bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A146: Stromal neuregulin-1 modulates the response to MEK inhibitors in WT BRAF/WT NRAS (WT/WT) melanomas
Authors: Capparelli Claudia , Purwin Timothy J. , Heilman Shea , Chervoneva Inna , Davies Michael A. , Gershenwald Jeffrey  E. , Aplin Andrew E. 
Published: August 2018

Abstract
MEK-ERK1/2 signaling is elevated in the majority of melanomas. While MEK inhibitors (MEKi) are FDA-approved for mutant BRAF melanoma, and have some activity against NRAS mutant tumors, they have shown little activity in patients with melanomas that are wild type for BRAF and NRAS (WT/WT). Since the tumor microenvironment (TME) often regulates drug resistance, we tested the effects of growth factors on WT/WT melanoma growth in the presence of MEKi. Neuregulin-1 (NRG1) protected patient-derived WT/WT human melanoma cell lines from growth inhibition mediated by trametinib (MEKi). Phospho-proteomic analysis and clinical grade neutralizing antibodies implicated adaptive activation of ErbB3/ErbB2 complexes in the protective effects of NRG1. NRG1 was detected in fibroblasts and cancer-associated fibroblasts (CAF), and CAF-conditioned medium activated ErbB3/ErbB2 signaling in MEK inhibited WT/WT melanoma cells. ErbB3 and ErbB2 neutralizing antibodies blocked the protective effects of fibroblast- and CAF-derived NRG1 in vitro and cooperated with MEKi to delay xenograft growth in vivo. Together our results provide a rationale for the treatment of WT/WT melanomas with the combination of MEKi and anti-ErbB3/ErbB2 antibodies.
Citation Format: Claudia Capparelli, Timothy J. Purwin, Shea Heilman, Inna Chervoneva, Michael A. Davies, Jeffrey E. Gershenwald, Andrew E. Aplin. Stromal neuregulin-1 modulates the response to MEK inhibitors in WT BRAF/WT NRAS (WT/WT) melanomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A146.
Abstract A180: The histone methyltransferase SETDB1 contributes to melanoma tumorigenesis
Authors: Orouji Elias , Federico Aniello , Larribere Lionel , Novak Daniel , Utikal Jochen 
Published: August 2018

Abstract
Histone modifications play a significant role in the development and progression of various cancers. The histone methyltransferase SETDB1 (SET domain, bifurcated 1) catalyzes the addition of methyl groups to histone H3 at lysine 9 (H3K9). In the present study, we demonstrate that SETDB1 contributes to melanoma tumorigenesis. We show SETDB1 to be highly amplified in melanoma tissues of patients with poor prognosis. The amplification of SETDB1 correlates with the increased expression of the protein.
Functional studies show an increased SETDB1 expression to be associated with a more proliferative, invasive and migratory phenotype and give rise to larger tumor masses in xenograft mouse models. In human primary melanomas, SETDB1 expression is elevated at the invasive borders. The activity of SETDB1 can be blocked by small molecules, which leads to reduced cell growth even in melanoma cell lines that are resistant towards BRAF and MEK inhibitors.
In conclusion, our findings support SETDB1 as a major driver of melanoma development and progression. We therefore suggest SETB1 as a potential future target for the treatment of melanoma.
Citation Format: Elias Orouji, Aniello Federico, Lionel Larribere, Daniel Novak, Jochen Utikal. The histone methyltransferase SETDB1 contributes to melanoma tumorigenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A180.
Abstract 1009: Reciprocal roles of cancer associated fibroblasts and CD4+ T cells in ovarian cancer progression
Authors: Hu Ye , Orsulic Sandra 
Published: August 2018

Abstract
Recent evidence suggests that the efficacy of tumor immunotherapy is reliant on the signals received from the tumor microenvironment. The two prevalent cell types in the tumor microenvironment are immune cells and cancer-associated fibroblasts (CAFs). The presence of CAFs has been associated with poor survival in multiple cancer types and CAF-targeting in several experimental mouse cancer models has been shown to improve tumoral immune response and therapeutic efficacy.
By conducting immunohistochemistry in 42 patient-matched primary, metastatic, and recurrent ovarian tumors, We have shown that both CAF activation and CD4+ T cell infiltration increase during cancer progression. Upon co-culturing human CAFs with CD4+ T cells, We found that CAFs physically attract CD4+ T cells. In turn, CD4+ T cells activate CAFs, as indicated by the increased ability of CAFs to contract extracellular matrix. Further experiments showed more immune suppressive T cell subtypes (Th2 and Treg cells), when co-culture activated human CAFs with CD4+ Naive T cells.
A recent analysis of chemokines has shown that their expression is highly variable in primary ovarian tumors. Differential expression of chemokines in different areas of the tumor may result in a skewed distribution of immune cell types. We searched for genes that belong to the KEEG pathway ‘cytokine-cytokine receptor interaction' that are differentially expressed in the mesenchymal and mesenchymal subtype-equivalent C1 subtypes compared to all other subtypes in the TGCA and GEO datasets. Our comparison of the top 50 differentially expressed cytokine-cytokine receptor interaction genes in the mesenchymal and C1 subtypes revealed high gene signature conservation, with 32 of 50 genes being shared, including CXCL12, CXCL14, CCL11, CCL26 and KDR. Flow cytometry results showed over-expression of some cytokines in CAFs could foster CAFs into more active state, which created an immune suppressive environment by turning more T cells to Th2 and Treg subtypes.
In summary, ovarian CAFs may have great impact on immune cells proliferation and differentiation, thus influence tumor progression.
Citation Format: Ye Hu, Sandra Orsulic. Reciprocal roles of cancer associated fibroblasts and CD4+ T cells in ovarian cancer progression [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 1009.
Abstract 1014: Pharmacological modulation of PDAC stroma to enhance checkpoint blockade immunotherapy
Authors: Zhao Jun , Xiao Zhilan , Overwijk Willem , Li Chun 
Published: August 2018

Abstract
Sonic hedgehog signaling pathway is an important regulator during the initiation and progression of pancreatic cancer, and sustained activation of this pathway contributes to excessive deposition of tumor stroma and maintenance of tumor-initiating cells. Cyclopamine (CPA) is a potent inhibitor of the SHH pathway. In this work, we encapsulated both paclitaxel (PTX) and CPA in a long-circulating polymeric micelles to obtain M-CPA/PTX. In a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) (KPC model), systemic administration of M-CPA/PTX significantly prolonged the median survival of mice with well-established tumors from 23 days with nab-paclitaxel or gemcitabine to 58 days post-enrollment (p&lt;0.0001). Further studies indicated that M-CPA/PTX modulated PDAC stroma by softening extracellular matrix, increasing blood perfusion, and alleviating hypoxia without depletion of α-smooth muscle actin-positive tumor-associated fibroblasts. Significantly, combination of M-CPA/PTX and anti-PD-1 immunotherapy significantly prolonged the survival of PDAC-bearing KPC mice compare with monotherapies (p&lt;0.01). In an immune-competent, orthotopic PDAC model bearing established murine PDAC, treatments with combined M-CPA/PTX and anti-PD-1 enhanced tumor infiltration of CD8+ T cells and IFNγ expression. Neutralization of either CD8 T cells or INFγ nullified the therapeutic gain achieved with combination therapy. Thus, M-CPA/PTX enhanced checkpoint blockade immunotherapy through modulation of PDAC stroma and enhanced tumor infiltration of effector immune cells.
Citation Format: Jun Zhao, Zhilan Xiao, Willem Overwijk, Chun Li. Pharmacological modulation of PDAC stroma to enhance checkpoint blockade immunotherapy [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 1014.
Abstract 1021: Clinical significance of tertiary lymphoid structures (TLS) and tumor-infiltrating plasma cells in ovarian cancer
Authors: Ukita Masayo , Hamanishi Junzo , Baba Tsukasa , Murakami Ryusuke , Abiko Kaoru , Mandai Masaki 
Published: August 2018

Abstract
Objective: Tertiary lymphoid structures (TLS) are transient ectopic lymphoid aggregates that reflect lymphoid neogenesis mainly through CXCL13 and develop under chronic inflammation. Recently TLS have been detected in several types of cancers; however, there are few reports about TLS in ovarian cancer. We investigated the clinical significance of TLS in ovarian cancer.
Methods: 28 patients who were diagnosed with high-grade serous ovarian cancer and treated surgically in our hospital were selected from microarray dataset (KOV-75; GSE39204/55512). We evaluated TLS, tumor-infiltrating lymphocyte (TIL) subsets (CD4+ T cell, CD8+ T cell, CD20+ B cell, CD38+ plasma cell), and the correlation between expression of CXCL13 and TIL subsets by immunohistochemical staining. We analyzed the correlation between gene expression of CXCL13 and the survival time of the patients (pts) by using KOV-75 and the cancer genome atlas (TCGA) datasets.
Results: Immunohistochemical staining revealed that TLS were detected in 64% (18 pts) of ovarian cancer patients, and the numbers of tumor-infiltrating CD8+ T cells, CD20+ B cells and CD38+ plasma cells were significantly higher in cases with TLS (p&lt;0.05). The numbers of tumor-infiltrating CD4+ T cells, CD8+ T cells, CD20+ B cells and CD38+ plasma cells were significantly higher in the CXCL13-high tumor than in the CXCL13-low tumor (p&lt;0.001). In the group with high intratumoral infiltration of CD8 T cells and plasma cells, progression-free survival and overall survival were both significantly extended (p&lt;0.05, respectively). In microarray analyses of KOV-75 and TCGA, high CXCL13 gene expression correlated significantly with both favorable progression-free survival and overall survival (p&lt;0.05, respectively).
Conclusion: CXCL13 contributes to better prognosis in ovarian cancer patients by inducing TLS and various subsets of TIL. Induction of CXCL13 might be a new therapeutic target for ovarian cancer patients.
Citation Format: Masayo Ukita, Junzo Hamanishi, Tsukasa Baba, Ryusuke Murakami, Kaoru Abiko, Masaki Mandai. Clinical significance of tertiary lymphoid structures (TLS) and tumor-infiltrating plasma cells in ovarian 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 1021.
Abstract 1027: Regulatory T-cell genes drive altered immune microenvironment in adult solid cancers and allow for immune contextual patient subtyping
Authors: Brouwer Jurriaan , Cheng Wei-Yi , Bauer-Mehren Anna , Maisel Daniela , Lechner Katharina , Andersson Emilia , Dudley Joel T. , Milletti Francesca 
Published: August 2018

Abstract
The tumor microenvironment is an important factor in cancer immunotherapy response. To further understand how a tumor affects the local immune system, we analyzed immune gene expression differences between matching normal and tumor tissues. We analyzed previously published and new gene expression data from solid cancers and isolated immune cell populations. We also determined the correlation between CD8, FoxP3 immunohistochemistry (IHC) and immune-related genes. Across solid TCGA cancers, we observed that regulatory T-cells (Tregs) were one of the main drivers of immune gene expression differences between normal and tumor tissues. A tumor-specific CD8 signature had slightly lower scores in tumor tissues compared to normal of most (12 of 16) cancers, while a Treg signature score was higher in tumor tissues of all cancers except liver. We clustered TCGA colorectal samples (626 patients) and a new separate testing data set (60 patients) into two groups according to Treg gene signature expression. The High Treg cluster had more colorectal tumors that were Consensus Molecular Subtype 1/4, right-sided and microsatellite-instable, compared to the Low Treg cluster. Finally, we determined the correlation between CD8, FoxP3 immunohistochemistry (IHC) and our gene signatures and found that in this small data set correlation between signature and IHC overall was low, but samples in the High Treg cluster had significantly more CD8+ and FoxP3+ cells compared to the Low Treg cluster. We conclude that high Treg signature expression scores correlate with high overall immune gene expression. Using this novel way of classifying patients, more colorectal tumors with high immune activation were identified compared to other colorectal subtyping methods. Further research will reveal if this Treg-based subtyping improves the identification of patients that may benefit from cancer immunotherapy.
Citation Format: Jurriaan Brouwer, Wei-Yi Cheng, Anna Bauer-Mehren, Daniela Maisel, Katharina Lechner, Emilia Andersson, Joel T. Dudley, Francesca Milletti. Regulatory T-cell genes drive altered immune microenvironment in adult solid cancers and allow for immune contextual patient subtyping [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 1027.
Abstract 1040: Patient derived xenografts of hematologic malignancies for translational research
Authors: Siegert Antje , Brzezicha Bernadette , Fuhrmann Stephan , Karawajew Leonid , Janz Martin , Schmitt Clemens , Fichtner Iduna , Hoffmann Jens 
Published: August 2018

Abstract
Acute leukemias and lymphomas represent a very heterogeneous group of hematologic malignancies and pose an important challenge in the clinical routine. They frequently develop resistance to the treatment with standard-of-care (SoC) drugs and have a high incidence of disease recurrence. Recent progress in molecular profiling has helped to identify new potential drivers for the different leukemia and lymphoma subtypes, with some of them being potential therapeutic targets. Further target validation and drug development projects are highly dependent on corresponding preclinical models representing the different clinical subtypes. Therefore, we started to establish and characterize new patient derived xenografts (PDX) of AML, ALL and lymphomas for drug development and translational research.
AML- and ALL-PDX were derived from bone marrow aspirates or peripheral blood samples, from primary or relapsed acute leukemia patients. Purified cells were transplanted either intravenously (i.v.) and/or subcutaneously (s.c.) into immunodeficient mice. Some mice developed a systemic AML, which was monitored by flow cytometric analysis of blood samples. Non-Hodgkin- or Hodgkin lymphoma-PDX were derived from peripheral blood, lymph node extirpations or core needle biopsies, and were usually transplanted subcutaneously into immunodeficient mice.
For further characterization, established PDX models were treated with SoC and investigational drugs. In parallel, gene expression profiles as well as mutations were analyzed within the first in vivo passages.
More than 20 new PDX models from AML, ALL, NHL and HL have been successfully established and characterized. Highly individual response to the treatments were observed, correlation analyses with mutations and gene expression are ongoing.
Our newly and extensively characterized PDX models from hematologic malignancies are suitable tools for preclinical drug development. They provide an exceptional platform for the identification and validation of new targets and allow the preclinical screening of new compounds and combinations for translational research projects.
Citation Format: Antje Siegert, Bernadette Brzezicha, Stephan Fuhrmann, Leonid Karawajew, Martin Janz, Clemens Schmitt, Iduna Fichtner, Jens Hoffmann. Patient derived xenografts of hematologic malignancies for translational research [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 1040.
Abstract 1045: Development of patient derived orthotopic xenografts from metastatic colorectal cancer
Authors: Santos Tiago Goss dos , Roque Bruno , Roque Caroline , Begnani Maria Dirlei , Lima Eduardo , Coimbra Felipe , Chojniak Rubens 
Published: August 2018

Abstract
The occurrence of liver metastasis is the major cause of death in colorectal cancer patients. The treatment consists of surgery and chemotherapy. However, the patient outcome is very unfavorable. Thus, the development of new therapeutic regimens to treat this condition is urgent and demand the establishment of good animal models. Among the models that have being used, the patient-derived xenografts (PDX) have emerged as one of the most promising. PDXs are preclinical models that faithfully represent the individuality of human cancer, by grafting fresh human tumor in severely immunodeficient mice which allows for higher tumor implantation rates and growth. Metastatic disease could be also modeled using orthotopic implantation into the affected organ. The patient-derived orthotopic xenografts (PDOX) can be interrogated for different treatment strategies based on the individualized gene signature of the human tumor, and the results can inform clinically relevant treatment strategies for the patient. With the objective to establish a PDOX from metastatic colorectal tumors in athymic nude mice, we implanted fresh tumor fragments into mouse liver parenchyma and propagated tumors from three patients which could be serially implanted in second and third mice generations. The morphological and immunohistochemical characterization indicate that xenografts recapitulate the tumor architecture and the expression of mismatch repair genes (MLH1, MSH2, MSH1, PMS2). After tumor implantation in first passage, the time of tumor growth decrease from 150-250 days to 30-100 days without loss of tumor identity. The growth of a post-transplantation lymphoproliferative disease (PTLD) was observed in one case. This pilot study was successful to establish the institutional PDX preclinical platform to study new therapeutic strategies, biomarkers of disease progression and treatment responsiveness.
Citation Format: Tiago Goss dos Santos, Bruno Roque, Caroline Roque, Maria Dirlei Begnani, Eduardo Lima, Felipe Coimbra, Rubens Chojniak. Development of patient derived orthotopic xenografts from metastatic colorectal 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 1045.
Abstract 1056: Cancer avatars are sensitive diagnosticians of the pleural space
Authors: Kuzmishin Gwendolyn B. , Gopal Priyanka , Abazeed Mohamed E. 
Published: August 2018

Abstract
The identification of malignant cells in pleural fluid has critical prognostic and therapeutic implications but is frequently a diagnostic challenge. The first step in determining the cause of a suspected malignant pleural effusion, thoracentesis, has an unsatisfying low sensitivity (~60-70%). Patient-derived xenografts (PDX) retain the principal characteristics of the tumor of origin. However, there has been little progress in the application of these models to guide diagnostic and staging strategies. We assessed the feasibility, cellular yield and comparative diagnostic accuracy of pleural-derived xenografts in patients with effusions.
An institutional review board-approved single-institution prospective registry of patients was used to identify patients undergoing diagnostic and/or therapeutic thoracentesis. Cells isolated from the pleural fluid of these patients were injected into NSG mice. A diagnosis of the cancer in the xenograft was confirmed by a staff pathologist with expertise in the correspondent cancer type.
All of the cases that were clinically positive for tumor cells in the pleural space demonstrated tumor engraftment. Samples taken from patients with known benign etiologies did not result in tumor engraftment. The developed xenografts provided ample tissue that can be made available for extensive molecular testing, even in cases where the cytological samples consisted of very few cells. Critically, two of 10 cases resulted in engraftment of the tumor despite no evidence of malignant cells on cytological examination, indicating a 20% improvement in the statistical power of pleural-based xenografting for the detection of malignancy.
Our study indicates that pleural-derived xenografts can enhance the sensitivity of malignant cell detection, reflecting the inherent limitations of cytological analyses of a few malignant cells. Moreover, the amplification of cellular material provides ample source material that can be used to satisfy the increasing demands for tissue-based molecular testing. To our knowledge, this is the first effort to effectively use patient-derived xenografts for the purpose of cancer staging and diagnosis.
Citation Format: Gwendolyn B. Kuzmishin, Priyanka Gopal, Mohamed E. Abazeed. Cancer avatars are sensitive diagnosticians of the pleural space [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 1056.