bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 29: Addition of Galunisertib to DC101 increased angiogenesis inhibition and tumor growth control in hepatocellular carcinoma (HCC)
Authors: Tijeras-Raballand Annemilai , Hobeika Christian , Payen Elise , Martinet Matthieu , Bonnin Philippe , Benhadji Karim A. , Eveno Clarisse , Pocard Marc , Faivre Sandrine , Raymond Eric , Gramont Armand de 
Published: July 2017

Abstract
Introduction: Galunisertib is a selective ATP-mimetic TGF-β receptor (TGFβR)-I inhibitor and DC101 is a rat antagonist antibody to mouse VEGFR-2 and is used to model VEGFR-2 blockade in murine tumor models. Ramucirumab and galunisertib being independently under clinical investigation in HCC patients, our study aimed at exploring the anti-tumoral potency of a combination of galunisertib and DC101 in an in vivo transgenic model of HCC.
Methods: Transgenic mice developing stage-defined HCC were treated for 8 weeks (W) from W8 to W16 with either vehicle, DC101 (40mg/kg, twice weekly, IP), galunisertib (100mg/kg, daily, oral gavage) or DC101 plus galunisertib. Tumor growth was evaluated by ultrasound (liver size) and by the number of macronodules at sacrifice. Angiogenesis was evaluated by doppler (blood flow in the coeliac trunk) and by CD31 staining.
Results: Liver size and the number of liver tumor macronodules were significantly lower in all treatment arms compared to placebo control at both the W12 intermediary sacrifice and W16 final sacrifice; the combination of galunisertib and DC101 showing increased tumor control at W16 (4,43±0,55 mean liver volume (in mm3) in the combination arm vs 5,22±0,86, 5,68±0,78, 7,09±1,54 in the DC101, galunisertib and placebo arms respectively). Angiogenesis assessed by measuring the mean blood flow in the coeliac trunk (TCm), decreased in all treatment arms compared to placebo. At W16, galunisetib potentiated the effect of DC101 with a TCm decrease of 66% compared to 59% and 10% in the DC101 and galunisertib, respectively. These results will be confirmed by the assessment of micronodules number on HPS section for tumor growth and CD31 staining for angiogenesis analysis (number of vessels and the vessel lumen area). The effects of the combination versus monotherapies will be evaluated on the immune landscape.
Conclusion: The combination of galunisertib and DC101 showed promising anti-tumor activities that were associated with decreased angiogenesis.
Citation Format: Annemilai Tijeras-Raballand, Christian Hobeika, Elise Payen, Matthieu Martinet, Philippe Bonnin, Karim A. Benhadji, Clarisse Eveno, Marc Pocard, Sandrine Faivre, Eric Raymond, Armand de Gramont. Addition of Galunisertib to DC101 increased angiogenesis inhibition and tumor growth control in hepatocellular carcinoma (HCC) [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 29. doi:10.1158/1538-7445.AM2017-29
Abstract 2913: Emergence of RAS or EGFR mutant clones affects duration of response to EGFR blockade in colorectal cancers
Authors: Arena Sabrina , Emburgh Beth Van , Siravegna Giulia , Lazzari Luca , Crisafulli Giovanni , Corti Giorgio , Mussolin Benedetta , Baldi Federica , Buscarino Michela , Bartolini Alice , Valtorta Emanuele , Vidal Joana , Bellosillo Beatriz , Germano Giovanni , Pietrantonio Filippo , Ponzetti Agostino , Albanell Joan , Siena Salvatore , Sartore-Bianchi Andrea , Nicolantonio Federica Di , Montagut Clara , Bardelli Alberto 
Published: July 2017

Abstract
Cetuximab and panitumumab are monoclonal anti-EGFR antibodies (moAbs) currently used for the treatment of advanced RAS wild type colorectal cancers (CRC). Emergence of acquired resistance invariably limits the efficacy of these agents, and the dynamics of clonal evolution during anti-EGFR blockade are poorly understood. At progression, RAS mutations represent the most common genetic alterations, while EGFR extracellular domain (ECD) mutations are acquired by a smaller cohort of patients. We found that the mutation profile correlates with the clinical outcome of patients; in particular those who develop RAS mutations upon EGFR blockade achieve reduced tumor shrinkage and shorter duration of response respect to patients in which EGFR ECD mutations emerge during therapy. We investigated in preclinical models the potential role of RAS and EGFR ECD mutations during the emergence of acquired resistance, by tracking the evolution of clones in a genetically barcoded population of CRC cells chronically treated with cetuximab. We observed that therapeutic (target therapy, chemotherapy) and environmental (reduced nutrient condition) pressures differentially shape the clonal composition of CRC cell populations, leading to the emergence of clones with the highest fitness in presence of the external pressure. In conclusion, a multistep clonal evolution process characterizes the development of drug resistance and is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies.
Citation Format: Sabrina Arena, Beth Van Emburgh, Giulia Siravegna, Luca Lazzari, Giovanni Crisafulli, Giorgio Corti, Benedetta Mussolin, Federica Baldi, Michela Buscarino, Alice Bartolini, Emanuele Valtorta, Joana Vidal, Beatriz Bellosillo, Giovanni Germano, Filippo Pietrantonio, Agostino Ponzetti, Joan Albanell, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Clara Montagut, Alberto Bardelli. Emergence of RAS or EGFR mutant clones affects duration of response to EGFR blockade in colorectal cancers [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 2913. doi:10.1158/1538-7445.AM2017-2913
Abstract 2921: Integrated exome- and single cell RNA-sequencing reveals a clone's genomic instability and multifaceted fitness
Authors: Andor Noemi , Maley Carlo C. , Ji Hanlee P. 
Published: July 2017

Abstract
DNA-damage therapy is the main line of defense against most cancers, especially at advanced stages of progression. DNA-damage therapy damages the cell’s DNA. We have identified that a cell’s cumulative extent of DNA damage - even when successfully repaired - is an indicator for future tolerance to new insults. This finding points to a quantitative measure of genomic instability as biomarker of sensitivity to DNA-damaging agents. However, quantifying genomic instability is difficult, especially because each individual tumor harbors clones with their own distinct genomic characteristics. Here we address the challenge of quantifying the complex phenotype of genomic instability across the clonal subpopulations that coexist within an individual tumor.
We identified coexisting clones from bulk-exome sequencing and calculated the copy number profile of each clone’s genome. We integrated mutations detected in both, single-cell RNA-sequencing (scRNA-seq) and exome sequencing, to assign single cells to clones. Because cells in G2/M phase of the cell cycle (further referred to as G2/M clones) have twice the ploidy compared to cells in other cell cycle phases, their presence represents an opportunity for validation. Using 15 gastric cancer cell lines - each sorted by cell cycle phase - we validated: i) clone-specific copy number and ii) assignment of single cells to clones. Here, the predicted size of G2/M clones is an indicator of how correct we quantify clone-specific copy number. The degree to which expression of cell cycle genes is exclusive to G2/M clones is an indicator as to how correct we assign single cells to clones. In addition to the dominant quiescent clone and the G2/M clone, we identified other discrete subclones in a subset of cell lines, suggesting that genetic intra-tumor heterogeneity is sometimes maintained in-vitro. This approach identified clone-specific markers that can be used for cytometry separation of cells of specific clonal subpopulations.
Overall, we demonstrate the power of combining exome sequencing and scRNA-seq to reveal how many clones are present in a tumor sample, how genomically unstable each clone is and how fit is each clone. When combined, these two techniques synergize into a powerful strategy to investigate the relationship between genomic instability, clone fitness and DNA-damage sensitivity.
Citation Format: Noemi Andor, Carlo C. Maley, Hanlee P. Ji. Integrated exome- and single cell RNA-sequencing reveals a clone's genomic instability and multifaceted fitness [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 2921. doi:10.1158/1538-7445.AM2017-2921
Abstract 2924: Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer
Authors: Thierry Alain R. , Pastor Brice , Jiang Zhi-Qin Camilla , Katsiampoura anastasia , Parseghian Christine , Loree Jonathan , Overman Michael J. , Sanchez Cynthia , Messaoudi Safia El , Ychou Marc , Kopetz Scott 
Published: July 2017

Abstract
Malignant tumors shed cell free DNA into the blood stream. Analyzing this new biological source may have important implications in a shift towards personalized medicine for diagnosing and/or monitoring malignancies. We recently showed the first clinical validation and clinical utility of circulating DNA (cfDNA) analysis in oncology by testing RAS/BRAF hotspot mutations in plasma from metastatic colorectal cancer patients (mCRC) (Nat Med. 2014 Apr;20(4):430-5). In addition, liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. We evaluated under blinded conditions the ability of cfDNA to detect RAS/BRAF mutations in the plasma of 42 mCRC patients treated on a phase Ib/II trial of FOLFOX and dasatnib, with or without cetuximab. Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%). Our cfDNA assay was able to detect mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41/42 patients (98%) had a cfDNA detected RAS/BRAF mutation. Of 22 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (50%) developed a second mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild type tumors at baseline, 4/5 (80%) developed new mutations. Patients may harbor mutations at very low frequency down to 0.01% before initiation or during treatment revealing the need of a high sensitive technique to detect mutant subclones. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation. Combined qualitative and quantitative cfDNA analysis allows tracking acquired resistance by studying the real-time clonal evolution of the tumor and might help physicians to adjust patient treatment. Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway, demonstrating a convergent evolutionary pattern.
Note: This abstract was not presented at the meeting.
Citation Format: Alain R. Thierry, Brice Pastor, Zhi-Qin Camilla Jiang, anastasia Katsiampoura, Christine Parseghian, Jonathan Loree, Michael J. Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou, Scott Kopetz. Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal 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 2924. doi:10.1158/1538-7445.AM2017-2924
Abstract 2933: Involvement of CXCL12-CXCR7 axis in adipocyte-induced TNBC metastasis
Authors: Choi Hyeongjwa , Ignacio Rosa Mistica C. , Gibbs Carla R. , Lee Eunsook , Adunyah Samuel E. , Son Deok-Soo 
Published: July 2017

Abstract
Breast cancer (BC) is the most frequent tumor in women worldwide. Although its mortality has significantly decreased owing to advanced therapies, triple negative breast cancer (TNBC) is still difficult to treat because of lack of estrogen receptor, progesterone receptor and HER-2. TNBC accounts for 12-24% of total BC and contributes to the aggressiveness and poorer outcomes. The risk of BC increases significantly in obese women. Obesity is also associated with the worse clinical prognosis of BC. But the underlying mechanisms between obesity and BC, particularly TNBC, remain unclear. Therefore, we compare the molecular mechanisms by which human adipocyte conditioned media (CM) affect TNBC cells (BT549) and non-TNBC cells (MCF7A). Adipocyte CM had no effect on the proliferation of both TNBC and non-TNBC cells. However, adipocyte CM enhanced significantly migration in TNBC cells compared to non-TNBC cells. Next, we examined the signaling pathway by which adipocyte CM promote migration of TNBC cell. AKT and ERK were activated in both TNBC cells and non-TNBC cells. However, phospho-STAT3 was significantly increased in TNBC cells. Also, N-cadherin, a marker for epithelial to mesenchymal transition (EMT), was increased at the late time point in TNBC cells. Furthermore, CXCR7 was specifically increased in TNBC cells after treatment with adipocyte CM using a PCR array. CXCR7 is chemoattractive to CXCL12 which is highly expressed in the lung, the bone marrow, and the liver, common sites of BC metastasis. Taken together, the results indicate that adipocyte CM may promote metastasis of TNBC cells through the CXCL12-CXCR7 axis by activating STAT3.
Citation Format: Hyeongjwa Choi, Rosa Mistica C. Ignacio, Carla R. Gibbs, Eunsook Lee, Samuel E. Adunyah, Deok-Soo Son. Involvement of CXCL12-CXCR7 axis in adipocyte-induced TNBC metastasis [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 2933. doi:10.1158/1538-7445.AM2017-2933
Abstract 2943: MYC functions as a master switch for natural killer cell-mediated immune surveillance of lymphoid malignancies
Authors: Swaminathan Srividya , Mosley Adriane , Horton Crista , Liefwalker Daniel F. , Deutzmann Anja , Dhanasekaran Renumathy , Gouw Arvin , Gentles Andrew , Eilers Martin , Maecker Holden T. , Felsher Dean W. 
Published: July 2017

Abstract
The MYC oncogene drives the pathogenesis of many hematopoietic malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). These malignancies are often “oncogene-addicted” to MYC. Using mass cytometry (CyTOF), we demonstrate that MYC-addicted T-ALL excludes specific immune subsets from the tumor microenvironment implicated in immune surveillance, including natural killer (NK) cells. MYC inhibition clears malignant lymphocytes from the spleen and restores the normal splenic NK composition. Concordantly, peripheral blood of T-ALL patients have reduced percentages of activated NK cells as compared to healthy individuals. We show that MYC excludes activated NK cells from sites of lymphomagenesis by suppressing ERK1/2-STAT1/2-Type I IFN signaling, in both murine and human lymphomas. Furthermore, MYC-associated BL patients with higher than median expression of STAT1/2, and cytotoxic NK cell genes, PRF1 and Granzymes, have favorable clinical outcomes. Hence, oncogenic MYC appears to causally and reversibly suppress NK-mediated immune surveillance during lymphomagenesis.
Citation Format: Srividya Swaminathan, Adriane Mosley, Crista Horton, Daniel F. Liefwalker, Anja Deutzmann, Renumathy Dhanasekaran, Arvin Gouw, Andrew Gentles, Martin Eilers, Holden T. Maecker, Dean W. Felsher. MYC functions as a master switch for natural killer cell-mediated immune surveillance of lymphoid malignancies [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 2943. doi:10.1158/1538-7445.AM2017-2943
Abstract 2944: miR-130a and -145 reprogram myeloid derived suppressor cells and enhance anti-tumor immunity
Authors: Ishii Hiroki , Vodnala Suman K. , Achyut Bhagelu R. , Hollander Christine M. , Lal Ashish , Yang Li 
Published: July 2017

Abstract
Myeloid derived suppressor cells (MDSCs) are increased in tumor bearing condition, and elicit immunosuppression via type 2 polarization. We have previously reported that TGF-β signaling in MDSCs is essential for tumor metastasis. TGFβR2, a receptor essential for TGF-β signaling, is elevated in MDSCs. Deletion of Tgfbr2 in MDSCs, the gene encoding TGFβR2, significantly decreased tumor metastasis. However, it is unclear how TGFβR2 is regulated in MDSCs. We identify microRNA-130a and -145, which directly target Tgfbr2 in MDSCs and inhibit the expression of TGF-β receptor II (TβRII). Both miRs levels were lower in MDSCs from advanced tumor bearing mice correlating to increased TβRII level. Overexpression of miR-130a or -145 in MDSCs shift their immunological phenotype from type 2 to type 1 polarization. Moreover, tumor metastasis was significantly suppressed in myeloid specific miR-130 transgenic mice. In pre-clinical mouse models, the number of lung metastasis was significantly decreased when mice were treated with combination therapy of miR-130a or -145 with paclitaxel when compared with miR-130a, -145, or paclitaxel alone. We proposed that reprogramming of MDSCs by miR-130a and -145 could be a novel strategy in therapeutic treatment for breast cancer metastasis.
Citation Format: Hiroki Ishii, Suman K. Vodnala, Bhagelu R. Achyut, Christine M. Hollander, Ashish Lal, Li Yang. miR-130a and -145 reprogram myeloid derived suppressor cells and enhance anti-tumor immunity [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 2944. doi:10.1158/1538-7445.AM2017-2944
Abstract 2948: A distinct CD8+ tumor infiltrating lymphocyte subset is associated with high TIL density, enhanced cytotoxicity and improved survival in patients with lung cancer
Authors: Ganesan Anusha Preethi , Wood Oliver , Garrido-Martin Eva , Chee Serena , Mellows Toby , Clarke James , Samaniego-Castruita Daniela , Singh Divya , Seumois Gregory , Altezani Aiman , Woo Edwin , Friedman Peter , Thomas Gareth , King Emma , Sanchez-Elsner Tilman , Vijayanand Pandurangan , Ottensmeier Christian H. 
Published: July 2017

Abstract
High tumor infiltrating lymphocyte (TIL) density predicts for good prognosis in several cancers and therapies that boost the anti-tumor responses of cytotoxic lymphocytes (CTLs) have shown promise in the clinic. However, clinical responses to currently available immunotherapeutic agents vary considerably, the molecular basis of which is unclear. We performed global transcriptional profiling of CTLs in tumors and adjacent non-tumor tissue from 36 patients with early stage lung cancer to define the molecular features associated with robustness and heterogeneity of anti-tumor immune responses. We observed major differences in the transcriptional program of tumor-infiltrating CTLs (CD8+ TILs) that is shared across tumor subtypes. Pathway analysis revealed enrichment of genes in cell cycle, TCR activation and co-stimulation pathways, indicating tumor-driven expansion of presumed tumor antigen-specific CTLs. We also observed marked heterogeneity in the expression of molecules associated with TCR activation and immune checkpoints, and their expression was positively correlated with the density of tumor-infiltrating CTLs. Interestingly, TILhigh tumors were also enriched for a distinct CD8+ tumor infiltrating lymphocyte subset that appeared to have enhanced cytotoxicity and independently predicted improved survival in patients with lung cancer. In summary, we define the molecular fingerprint of tumor-infiltrating CTLs and identify a number of novel targets that may be important in modulating the magnitude and specificity of anti-tumor immune responses in lung cancer.
Citation Format: Anusha Preethi Ganesan, Oliver Wood, Eva Garrido-Martin, Serena Chee, Toby Mellows, James Clarke, Daniela Samaniego-Castruita, Divya Singh, Gregory Seumois, Aiman Altezani, Edwin Woo, Peter Friedman, Gareth Thomas, Emma King, Tilman Sanchez-Elsner, Pandurangan Vijayanand, Christian H. Ottensmeier. A distinct CD8+ tumor infiltrating lymphocyte subset is associated with high TIL density, enhanced cytotoxicity and improved survival in patients with 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 2948. doi:10.1158/1538-7445.AM2017-2948
Abstract 2968: Examining the role of breast cancer Neuregulin1 and macrophage ErbB3 in intravasation
Authors: Cabrera Ramon , Chiang Serena , Segall Jeffrey 
Published: July 2017

Abstract
The purpose of our studies is to investigate the role of Neuregulin1 (NRG1) and ErbB3 signaling between breast cancer cells and macrophages in facilitating tumor cell intravasation. The interaction of breast cancer cells with other cell types within the tumor microenvironment plays an important role in metastasis. These interactions are thought to influence tumor cell invasion and intravasation, two important steps in the process of metastasis. Our studies are specifically interested in examining the signaling occurring between tumor cells and macrophages. Previous studies have established the presence of paracrine signaling between breast cancer cells and macrophages, where colony stimulating factor 1 (CSF-1) produced by the tumor cells stimulates the production of epidermal growth factor (EGF) by macrophages, leading to chemotactic invasion of the tumor cells. In addition to this paracrine loop signaling between tumor cells and macrophages, it has been seen that macrophage expression of ErbB3, a member of the EGFR family of receptor tyrosine kinases, may play a role in facilitating tumor cell invasion. In order to examine the effects of signaling between tumor cells and macrophages in intravasation, we utilize an in vitro transendothelial migration (iTEM) assay. This assay uses transwells coated with matrigel and endothelial cells in order to mimic the entry of tumor cells into blood vessels. We show that using an ErbB3 blocking antibody results in a significant reduction of macrophage-induced transendothelial migration of breast cancer cells. Additionally, reduction of expression of the ErbB3 receptor ligand Neuregulin1 in tumor cells yields a similar result. Stimulation of macrophages with NRG1 leads to increased expression of Jagged1 (JAG1), a ligand of the Notch receptor. Activation of the Notch receptor pathway has been shown to be involved in tumor cell invasion. Overall our studies look to further examine the interaction between tumor cells and macrophages, and these observations indicate that ErbB3, NRG1, and JAG1 could all serve as novel targets in metastasis and the tumor microenvironment.
Citation Format: Ramon Cabrera, Serena Chiang, Jeffrey Segall. Examining the role of breast cancer Neuregulin1 and macrophage ErbB3 in intravasation [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 2968. doi:10.1158/1538-7445.AM2017-2968