bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3970: Targeting the adenosine immunosuppressive pathway for cancer immunotherapy with small molecule agents
Authors: Fons Pierre , Esquerré Michael , Versluys Stéphanie , Mambrini Gigliola , Paillasse Michael , Bell Andy , Schreyer Adrian , Cox Richard , Bickerton Richard , Lisztwan Joanna , Whittaker Mark , Bono Françoise , Johnstone Craig , Hopkins Andrew 
Published: July 2017

Abstract
Standard Immune Checkpoint Therapies, such as anti-CTLA-4 or anti-PD-1/PD-L1 mAb, demonstrate long progression-free-survival for responding patients but with a low response rate. This can be due to additional immunosuppressive mechanisms developed by resistant tumors. The adenosine pathway is one of the main drivers of tumor progression by acting on two key features of the TME (Tumor Micro-Environment); immunity and angiogenesis. Expression of CD73 on tumor cells and on immunosuppressive cell subsets leads to the generation of adenosine from AMP. Adenosine inhibits the biological functions of T lymphocytes infiltrating the tumor by binding to the A2AR (receptor). Evotec and Exscientia are collaborating to accelerate small molecule drug discovery in the field of Immuno-Oncology by integrating a unique biophysical screening approach to the adenosine receptors and CD73 to drive automated medicinal chemistry design with a translational-focused screening cascade, to discover novel agents that target the adenosinergic pathway in immuno-oncology. We have firstly sought to generate novel A2AR antagonists and secondly to create A2AR/CD73 bi-specific inhibitory molecules with a dual pharmacological profile, from fragment screening and de novo design approaches. In vivo combination study demonstrate the advantages of targeting CD73 and A2AR. We have obtained active molecules illustrated by in vitro data on primary human T lymphocytes. These results, have paved the way to an optimized process to identify adenosinergic pathway inhibitors with properties optimized for immuno-oncology.
Citation Format: Pierre Fons, Michael Esquerré, Stéphanie Versluys, Gigliola Mambrini, Michael Paillasse, Andy Bell, Adrian Schreyer, Richard Cox, Richard Bickerton, Joanna Lisztwan, Mark Whittaker, Françoise Bono, Craig Johnstone, Andrew Hopkins. Targeting the adenosine immunosuppressive pathway for cancer immunotherapy with small molecule agents [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 3970. doi:10.1158/1538-7445.AM2017-3970
Abstract 399: CPTAC phase II final report
Authors: Thiagarajan Mathangi 
Published: July 2017

Abstract
National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) is a comprehensive and coordinated effort to accelerate the understanding of the molecular basis of cancer through the application of robust, quantitative, proteomic technologies and workflows. The primary goal for this program is to systematically identify proteins that derive from alterations in cancer genomes and related biological processes, integrate the genomic and proteomic data from analysis of common cancer biospecimen and provide this data with accompanying assays and protocols to the community. The phase II effort managed by the Leidos Biomedical Research Inc. had a goal to procure and qualify a minimum of 100 cases from 3 cancer types (Breast, Ovarian and Colon). Tissues and analytes from the 100 cases were sent to proteomic and genomic characterization centers for analysis. The proteomic data were made available through the Data Coordinating Center (DCC) and the genomic data were made available through NCI’s Genomic Data Commons (GDC). The success from the phase II effort has set precedence for a much larger phase III effort that will focus on additional cancer types and cases. Preliminary analysis results confirm the need for the combination of the genomic and proteomic approaches to produce a more comprehensive inventory of the detectable proteins in a tumor and advance our understanding of cancer biology.
Citation Format: Mathangi Thiagarajan. CPTAC phase II final report [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 399. doi:10.1158/1538-7445.AM2017-399
Abstract 4: Inhibitory effects of aprotinin on survival and local invasion of human breast cancer cell lines
Authors: Soleyman-Jahi Saeed , Zendehdel Kazem , Sadeghi Fatemeh , Afshari Ziba , Barati Tahereh , Mohammadnezhad Samad , Ghasemi Sevil , Amanpour Saeed 
Published: July 2017

Abstract
Background: Aprotinin is a nonspecific serine protease inhibitor, which can inhibit kallikrein and many downstream extracellular matrix degrading enzymes. In this study, we assessed inhibitory effects of aprotinin on local invasion of human breast cancer cell lines.
Methods: We assessed effects of aprotinin on local invasion and survival of human breast cancer cell lines MDA-MB231 and SK-BR-3 in vitro. CHEMICON Cell Invasion Assay Kit was used to assess local invasion of tumoral cells. MTT assay was used to determine the anti-proliferative activity of aprotinin on different cancer cell lines. Mean optical densities of duplicate experiments were calculated for both assays. HDF-1 human fibroblast cell line was used as control normal cell. In addition, local invasion and survival of tumor cell lines treated with aprotinin were compared with untreated experiments.
Results: Cancer cell lines showed more invasion compared to HDF-1. Aprotinin significantly decreased the invasiveness of MDA-MB231 in concentration of 1 TIU/ml, 1.3 TIU/ml, and 1.7 TIU/ml in comparison with untreated group (ANOVA P &lt;0.001). Treatment of SK-BR-3 with 1.3 TIU/ml aprotinin trended towards reduction of invasion optical density (P = 0.06). Treatment with different concentrations of aprotinin significantly decreased the surviving fraction and significantly inhibited the growth of all cell lines tested in this study (ANOVA P &lt;0.001).
Conclusion: Aprotinin inhibited the survival and local invasion of human breast cancer cell lines MDA-MB231 and SK-BR-3. Although the growth inhibitory effect was significant in both cell lines, inhibition of local invasion was more pronounced in case of MDA-MB231. Future molecular studies could shed further lights on mechanisms underlying anti-neoplastic effects of aprotinin and its potential therapeutic effects.
Citation Format: Saeed Soleyman-Jahi, Kazem Zendehdel, Fatemeh Sadeghi, Ziba Afshari, Tahereh Barati, Samad Mohammadnezhad, Sevil Ghasemi, Saeed Amanpour. Inhibitory effects of aprotinin on survival and local invasion of human breast cancer cell lines [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 4. doi:10.1158/1538-7445.AM2017-4
Abstract 4172: Activation of AR signaling by mifepristone enhances prostate cancer growth and impairs enzalutamide response
Authors: Zhou Haiying , Jachan Nadine , Singh Mallika , Tran Chris , McWeeney Dan , Balbas Minna , Schenkein Emily , Zovorotinskaya Tatiana , Jackson Erica L. , Medina Julio , Sun Daqing , Rew Yosup , Du Xiaohui , Eksterowicz John , Yan Xuelei , Zhu Liusheng , Ye Qiuping , Fantin Valeria 
Published: July 2017

Abstract
Androgen receptor (AR) signaling is crucial for normal development and homeostasis of the prostate, and is a key driver of prostate cancer initiation and progression. Hormone therapies that deprive the cancer of androgen have long been a mainstay of prostate cancer treatment. More recently, anti-androgens, such as abiraterone and enzalutamide, have been approved for use in metastatic castration resistant prostate cancer (mCRPC). Evidence also suggests that AR may play an oncogenic role in certain breast cancers. Several recent publications have demonstrated that activation of the Glucocorticoid Receptor (GR) can confer resistance to enzalutamide, and GR has also been shown to provide protection from conventional chemotherapies in other solid tumor indications. Mifepristone, is a synthetic steroidal antagonist of progesterone receptor, and to a lesser extent of GR and AR. It is currently being tested in clinical trials in combination with enzalutamide in mCRPC, and in combination with chemotherapy in triple negative breast cancer (TNBC). We sought to characterize the effect of mifepristone in pre-clinical models of prostate and breast cancer. Here we show that in the absence of androgen, mifepristone acts as a partial AR agonist, and this agonism can only be partially overcome by enzalutamide. We find that in low androgen conditions, mifepristone promotes the growth of prostate cancer cells in vitro and accelerates the growth of prostate tumors in xenograft models. Moreover, when given in combination, mifepristone significantly reduces the efficacy of enzalutamide in the LN-AR xenograft model. We are currently assessing the effects of mifepristone treatment in TNBC. Our findings suggest that partial AR agonist activity of mifepristone may have a negative impact in prostate and other AR positive cancers. We have developed a GR antagonist that is devoid of AR agonism to circumvent undesired effects on proliferation and drug response.
Citation Format: Haiying Zhou, Nadine Jachan, Mallika Singh, Chris Tran, Dan McWeeney, Minna Balbas, Emily Schenkein, Tatiana Zovorotinskaya, Erica L. Jackson, Julio Medina, Daqing Sun, Yosup Rew, Xiaohui Du, John Eksterowicz, Xuelei Yan, Liusheng Zhu, Qiuping Ye, Valeria Fantin. Activation of AR signaling by mifepristone enhances prostate cancer growth and impairs enzalutamide response [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 4172. doi:10.1158/1538-7445.AM2017-4172
Abstract 4182: The two novel BTK-inhibitors M2951 and M7583 show in vivo anti-tumor activity in pre-clinical models of B cell lymphoma
Authors: Gaudio Eugenio , Tarantelli Chiara , Zucca Emanuele , Rossi Davide , Stathis Anastasios , Bertoni Francesco 
Published: July 2017

Abstract
Background. Diffuse large B cell lymphoma of the activated B cell like type (ABC DLBCL) is an aggressive lymphoma in which the inhibition of the Bruton’s tyrosine kinase (BTK) has shown biologic and clinical relevance. M7583 and M2951 are two novel highly selective irreversible BTK inhibitors (Fest C et al, 2016). M7583 has shown activity in a mouse model of lupus erythematosus (Bender et al, 2016). Here, we evaluated the anti-tumor activity of M2951 and M7583 in an in vivo ABC DLBCL model.
Methods. Xenografts were established by s.c. injecting TMD8 lymphoma cells (100 µL of PBS, 107 cells/mouse) into the left flanks of female NOD-SCID mice (6 weeks of age and around 20g of body weight). Treatments (QD, po) were started with an average tumor volume of 100mm3 on groups of 10 mice each.
Results. NOD-SCID mice engrafted with the ABC DLBCL TMD8 were treated with three different concentrations of M7583 (1 mg/Kg; 3 mg/Kg; 10mg/Kg) or M2951 (5 mg/Kg; 15 mg/Kg; 25mg/Kg) or vehicle, as control group. M2951 slowed tumor growth at all doses starting after 10 days of treatment. M7583 at 3 and 10 mg/Kg showed stronger anti-tumor activity than M2951, already evident after 5 days of treatment (P&lt;0.05) and improving with time (after 10 days, P&lt; 0.005). Moreover, while most groups had to be stopped after 2 weeks of treatment (D30 after engraftment) because of the reaching of the maximum tumor volume, allowed by the ethical veterinary committee, mice treated with M7583 at the two highest doses were able to continue treatment for additional six (3 mg/Kg) or ten days (10mg/Kg), when tumors became bigger than 2000 mm3, indicating a high activity of M7583. No body weight losses and sign of toxicity were detected.
Conclusion. The two novel BTK inhibitors M2951 and M7583 showed promising in vivo anti-tumor activity in an ABC-DLBCL model. These data provide the rational for further investigating these compounds.
Citation Format: Eugenio Gaudio, Chiara Tarantelli, Emanuele Zucca, Davide Rossi, Anastasios Stathis, Francesco Bertoni. The two novel BTK-inhibitors M2951 and M7583 show in vivo anti-tumor activity in pre-clinical models of B cell lymphoma [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 4182. doi:10.1158/1538-7445.AM2017-4182
Abstract 4183: A novel selective DNA-PK inhibitor, M3814, as a potential combination partner of Etoposide and Cisplatin in the therapy of lung cancer
Authors: Sirrenberg Christian , Zimmermann Astrid , Grombacher Thomas , Vassilev Lyubomir T. , Damstrup Lars , Zenke Frank T. , Blaukat Andree 
Published: July 2017

Abstract
M3814 is a potent and selective inhibitor of DNA-PK, one of the key cellular regulators of DNA damage induced by ionizing radiation or certain cytostatics used in the treatment malignant disease. One of these drugs, Etoposide, induces double strand breaks (DSB) in cellular DNA. DSBs are most difficult to repair and, if left unrepaired, can lead to induction of cell cycle arrest and/or apoptosis and ultimately cell death. DNA-PK plays a critical role in the repair of DSB via the non-homologous end-joining pathway. M3814 was tested for activity in combination with Etoposide in a panel of 98 cancer cell lines derived from lung cancer. A broad potentiation effect of DNA-PK inhibitor was observed in most cancer cell lines. As a rule, cell lines sensitive to Etoposide demonstrated increased sensitivity to the combination. M3814 did not show significant effect on cancer cell growth/viability in combination with Cisplatin compared to Cisplatin alone at concentrations that effectively inhibit DNA-PK activity. At the same time, M3814 did not negatively affect the antitumor activity of Cisplatin. The therapeutic effect of M3814 in combination with the standard of care (SoC) regimen of Etoposide and Cisplatin was tested in the human small cell lung cancer xenograft model, NCI-H520. Triple combination of M3814, Etoposide and Cisplatin resulted in increased efficacy compared to SoC treatment arm. Since myeloid and lymphoid suppression is one of the dose limiting toxicities of the SoC regimen in patients, the effect of the triple combination on myeloid and lymphoid blood cells was investigated in immunocompetent mice. Whereas the SoC treatment showed reduction of the myeloid and lymphoid compartments, the addition of M3814 did not additionally reduce these cells neither in the treatment nor the recovery phase. Our results warrant further investigations to explore the potential of the combination in the clinical setting.
Citation Format: Christian Sirrenberg, Astrid Zimmermann, Thomas Grombacher, Lyubomir T. Vassilev, Lars Damstrup, Frank T. Zenke, Andree Blaukat. A novel selective DNA-PK inhibitor, M3814, as a potential combination partner of Etoposide and Cisplatin in the therapy of 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 4183. doi:10.1158/1538-7445.AM2017-4183
Abstract 4198: Highly potent and selective DNA-PK inhibitor M3814 with sustainable anti-tumor activity in combination with radiotherapy
Authors: Fuchss Thomas , Mederski Werner W. , Emde Ulrich , Buchstallter Hans-Peter , Zenke Frank , Zimmermann Astrid , Sirrenberg Christian , Vassilev Lubo , Damstrup Lars , Urbahns Klaus , Blaukat Andree 
Published: July 2017

Abstract
Physical or chemical agents that damage DNA such as ionizing radiation are among the most widely used classes of cancer therapeutics today. Double strand breaks (dsb) generated in DNA by radiation induce a multitude of cellular responses, including DNA repair, cell cycle arrest or cell death once the damage is left unrepaired. A complex set of molecular events are responsible for DNA repair mediated by two major repair mechanisms - homologous recombination (HR) or non-homologous end joining (NHEJ). DNA-PKcs together with its regulatory protein subunits Ku70 & Ku80, is an integral component of the NHEJ process and considered an attractive intervention point to inhibit DNA dsb repair. We have developed an orally bioavailable, highly potent & selective inhibitor of DNA-PK, M3814, for cancer therapy in combination with DNA damaging modalities such as radiation & radio-chemotherapy. Here, we present the optimization of initial hit matter & its structure-activity relationships leading to M3814, its chemical structure (first-time disclosure) & preclinical characterization using biochemical, cellular & human tumor xenograft models. M3814 sensitized multiple tumor cell lines to radiation therapy in vitro and strongly enhanced the anti-tumor activity of ionizing radiation in vivo with complete tumor regression by applying a clinically relevant fractionated radiation regimen. These effects are due to inhibition of DNA-PK protein kinase activity as demonstrated by the levels of DNA-PK autophosphorylation in human tumor cell lines & xenograft tumors. M3814 is currently being investigated in PhI/II clinical trials.
Citation Format: Thomas Fuchss, Werner W. Mederski, Ulrich Emde, Hans-Peter Buchstallter, Frank Zenke, Astrid Zimmermann, Christian Sirrenberg, Lubo Vassilev, Lars Damstrup, Klaus Urbahns, Andree Blaukat. Highly potent and selective DNA-PK inhibitor M3814 with sustainable anti-tumor activity in combination with radiotherapy [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 4198. doi:10.1158/1538-7445.AM2017-4198
Abstract 4302: Disulfiram possesses antitumor activity and inhibits cancer stem-like properties via inhibition of STAT3 activation in triple-negative breast cancer cells
Authors: Kim Yoon-Jae , Lee Nahyun , Oh Eunhye , Sung Daeil , Cho Tae-Min , Kim Ji Young , Seo Jae Hong 
Published: July 2017

Abstract
Disulfiram (DSF), a clinically used treatment for alcohol dependence, is considered as a potential anti-cancer agent due to its cytotoxicity in many cancer cell types on copper (Cu)-dependent processes. However, the molecular mechanisms underlying DSF-induced antitumor activity in triple-negative breast cancer (TNBC) are still poorly understood. Here, we hypothesized that DSF induces antitumor effects by targeting cancer stem cells (CSCs) and STAT3 signaling in TNBC. We then examined the effects of DSF in combination with Cu on the cell viability and apoptosis, cell proliferation and survival, as well as CSC-like properties in MDA-MB-231 and 4T1 TNBC cell lines. DSF/Cu effectively induced cytotoxicity and apoptotic cell death, concomitant with caspase-3 activation and PARP cleavage. DSF/Cu also significantly suppressed cell migration and mammosphere formation, which are accompanied by a remarkable decrease in the CD44+/CD24- (or CD49f+/CD24+ in mouse 4T1 cells) stem-like population and ALDH1 activity. These effects were functionally associated with the inhibition of STAT3 phosphorylation (Tyr705). Furthermore, DSF/Cu treatment resulted in the downregulation of cyclin D1 and survivin expression, which are downstream targets of STAT3 signaling. Interestingly, phosphorylated STAT3 and STAT3 downstream signaling were highly upregulated in the mammospheres, and these upregulated molecules were significantly decreased by DSF/Cu treatment. In MDA-MB-231-derived xenograft model, DSF administration elicited a significant reduction in tumor growth with a noticeable downregulation of CD44, ALDH1 and phosphorylated STAT3 levels. Taken together, our results suggest that therapeutic treatment to DSF can effectively manifest antitumor activity by reducing CSC-like properties, and that STAT3 could be a key molecule of aggressive TNBC that is targeted by DSF.
Note: This abstract was not presented at the meeting.
Citation Format: Yoon-Jae Kim, Nahyun Lee, Eunhye Oh, Daeil Sung, Tae-Min Cho, Ji Young Kim, Jae Hong Seo. Disulfiram possesses antitumor activity and inhibits cancer stem-like properties via inhibition of STAT3 activation in triple-negative breast cancer 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 4302. doi:10.1158/1538-7445.AM2017-4302
Abstract 4362: Coordinated regulation of several microRNAs in lung cancer patients
Authors: Ferrer Irene , Salinas Ana , Marrugal Angela , Zugazagoitia Jon , Carnero Amancio , Paz-Ares Luis , Molina-Pinelo Sonia 
Published: July 2017

Abstract
Background Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. NSCLCs are mainly classified adenocarcinoma and squamous cell carcinoma. It seems more and more obvious that specific molecular analyses are necessary to elucidate the complexity of clinically relevant phenotypes which determine the lung carcinogenesis. This includes the role of microRNAs (miRNAs) in the disease, involved in the complexity of gene expression regulation. Different modulator mechanisms are involved in the biogenesis and function of miRNAs, one of them is DNA methylation. Alterations in these mechanisms may contribute to the tumor genesis and progression. The purpose of this study was to assess miRNA methylation patterns in patients with NSCLC to study the potential of coordinate regulation of miRNAs as a relevant mechanism involved in this pathogenesis.
Materials and Methods DNA methylation of gene clusters was analyzed by Illumina 70 subjects. The samples were divided into two cohorts. A first cohort constituted from 47 patients who had undergone surgical resection for clinical early stage NSCLC. A second group from 23 subjects was used as health cohort. DNA was extracted using the QIAamp DNA Mini Kit. For each assay, 500 ng of DNA was treated with sodium bisulfate using EZ DNA Methylation™ Kit and cleaned with ZR-96 DNA Clean-up Kit™, before standard Illumina amplification, hybridization, and imaging steps. Methylation data were processed using the RnBeads R package.
Results We identified two clusters clearly corregulated by methylation in lung cancer, involving 49 miRNAs differentially hypomethylated in tumor samples respect to control tissue. Some of these miRNAs have been implicated in several pathways in cancer.
Conclusions Our results strongly imply hypomethylation of two miRNA clusters, which represent key targets in unravelling of the mechanism of lung tumorigenesis.
Citation Format: Irene Ferrer, Ana Salinas, Angela Marrugal, Jon Zugazagoitia, Amancio Carnero, Luis Paz-Ares, Sonia Molina-Pinelo. Coordinated regulation of several microRNAs in lung cancer patients [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 4362. doi:10.1158/1538-7445.AM2017-4362