to inform biology and improve prognostication for patients with acute myeloid leukemia (AML), myelodysplasia (MDS), and myeloroliferative neoplasms (MPN). Most recently, a series of candidate gene and whole genome studies have identified recurrent somatic mutations in AML patients including TET2, ASXL1, DNMT3A, and cohesin complex mutations. Moreover, these mutations can be used to improve risk stratification in AML independent of established clinical parameters. Integrating mutational data with dose-intensity revealed that high-dose daunorubicin improved survival in patients with DNMT3A/NPM1 mutations or MLL translocations relative to treatment with standard dose daunorubicin, but not in patients wild-type for these alterations. These data provide important clinical implications of genetic alterations in AML by delineating mutation combination genotypes that predict outcome in AML and improve AML risk stratification. Of biologic importance, the TET family of proteins have been shown to place a hydroxyl mark on methylated DNA and lead to DNA demethylation. We and others have found that TET2/IDH mutations leads to loss of DNA hydroxymethylation and a hypermethylation phenotype in leukemia patients. In addition, in vitro and in vivo studies show that TET2 loss or neomorphic IDH1/2 mutations leads to impaired hematopoietic differentiation, increased stem cell self-renewal, and myeloid transformation in vivo. We have also investigated the role of mutant DNMT3A in AML pathogenesis,a and shown these mutations cooperate with other disease alleles to induce leukemic transformation and to confer chemoresistance due to impaired DNA damage sensing. We will present novel data showing how these mutations coopt the epigenetic state of hematopoietic stem/progenitor cells in order to contribute to transformation and that these mutations have biologic and prognostic relevance.
Citation Format: Ross L. Levine, Alan Shih, Olga Guryanova, Cem Maydan, Ari Melnick. Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN08-01.
Abstract ED01-01: Immunity against cancer: How to be enhanced?
Authors: Vries Jolanda De , Gerritsen Winald , Figdor Carl G. 
Published: May 2016

Abstract
Prevention of infectious diseases through immunization is one of the greatest achievements of modern medicine. Nonetheless, considerable challenges remain for improving the efficacy of vaccines currently employed to treat devastating diseases such as cancer. Dendritic cells (DC) are considered professional antigen-presenting cells of the immune system highly effective in initiating primary immune responses. Following infection or inflammation they undergo a complex process of maturation, and migrate to lymph nodes (LN) where they present antigens to T cells. Their decisive role in inducing immunity formed the rationale for DC immunotherapy: DC loaded with tumor antigens are injected into cancer patients to stimulate T cells to eradicate tumours. A major advantage of immunotherapy when compared to radio-, chemo- and targeted therapy is its low toxicity. To date, dendritic cell (DC)-based immunotherapy is explored worldwide in clinical vaccination trials with cancer patients. Although during the past 15 years the concept of DC vaccination has been clearly proven and found safe, the number of patients that have long-term benefit is still limited. Therefore the development of bioassays that predict clinical outcome are essential to optimize cellular anticancer immunotherapy. We have developed a robust and simple skin test to evaluate the capacity of tumor-specific T cells to migrate, recognize their targets, and exert effector functions. This bioassay detects skin infiltrating T lymphocytes (SKILs) with an elevated antineoplastic potential and hence identifies patients responding to immunotherapy once started. The identification of a biomarker already available before start of treatment would facilitate decision-making regarding (prophylactic) immunotherapy. We recently identified that the ratio between peri/intratumoral T cells in the primary tumor, is an excellent predictor of survival after DC-based immunotherapy in metastatic melanoma patients.
Citation Format: Jolanda De Vries, Winald Gerritsen, Carl G. Figdor. Immunity against cancer: How to be enhanced?. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr ED01-01.
Abstract ED02-01: National-scale cancer sequencing and treatment response data integration in The Netherlands
Authors: Cuppen Edwin 
Published: May 2016

Abstract
Next-generation DNA sequencing has boosted the promises of personalising cancer treatment. It has now become possible to routinely sequence the complete genome of a tumor from a patient. However, a main challenge remains how to optimally use such information for guiding therapy choice. Furthermore, it becomes clear that mutational profiling increasingly provides insight in the molecular processes driving tumorigenesis, but knowledge on prediciting the outcome of specific targeted treatments, both approved therapies and novel drugs that start becoming available for patients, remains difficult. While patient stratification based on a limited number of genetic measurements is steadily increasing, retrospective systematic analyses of genetic information and treatment outcome are still warranted to improve stratification as significant numbers of selected patients for specific treatments are non-responsive, yet may experience severe treatment side effects. In addition, ineffective treatment contributes significantly to the increasing economical burden of novel cancer treatment drugs on our national health care costs.
In 2010, we established the Center for Personalized Cancer Treatment (CPCT), a collaboration between all academic medical centers in the Netherlands and an increasing number of teaching hospitals, to address this challenge and work towards implementation of DNA-guided therapy choice into routine care in the Netherlands. In all associated hospitals, we have implemented trials to collect biopsies from tumor metastases before patients start treatment with specific targeted drugs. We aim for the discovery of predictive biomarkers or treatment resistance pathways. Within our nation-wide trials, we systematicly collect and integrate tumor sequencing data (whole exome and whole genome sequencing) plus clinical and treatment response data. In addition, we feed back therapy guidance information to the treating physician in case a patient does not respond to the current treatment. In this setup, both current and future patients may benefit from comprehensive DNA analyses. I will present the choices we made towards achieving our goals and discuss the operational and IT challenges in these processes.
Citation Format: Edwin Cuppen. National-scale cancer sequencing and treatment response data integration in The Netherlands. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr ED02-01.
Abstract KN01: Updates on engineered T cells as cancer therapies
Authors: June Carl H. 
Published: May 2016

Abstract
The field of adoptive cell transfer (ACT) is currently comprised of chimeric antigen receptor (CAR T) and TCR engineered T cells and has emerged from principles of basic immunology to paradigm-shifting clinical immunotherapy. ACT of T cells engineered to express artificial receptors that target cells of choice is an exciting new approach for cancer, and it holds equal promise for chronic infection and autoimmunity. Using principles of synthetic biology, advances in immunology, and genetic engineering have made it possible to generate human T cells that display desired specificities and enhanced functionalities. Clinical trials in patients with advanced B cell leukemias and lymphomas treated with CD19-specific CAR T cells have induced durable remissions in adults and children. The prospects for the widespread availability of engineered T cells have changed dramatically given the recent entry of the pharmaceutical industry to this arena. In this presentation, I will discuss some of the challenges and opportunities that face the field of ACT.
References:
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2. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, and Mackall CL. How I treat: current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-95.
3. Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, Badros AZ, Garfall A, Weiss B, Finklestein J, Kulikovskaya I, Sinha SK, Kronsberg S, Gupta M, Bond S, Melchiori L, Brewer JE, Bennett AD, Gerry AB, Pumphrey NJ, Williams D, Tayton-Martin HK, Ribeiro L, Holdich T, Yanovich S, Hardy N, Yared J, Kerr N, Philip S, Westphal S, Siegel DL, Levine BL, Jakobsen BK, Kalos M, and June CH. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nature Medicine. 2015;21(8):914-21.
4. Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, Dengel K, Kerr ND, Bagg A, Levine BL, June CH, and Stadtmauer EA. Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. N Engl J Med. 2015;373(11):1040-7.
Citation Format: Carl H. June. Updates on engineered T cells as cancer therapies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr KN01.
Abstract LB-A11: Expression of steroid sulfatase induces the integrin signaling pathway in HeLa cells
Authors: Ye Dong-Jin , Kwon Yeo-Jung , Shin Sangyun , Hong Mihye , Baek Hyoungseok , Ahn Seung-Ki , Shin Dongwon , Chun Young-Jin 
Published: May 2016

Abstract
Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates. STS has a pivotal role in regulating the level of estrogen and androgen responsible for growth of hormone-dependent tumors, such as breast or prostate cancer. However, the molecular function for tumor growth of STS is still not clear. To elucidate possible role of STS on cancer cell proliferation, we investigated whether STS is able to regulate integrin signaling pathway. In this study, we observed that overexpression of STS in HeLa cells induces the expression of integrin β1 and fibronectin, a ligand of integrin α5β1 at protein and mRNA levels. Dehydroepiandrosterone (DHEA), one of the main metabolite of STS, also induces mRNA and protein level of integrin β1 and fibronectin. We found that STS expression and DHEA enhance phosphorylation of focal adhesion kinase (FAK) at tyrosine 925 residue. Moreover, phosphorylation of ERK at threonine 202 and tyrosine 204 residues was also induced, indicating that STS may activate Ras/Raf/MEK signaling pathway. In conclusion, these results suggest that STS expression and DHEA may enhance Ras/Raf/MEK signaling through upregulation of integrin β1 and activation of FAK.
Citation Format: Dong-Jin Ye, Yeo-Jung Kwon, Sangyun Shin, Mihye Hong, Hyoungseok Baek, Seung-Ki Ahn, Dongwon Shin, Young-Jin Chun. Expression of steroid sulfatase induces the integrin signaling pathway in HeLa cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A11.
Abstract LB-A12: New target for cancer metabolism : Steroid Sulfatase
Authors: shin sangyun , Kwon Yeo-Jung , Ye Dong-Jin , Baek Hyoung-Seok , Chun Young-Jin 
Published: May 2016

Abstract
Steroid sulfatase (STS) expression has been considered to play a pivotal role in estrogen-dependent cancers. STS is known as a target enzyme for suppressing estrogen-mediated carcinogenesis. STS is able to convert estrogen sulfate to estrone form, like dehydroepiandrosterone sulfate (DHEA-S) to its' active form dehydroepiandrosterone (DHEA). Aerobic glycolysis is a hallmark of cancer metabolism. Lactic acid production was also increased by STS and DHEA.STS and its' major product DEHA reduced Oxygen consumption rate. STX064, a STS specific inhibitor inhibited DHEA formation and lactic acid production, recovered mitochondria resperation in HeLa cells. Hypoxia inducing factor 1 subunit HIF1α is recognized as an important regulator of aerobic glycolysis. To elucidate whether STS is able to regulate cancer metabolism, the effects on aerobic glycolysis were determined. STS overexpression significantly converted DHEA-S to DHEA. STS and the major product DHEA enhanced HIF1α protein, mRNA, promoter activity in HeLa cells. Glycolytic enzymes such as hexokinase 2 (HK-2) and glucose transporter (GLUT) were increased by STS overexpression and DHEA treatment in protein and mRNA levels. When cells were treated with HIF1α siRNA, all glycolytic enzymes induced by STS and DHEA were down-regulated. STS also regulated pyruvate kinase M (PKM)splicing. STS up-regulated PKM2 level and inhibited PKM1 level through transcription factor c-Myc. Phosphorylation of PKM2 was also induced by STS. In conclusion, STS and the major product DHEA may regulate aerobic glycolysis via HIF1α induction and c-Myc related PKM2 alternative splicing.
Citation Format: sangyun shin, Yeo-Jung Kwon, Dong-Jin Ye, Hyoung-Seok Baek, Young-Jin Chun. New target for cancer metabolism : Steroid Sulfatase. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A12.
Abstract LB-A13: Cellular characterization of the selective inhibition of UBA5 by organometallic, adenosine-based inhibitors
Authors: da Silva Sara R. , Geletu Mulu , Javed Fiza , Paiva Stacey-Lynn , Lewis Andrew M. , Li Honglin , Gunning Patrick T. 
Published: May 2016

Abstract
Cells that undergo higher protein turnover, such as pancreatic secretory cells and cancerous cells, have the propensity to undergo endoplasmic reticulum (ER) stress. If left uncorrected, ER stress can result in the initiation of apoptosis. To avoid these fates, cells have developed support systems to counteract the apoptotic effects of ER stress, such as conjugation of certain stress-associated proteins with the ubiquitin-fold modifier 1 (UFM1) ubiquitin-like protein. Our research has recently focused on the discovery and in vitro validation of the first selective inhibitor of the UFM1 pathway, 5C-Z, which selectively targets the UFM1 E1 enzyme (UBA5) over other related enzymes and a panel of over 90 human kinases. This novel strategy of inhibiting UBA5 and subsequent UFMylation would make cancer cells that are highly dependent on this system more susceptible to pharmacological disturbances in ER homeostasis, which could lead to the use of milder drug dosing strategies. Our current efforts are focused on studying the effects of 5C-Z on intracellular signalling, the cellular distribution of proteins in the UFM1 pathway, and phenotypic changes within a lung cancer cell lung line (Sk-Luci6). Treatment of lung cancer cells that exhibit high levels of UBA5 protein expression results in decreased cell proliferation (EC50 = 216.9 μM, 95% C.I. = 211.5 - 222.5 μM), yet does not induce cell death in other diseased (A549) or healthy (MRC9) lung cells (up to 200 μM). The decreased cellular proliferation upon 5C-Z treatment mirrors the effect of treatment with UBA5 siRNA. Using immunocytochemistry, it appears that treatment with 5C-Z also induces changes in both cellular morphology and the distribution of UBA5-like staining within the cell. Furthermore, there is an apparent decrease in UFM1-like co-localization with its E2 conjugating enzyme (UFC1) after prolonged incubation with 5C-Z, although further intracellular analysis is required to confirm this observation. Preliminary work also indicates that these cellular effects may also be selective against the UFM1 pathway compared to related ubiquitin-like labelling pathways. We are currently evaluating the effects of 5C-Z on ER stress signalling pathways connected to the UFM1 labelling system.
Citation Format: Sara R. da Silva, Mulu Geletu, Fiza Javed, Stacey-Lynn Paiva, Andrew M. Lewis, Honglin Li, Patrick T. Gunning. Cellular characterization of the selective inhibition of UBA5 by organometallic, adenosine-based inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A13.
Abstract LB-A14: Targeting BAG3-dependent paracrine loop reduces growth and metastatic spreading of Pancreatic adenocarcinoma
Authors: De Laurenzi Vincenzo , Rosati Alessandra , Sala Gianluca , Turco Maria Caterina 
Published: May 2016

Abstract
Incidence and death rate of Pancreatic Ductal Adenocarcinoma (PDAC) has increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumor formation and development of metastasis. We have recently shown (manuscript in press) that PDAC cells secrete BAG3 that binds and activates macrophages trough a specific receptor (IFITM2), inducing their activation and the secretion of PDAC supporting factors.
Treatment with a murine monoclonal antibody (AC-2) targeting BAG3 reduced tumor growth and impaired metastasis formation in mouse models. Here we report further characterization of the in vivo activity of the antibody. Moreover, we have now successfully generated humanized variants of the AC-2 antibody and report the in vitro and in vivo activity of the humanized antibodies. Both appear to have the ability to inhibit macrophage activation in vitro and reduce tumor growth in PDAC models to an extent comparable to the murine parental antibody (AC-2).
In conclusion, we have identified a novel paracrine loop involved in PDAC growth and metastatic spreading and shown that its pharmacological blockage with an anti-BAG3 antibody has therapeutic potential for PDAC treatment.
Citation Format: Vincenzo De Laurenzi, Alessandra Rosati, Gianluca Sala, Maria Caterina Turco. Targeting BAG3-dependent paracrine loop reduces growth and metastatic spreading of Pancreatic adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A14.