bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-124: Promoting an anti-tumor immune environment with a novel, exquisitely selective CSF1R inhibitor
Authors: Suzuki Erika , Kovacs Jeffrey J. , Spencer Nakia D. , Sonal Sonal , Feng Ningping , Harris Angela L. , Mullinax Robert A. , Zuniga Andy M. , Johnson Sarah B. , Mahendra Mikhila , Khor Tin Oo , Mseeh Faika , Liu Zhen , Burke Jason P. , Mikule Keith , Tremblay Martin , Heffernan Timothy P. , Jones Philip , Czako Barbara , Marszalek Joseph R. 
Published: August 2018

Abstract
Tumor-associated macrophages (TAMs) are critical drivers of tumor progression and immunosuppression within the tumor microenvironment. The dominant TAM phenotype is broadly characterized as harboring M2-like macrophage properties, which are anti-inflammatory and pro-tumor, as opposed to M1-like macrophages, which possess tumoricidal and pro-inflammatory characteristics. The dependence of M2 TAMs on CSF1 receptor (CSF1R) kinase signaling has made CSF1R a desirable therapeutic target, and the need for highly selective therapies for use in combinations. Through an extensive medicinal chemistry campaign, we identified a series of orally bioavailable, highly potent, exquisitely selective inhibitors of CSF1R (IC50 &lt; 10 nM) with excellent pharmacologic properties that are appropriate for evaluation as a cancer therapy. The aim of our study was to assess the biological impact of our lead CSF1R inhibitor (CSF1Ri) on macrophage populations and the consequent effect on T effector cells. In vitro biochemical activity was evaluated in various kinase assays comparing our CSF1Ri to BLZ945. The compound was evaluated using syngeneic murine models of colorectal cancer (MC38) and pancreatic adenocarcinoma (PANC02). Tumors were immune profiled using NanoString, immunohistochemistry and flow cytometric analysis establishing that there was a depletion of macrophages and a reduction in the relative amount of M2+ (CD206+MHCII-) cells, with a concomitant increase in M1+ (MHCII+CD206-) cells. Myeloid-derived suppressor cells (MDSCs), CD4, and CD8 cell infiltration were also altered with an elevation of cytotoxic immune cells. In conclusion, we have identified and characterized a novel potent and selective inhibitor of CSF1R with highly favorable PK/PD properties, that compares favorably to BLZ945. We also have clear evidence that our novel CSF1R inhibitors modulates TAM infiltration and phenotype altering the immune cell milieu toward a more favorable anti-tumor environment.
Citation Format: Erika Suzuki, Jeffrey J. Kovacs, Nakia D. Spencer, Sonal Sonal, Ningping Feng, Angela L. Harris, Robert A. Mullinax, Andy M. Zuniga, Sarah B. Johnson, Mikhila Mahendra, Tin Oo Khor, Faika Mseeh, Zhen Liu, Jason P. Burke, Keith Mikule, Martin Tremblay, Timothy P. Heffernan, Philip Jones, Barbara Czako, Joseph R. Marszalek. Promoting an anti-tumor immune environment with a novel, exquisitely selective CSF1R inhibitor [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 LB-124.
Abstract LB-125: Atovaquone suppresses triple negative breast tumor growth by inhibiting myeloid derived suppressor cells
Authors: Gupta Nehal , Wright Stephen , Srivastava Sanjay 
Published: August 2018

Abstract
Triple negative breast cancer (TNBC) is considered to be the most aggressive and malignant neoplasm and is highly metastatic in nature. Metastatic TNBC is difficult to treat thus leading to extremely poor survival. The major contributing factor in TNBC progression and resistive nature is its ability to evade the immune surveillance. Modulating the immune system in breast tumors could be an important strategy for cancer therapeutics. The present study evaluates the immune response of atovaquone, an antiprotozoal drug in various TNBC cell lines and its efficacy in three independent in vivo models. In the first experiment, HCC1806 human breast cancer cells were orthotopically implanted in mammary fat of female mice. Oral administration of atovaquone reduced HCC1806 breast tumor growth by 45%. On the other hand, oral administration of atovaquone inhibited the growth of highly aggressive CI66 breast tumors by 70%. Paclitaxel is the first line chemotherapeutic agent for metastatic breast cancer. In third in vivo experiment, 4T1 paclitaxel resistant (4T1R) cells were injected in mice and atovaquone suppressed paclitaxel resistant tumor growth by 42%. Myeloid derived suppressor cells (MDSCs) are known to suppress immune function. Our current results demonstrated 70% and 30% suppression of tumor and blood MDSCs respectively, with atovaquone treatment in mouse bearing HCC1806 tumors. We also observed about 25% reduction in MDSCs with atovaquone treatment in mice with CI66 as well as 4T1R tumors. MDSCs induce regulatory T cells (Treg cells) which are immunosuppressive. Our results showed reduction of Treg cells by 12% and 17% with atovaquone treatment in HCC1806 tumors and in 4T1R tumors respectively. In addition, decrease in TGF-beta (13%) and IL-10 (40%) in HCC1806 tumor lysates was observed by atovaquone, an evidence of reduction in immunosuppressive cytokines produced by MDSCs. It appears that the mechanism of immune suppression of atovaquone by MDSCs in our model may be through TGF-β and IL-10, which are potent immunosuppressive cytokines and induce Treg cells that allow cancer cells to escape from immune surveillance. This is the first report demonstrating that immune modulation by atovaquone treatment is associated with breast tumor growth suppression, prompting further investigation to establish atovaquone as a treatment option for TNBC patients.
Citation Format: Nehal Gupta, Stephen Wright, Sanjay Srivastava. Atovaquone suppresses triple negative breast tumor growth by inhibiting myeloid derived suppressor 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 LB-125.
Abstract LB-139: Panel-based NGS identifies prognostic and actionable genes in childhood acute lymphoblastic leukemia and suits for clinical sequence
Authors: Ishida Hisashi , Iguchi Akihiro , Aoe Michinori , Matsubara Takehiro , Tsukahara Hirokazu , Shimada Akira 
Published: August 2018

Abstract
Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Whereas the cure rate has been much improved, considerable number of patients suffered from leukemia relapse. The cure rates of relapsed ALL patients remained poor as low as 40%, thus ALL is leading cause of cancer death during childhood. To improve the cure rates of these patients, precise re-stratification and newer targeted therapy are needed. For those reasons, detecting genes that had prognostic value and that are potentially actionable for in a short time is desired in clinical settings.
Methods: We perform next generation sequence of matched diagnosis, remission, and relapse samples of eighteen relapsed ALL patients. We use the desktop sequencer MiSeq (Illumina, Inc., San Diego, CA, USA) and HaloPlex custom panels (Agilent Technologies, Santa Clara, CA, USA). These HaloPlex custom panels include more than 150 cancer-related genes. In the same sequencing run, we checked single nucleotide variations (SNV), insertion/deletion, and copy number variations (CNV) simultaneously. We also compare the genetic alterations between diagnosis and relapse samples, and presume the type of clonal evolutions.
Results: We identified total 16 SNV and insertion/deletion and 19 CNV at diagnosis, and 28 SNV and insertion/deletion and 22 CNV at relapse. With these gene alterations, we could re-stratify many patients otherwise without any high-risk features (4/8 B-cell precursor ALL patients, 50%). We could also detect potentially actionable gene variants in most patients (13/17 of all patients, 76.5%). Among them, one patient harbored widely reported germline TP53 R248Q mutation, thus regarded as Li-Fraumeni syndrome. Most relapse samples (9/13 analyzed cases, 69.2%) acquire new lesions and lost some lesions present at diagnosis, suggesting their clonal evolution from ancestral clones. Remaining four cases (4/13 cases, 30.7 %) showed clonal evolution direct from diagnosis clones.
Conclusion: This inexpensive, rapid, sequential next generation sequence method will immediately apply as clinical sequence, and lead to better management of these patients and potential improvement in survival rate in childhood ALL.
Citation Format: Hisashi Ishida, Akihiro Iguchi, Michinori Aoe, Takehiro Matsubara, Hirokazu Tsukahara, Akira Shimada. Panel-based NGS identifies prognostic and actionable genes in childhood acute lymphoblastic leukemia and suits for clinical sequence [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 LB-139.
Abstract LB-144: Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy
Authors: Hong Xin , Sullivan Ryan J. , Kalinich Mark , Kwan Tanya , Pan Shiwei , LiCausi Joseph A. , Milner John D. , Nieman Linda T. , Wittner Ben S. , Ho Uyen , Chen Tianqi , Kapur Ravi , Lawrence Don , Flaherty Keith T. , Sequist Lecia V. , Ramaswamy Sridhar , Miyamoto David T. , Lawrence Michael , Giobbie-Hurder Anita , Toner Mehmet , Isselbacher Kurt J. , Maheswaran Shyamala , Haber Daniel A. 
Published: August 2018

Abstract
A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-L1 expression and mutational burden, are insufficiently precise to guide treatment selection and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma Circulating Tumor Cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC-Score) applied to microfluidically-enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (N=42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC-Score within 7 weeks of therapy correlates with marked improvement in progression-free survival (Hazard Ratio (HR): 0.17, P=0.008) and overall survival (HR: 0.12, P=0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.
Citation Format: Xin Hong, Ryan J. Sullivan, Mark Kalinich, Tanya Kwan, Shiwei Pan, Joseph A. LiCausi, John D. Milner, Linda T. Nieman, Ben S. Wittner, Uyen Ho, Tianqi Chen, Ravi Kapur, Don Lawrence, Keith T. Flaherty, Lecia V. Sequist, Sridhar Ramaswamy, David T. Miyamoto, Michael Lawrence, Anita Giobbie-Hurder, Mehmet Toner, Kurt J. Isselbacher, Shyamala Maheswaran, Daniel A. Haber. Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy [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 LB-144.
Abstract LB-151: Prophylactic TNFα blockade unplugs toxicity and efficacy in immunotherapy anti-PD-1 + anti-CTLA-4 combinations
Authors: PEREZ-RUIZ ELISABETH , MINUTE LUNA , OCHOA MARIA CARMEN , AZPILICUETA ARANTXA , GARASA SARAY , RODRIGUEZ-RUIZ M E , BELSUE VIRGINIA , MOLINA CARMEN , BERRAONDO PEDRO , MELERO IGNACIO 
Published: August 2018

Abstract
The combination of anti-CTLA-4 and anti-PD-1 checkpoint inhibitors ipilimumab and nivolumab (DIT) has improved survival of patients with metastatic melanoma and renal cell carcinoma in exchange for frequent immune-mediated serious side effects (mainly gastrointestinal), leading to treatment cessation in about one third of the patients and the need to reduce doses of these immunotherapy agents when used in combination. Tumor necrosis factor-α (TNF-α) is an important actionable mediator in inflammatory bowel disease (both ulcerative colitis and Crohn's disease) and its blockade with monoclonal antibodies has been recommended to treat steroid-resistant colitis following checkpoint inhibitors. We have studied whether prophylactic TNFα blockade is able to reduce immune toxicity associated with DIT without altering antitumor activity. Experiments were performed in C57BL/6 mice harboring subcutaneous tumors derived from the MC38 and B16OVA cell lines. Acute immune-mediated colitis was induced by exposure to 3% dextran sulfate sodium (DSS) in drinking water for 3 days. For TNFα blockade etanercept (hTNFR2-IgG chimera) or a mouse anti-TNF-α monoclonal antibody were used. Anti-tumor efficacy was tested following individual tumor sizes upon combined treatment with anti-mPD-1 + anti-mCTLA4 mAbs. Severity of DSS colitis was assessed and scored by daily weight, ultrasound evaluation of intestinal wall thickness and histological assessment on day 7. We observed that the antitumoral efficacy of PD-1+CTLA-4 blockade against MC38 of B16OVA established tumors was not reduced with the prophylactic association of TNF-α blockade. Intriguingly, an improvement of antitumor activity was observed in those mice in which DSS colitis was induced. Importantly, in mice suffering DSS-induced colitis that were co-treated with DIT and TNF-α blockade, digestive toxicity ameliorates as shown by body weight, ultrasound examination and histology. Therefore, TNF-α blockade can be prophylactically associated with anti-PD1 + anti-CTLA-4 mAb combination regimens to prevent toxicity without hindrance of anti-tumor efficacy. These results in mouse models warrant a clinical trial testing profilactic etanercept to improve the safety profile of the nivolumab + ipilimumab combination widening its therapeutic window.
Citation Format: ELISABETH PEREZ-RUIZ, LUNA MINUTE, MARIA CARMEN OCHOA, ARANTXA AZPILICUETA, SARAY GARASA, M E RODRIGUEZ-RUIZ, VIRGINIA BELSUE, CARMEN MOLINA, PEDRO BERRAONDO, IGNACIO MELERO. Prophylactic TNFα blockade unplugs toxicity and efficacy in immunotherapy anti-PD-1 + anti-CTLA-4 combinations [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 LB-151.
Abstract LB-153: KY1055, a novel ICOS-PD-L1 bispecific antibody, efficiently enhances T cell activation and delivers a potent anti-tumour response in vivo
Authors: Sainson Richard C. , Parveen Nahida , Borhis Gwenoline , Kosmac Miha , OKell Tracey , Taggart Emma , Carvalho Joana , McCourt Matthew , Ali Hanif , Craig Hannah , Labokha Aksana 
Published: August 2018

Abstract
Antibodies blocking the PD-1/PD-L1 axis present significant breakthroughs in the treatment of hitherto untreatable cancers. However, despite the highly encouraging progress that has been made, multiple tumour types demonstrate limited response to these therapies. The emerging picture is that combination with other therapies is required to improve response rates and/or the durability of response. Additional benefit could be achieved by combining an anti-PD-L1 approach with another modulator of T cell activation. ICOS is a co-stimulatory molecule expressed on activated T cells such as TEff and TReg cells present in the tumour microenvironment (TME). ICOS agonism has been demonstrated to improve TEff cell survival and IFNγ release, resulting in the activation of T cell-dependent eradication of the tumour. In addition, the high expression of ICOS observed on TReg cells in the TME allows these highly immunosuppressive cells to be selectively depleted when using the appropriate antibody format. With the aim of targeting both ICOS and PD-L1, we have developed a bispecific mAb² (KY1055) as a human IgG1 format that consists of fully human Fab arms targeting ICOS and a modified Fc (Fcab) containing binding sites to PD-L1. We demonstrate potent (single digit nM) binding to ICOS via the Fab and to PD-L1 via the Fcab. Furthermore, in vitro studies reveal that KY1055 can bridge together ICOS- and PD-L1-expressing cells and can activate ICOS signalling through this cross-presentation. Functionality of the Fcab was validated by demonstrating that it blocks the PD-1-PD-L1 inhibitory pathway, resulting in the up-regulation of IFNγ in monocyte:T cell co-culture assays. We also demonstrate the ability of KY1055 to deplete ICOShigh cells in vitro by ADCC. In vivo, we confirm the anti-tumour efficacy of KY1055 in several syngeneic models that are poorly responsive to the respective monotherapies and further demonstrate improved anti-tumour efficacy when combined with anti-CTLA4 and anti-PD-1 in vivo. Finally, we demonstrate that KY1055 depletes TRegs and improves the TEff : TReg ratio in vivo in a CT26 model of tumour growth. Altogether, these data warrant further development of KY1055 for the treatment of solid tumours.
Citation Format: Richard C. Sainson, Nahida Parveen, Gwenoline Borhis, Miha Kosmac, Tracey OKell, Emma Taggart, Joana Carvalho, Matthew McCourt, Hanif Ali, Hannah Craig, Aksana Labokha. KY1055, a novel ICOS-PD-L1 bispecific antibody, efficiently enhances T cell activation and delivers a potent anti-tumour response in vivo [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 LB-153.
Abstract LB-164: Global study of chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci
Authors: Glubb Dylan M. , Kho Pik Fang , Consortium Endometrial Cancer Association , Thompson Deborah , Spurdle Amanda , O'Mara Tracy 
Published: August 2018

Abstract
We have previously used genome-wide association studies and meta-analyses to uncover 17 genetic risk loci for endometrial cancer. However, the regulatory gene targets of these loci have not been systematically evaluated. To identify candidate gene targets at endometrial cancer risk loci, we have assessed chromatin looping interactions between endometrial cancer risk variants and neighboring genes using the global HiChIP chromatin conformation capture technique. To perform HiChIP, estrogen-stimulated Ishikawa endometrial cancer cells were cross-linked and proximity ligation performed. Chromatin associated with RNA polymerase II was isolated and HiChIP libraries prepared before sequencing using the Illumina HiSeq 4000 system. HiChIP paired-end reads were aligned using the HiC-Pro pipeline and filtered for valid reads. The hichipper package was used to identify and characterise global chromatin interactions (FDR &lt; 0.01). At 11 of the 17 endometrial cancer risk loci, we identified chromatin interactions between risk variants and genes (37 coding and 10 non-coding). Interaction distances ranged from 8 kb to 1.7 Mb. Expression of candidate target genes CUX2, CYP19A1, SKAP1, SNX11 and EIF2AK4 was found to associate with endometrial cancer risk in whole blood transcriptome-wide association studies (TWAS). Ingenuity Pathway Analysis revealed that candidate genes were enriched for relevant functional annotations such as tumorigenesis, cell migration, necrosis and viability. Furthermore, enrichment of candidate genes (p=0.001) was observed in the CXCR4 signaling pathway, which is involved with endometrial cancer development, invasion and progression. In summary, we have performed the first global study of chromatin interactions in endometrial cancer cells. This analysis has revealed biologically relevant candidate target genes at endometrial cancer risk loci, five of which are supported by TWAS. Transcriptional regulation of candidate target genes by endometrial cancer risk variants will be verified in future studies.
Citation Format: Dylan M. Glubb, Pik Fang Kho, Endometrial Cancer Association Consortium, Deborah Thompson, Amanda Spurdle, Tracy O'Mara. Global study of chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci [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 LB-164.
Abstract LB-174: Novel AC electrokinetic platform for rapid isolation and characterization of extracellular vesicles from NSCLC patients
Authors: Krishnan Rajaram , Hinestrosa Juan P. , Searson David , Turner Robert , Kovelman Robert , Balcer Heath , Madsen James , Bodkin David 
Published: August 2018

Abstract
We have developed a novel Alternating Current Electrokinetics (ACE) platform to isolate macromolecules such as circulating cell-free DNA (ccfDNA) and nanoparticles, including cell-derived extracellular vesicles (EVs). ccfDNA and EV isolation, and antibody staining using the platform required less than two hours to complete. EVs isolated by ultracentrifugation from the pancreatic cancer cell line ASPC-1 were used to validate the ACE platform's performance. EVs from pancreatic cancer ASPC-1 cells were detected using an anti-CD63 antibody and an antibody to the pancreatic cancer specific membrane protein Glypican-1, confirming that the ACE platform could isolate EVs and identify membrane-bound proteins. Recovered EVs were isolated and EV-associated RNA was amplified by RT-PCR. EVs from isolated from NSCLC patient plasma on the ACE platform contained higher levels of PD-L1 compared to healthy individuals (p&lt;0.001). In parallel on the ACE platform, ccfDNA was isolated and quantified from the same samples, with increased levels measured in cancer patients. Improved differentiation between the NSCLC patients and the healthy normals was achieved when both markers were included in the analysis. Therefore, we believe the ACE platform has the potential to become a multimodal analytics tool for cancer diagnostics and treatment monitoring.
Citation Format: Rajaram Krishnan, Juan P. Hinestrosa, David Searson, Robert Turner, Robert Kovelman, Heath Balcer, James Madsen, David Bodkin. Novel AC electrokinetic platform for rapid isolation and characterization of extracellular vesicles from NSCLC patients [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 LB-174.