tbuckley/cabot-search huggingface dataset:
Abstract 4319: Epigenetic reprogramming associated with BRCA1 loss of function in ovarian cancer induces enhanced interferon gamma signaling
Authors: Horacio Cardenas, Jessica Thomes Pepin, Guanglong Jiang, Salvatore Condello, Kenneth P. Nephew, Yunlong Liu, Daniela Matei
Journal: Cancer Research (2018)

Abstract Inactivating mutations of the breast cancer type 1 susceptibility protein (BRCA1) have been implicated in breast and ovarian cancer (OC) initiation. Having observed differential response of OC cells to histone deacetylase inhibitors (HDACi) dependent on the presence of a functional BRCA1, we mapped promoters marked by acetylation of lysine 9 or lysine 27 of histone H3 (H3K9ac, H3K27ac) by ChIP-sequencing, and measured gene expression by RNA-sequencing in the isogenic OC cell lines UWB1.289 carrying an inactivating mutation of BRCA1 (BRCA1-null) and UWB1.289 cells with restored BRCA1 gene (BRCA1+). Significant differences in promoter levels of H3K9 and H3K27 acetylation were associated with marked alteration of gene expression levels between BRCA-null and BRCA1+ cells and in response to the HDACi, entinostat. Pathway analyses revealed cellular movement, cellular development, cellular growth and proliferation, TGFβ1, TNF, and INF-γ among the top cellular/molecular functions and upstream regulators enriched by the absence of BRCA1 among H3K9ac differentially marked and differentially expressed genes. Importantly, the same pathways and regulators were enriched in response to entinostat in BRCA1+ cells, indicating that changes in gene expression affecting these functions and regulators in BRCA1-null cells depend on promoter-associated histone acetylation. Integrated analyses revealed that TGFβ1 and IFN-γ were also activated in BRCA1-null/or low vs. BRCA1-normal ovarian tumors in the TCGA database. IFN-γ target genes were upregulated at baseline and responded less to IFN-γ stimulation in BRCA1-null vs. BRCA1+ cells. Binding of HDAC1 to promoters of IFN-γ target genes was increased in BRCA1-null cells. Similarly, the BRCA1-null breast cancer cell line HCC1937 responded less to IFN-γ stimulation compared with HCC1937 cells in which BRCA1 was restored. The knockdown of STAT1, the main IFN-γ signaling transduction molecule, inhibited BRCA1+ cell proliferation, but did not affect BRCA1-null cells. We conclude that the transcriptome of BRCA1-null cells and tumors is altered through changes in histone acetylation affecting cancer-related pathways, including IFN-γ cellular responses. These changes could alter tumor progression in BRCA-null OC and impact response to immunotherapy. Citation Format: Horacio Cardenas, Jessica Thomes Pepin, Guanglong Jiang, Salvatore Condello, Kenneth P. Nephew, Yunlong Liu, Daniela Matei. Epigenetic reprogramming associated with BRCA1 loss of function in ovarian cancer induces enhanced interferon gamma signaling [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 4319.
Abstract 3573: Novel DNA vectors encoding a chimeric antigen receptor mediate long term expression without genomic integration
Authors: Patrick Schmidt, Matthias Bozza, Aileen Berger, Claudia Luckner-Minden, Alexandra Tuch, Inka Zörnig, Dirk Jäger, Richard Harbottle
Journal: Cancer Research (2018)

Abstract Adoptive immunotherapy is one of the most encouraging therapeutic strategies for the treatment of a range of cancers. One particularly promising avenue of research is the functional introduction of Chimeric Antigen Receptors (CARs) into naive Human T-Cells for autologous-immunotherapy. Currently, the genetic engineering of these cells is achieved through the use of proprietary integrating vector systems such as lentiviruses or the sleeping beauty transposon system which present a risk of genotoxicity associated with their random genomic integration. We have invented a novel DNA Vector platform for the safe and efficient generation of genetically engineered T-Cells for Human Immunotherapy. This DNA vector system contains no viral components and comprises only clinically approved sequences, it does not integrate into the target cell's genome but it can replicate autonomously and extrachromosomally in the nucleus of dividing human primary cells. These DNA Vectors offer several advantages over currently used vector systems; they are not subject to commercial licences, they are cheaper and easier to produce, and they can more quickly genetically modify human cells without the inherent risk of integrative mutagenesis. In preclinical experiments we have successfully generated genetically engineered human T-Cells expressing the CAR receptor against several epitopes and have demonstrated their viability and capability in targeting and killing human cancer cells which express these epitopes. The long term anti-tumor activity of our DNA-CAR-T cells has been confirmed in vivo using xenotransplanted cell lines in immunodeficient mice. We believe that this novel DNA Vector system provides a unique and innovative approach to this exciting therapeutic strategy for cancer therapy. We estimate that this novel methodology will provide a simpler method of CAR T-cell manufacturing, resulting in a 10-fold reduction in the cost of the CART-product. Citation Format: Patrick Schmidt, Matthias Bozza, Aileen Berger, Claudia Luckner-Minden, Alexandra Tuch, Inka Zörnig, Dirk Jäger, Richard Harbottle. Novel DNA vectors encoding a chimeric antigen receptor mediate long term expression without genomic integration [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 3573.
Abstract 625: Cytotoxic T lymphocyte antigen 4 (CTLA-4) expression in ductal carcinoma in situ (DCIS) of the breast
Authors: Jorge E. Novo, Lauren Rosen, Julianne M. Ubago, Jennifer Pincus, Luis Blanco, Kalliopi P. Siziopikou
Journal: Cancer Research (2018)

Abstract Background: Ductal carcinoma in situ (DCIS) consists of a heterogeneous group that can be subclassified by molecular signatures. High grade DCIS is commonly associated with periductal inflammation, a feature associated with increased risk for microinvasion. We previously assessed the immune microenvironment of DCIS and reported that HER2+ DCIS has increased numbers of tumor infiltrating lymphocytes (TILs), with significant expression of PD-L1. CTLA-4 is a supplementary immunomodulatory marker, which serves as a negative regulator of T-cell response. Targeted therapy is currently available against both PD-L1 and CTLA-4, and studies suggest an enhanced response with combination therapy as these therapies act though different mechanisms. In this study we evaluated the expression of CTLA-4 in both TILs and tumor cells in DCIS. Design: The study population consisted of 74 cases of DCIS treated with surgical excision from 2008-2012. The molecular subtypes of DCIS were determined based on ER and HER2 expression. Tissue microarrays were constructed (3 cores/case) to account for tumor heterogeneity. The TMAs were immunostained for CTLA-4 and the expression CTLA-4 was assessed. Results: Of the 74 cases, 41 were classified as Luminal A (ER+/HER2-), 17 as Luminal B (4 as Luminal B HER2- [ER+/HER2-/high Ki-67] and 13 as Luminal B HER2+ [ER+/HER2+]), 11 as HER2+ (ER-/HER2+) and 5 as basal (ER-/HER2-). Overall, the DCIS tumor cells expressed CTLA-4 in 58% of Luminal B (HER2+ 53% [7/13]; HER2- 75% [3/4]) and 36% of HER2+ (4/11), while only 39% of Luminal A (16/41), and one basal DCIS (1/5) did. In addition, the presence of CTLA-4 positive TILs was strongly associated with HER2+ expression (Luminal B HER2+=21.8%, HER2+=13.4%), compared to HER2- DCIS (Luminal B HER2-=8.5%, Luminal A=7.3%, Basal=6.4%) (p=0.026). Conclusion: 1. CTLA-4 expression in TILs is increased in HER2+ DCIS. 2. A significant percent of tumor cells express CTLA-4 in all DCIS subtypes. Our results further advance our understanding of the role of the immune microenvironment in DCIS. Additional studies are needed to further elucidate the complex interplay between the host immune system and DCIS, which may offer insights into breast carcinoma progression and possible use of novel immune-based therapies. Citation Format: Jorge E. Novo, Lauren Rosen, Julianne M. Ubago, Jennifer Pincus, Luis Blanco, Kalliopi P. Siziopikou. Cytotoxic T lymphocyte antigen 4 (CTLA-4) expression in ductal carcinoma in situ (DCIS) of the breast [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 625.
Abstract 15736: The Effect Of Genotype on the Clinical Presentation and Outcomes in Newly Diagnosed Patients With ARVC
Authors: Barbara Szepietowska, Jeffrey A Towbin, Frank Marcus, Luisa Mestroni, Bronislava Polonsky, Wojciech Zareba
Journal: Circulation (2015)

Objective: The aim of the study was to compare clinical presentation of newly diagnosed patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) by presence of genes mutations, and the effect of known genotype on the risk of ventricular tachyarrhythmias (VT/VF) or death. Methods: There were 109 newly identified probands diagnosed with ARVC according to the 2010 Task Force criteria for ARVC and tested for the following genes: (numbers of specific mutations identified are provided in parentheses): Plakophilin 2 (n=29), Plakoglobin (n=8), Desmocollin (n=1), Desmocollin 2 (n=1), Desmoglein (n=3), Desmoglein 2 (n=2), Desmoplakin (n=8). Results: There were 32 (29.4%) genotype positive patients for mutation in just one of the tested genes and 9 (8.3%) patients had 2 or 3 mutation concomitantly, in 6 of them the co-present mutation was Plakophilin 2. The remaining 68 (62%) patients were genotype negative for the above genes. Gene-positive patients for single and for multiple mutations patients and patients with unknown yet gene mutations did not differ significantly in clinical presentation including: age at clinical presentation, age at the first VT/VF, family history of ARVD, diagnostic criteria points, arrhythmic events (VT/VF) prior to enrolment and ICD implantation, ECG presentation, EP testing, ECHO or MRI parameters. Figure below shows the risk of VT/VF/ Death in three groups of patients: single mutations vs. multiple mutations vs. unknown gene group. Conclusion: ARVC patients with unknown genes show similar clinical, ECG, and MRI presentation and similar outcome to patients with single or multiple mutations. Future studies are needed to uncover unknown genes underlying ARVC.
Abstract 3516: Discovery of novel SHMT small molecule inhibitors for cancer treatment
Authors: Anna Bartosik, Pawel Guzik, Marta Sowinska, Karolina Gluza, Marcin Krol, Anna Wrobel, Agnieszka Dreas, Faustyna Iwanska, Magdalena Zastawna, Urszula Kulesza, Nicolas Boutard, David Schultz, Justyna Wujkowska, Karolina Pyziak, Agnieszka Sroka-Porada, Agnieszka Przybylowicz, Agnieszka Adamus, Magdalena Sieprawska-Lupa, Przemyslaw Golik, Piotr Kowalczyk, Krzysztof Brzozka, Tomasz Rzymski, Mateusz Nowak
Journal: Cancer Research (2018)

Abstract Over-activation of the serine synthesis pathway, upregulation of SHMT2 has been described in over 20% of solid tumors (e.g. breast, lung, colorectal cancers). Such cancer cells are highly dependent on serine. Serine hydroxymethyltransferase (SHMT) plays a key role in a so-called one-carbon pathway, a group of biochemical reactions involved in amino acid metabolism. SHMT catalyzes the conversion of serine to glycine and also plays a role in the folate (vitamin B9) cycle. Antagonists of folate metabolism or antifolates are an established chemotherapy in certain cancers. Folate antagonism disrupts cell division, DNA/RNA synthesis and protein synthesis. Pemetrexed (for non-small cell lung carcinoma, mesothelioma) and methotreaxate (for autoimmune conditions like rheumatoid arthritis and certain cancers) are two well established and effective antifolates. The main drawback with antifolates in cancer treatment, however, is the development of resistance. In this study we report development of a series of small molecule SHMT1/2 inhibitors. Synthetized compounds exert potency in SHMT1/2 biochemical assay as well as in cellular assay (measured by the C13 serine to glycine conversion) with the low nanomolar range. Therapeutic effect of the compounds was investigated in the panel of cancer cell lines with different genetic background as well as with different SHMT2 levels. We identified several cell lines in which tested compounds inhibited cancer cell grow with nM GI50 values. Taken together, presented data supports our rationale for using SHMT1/2 inhibitors as a novel and interesting approach for the cancer therapy. Citation Format: Anna Bartosik, Pawel Guzik, Marta Sowinska, Karolina Gluza, Marcin Krol, Anna Wrobel, Agnieszka Dreas, Faustyna Iwanska, Magdalena Zastawna, Urszula Kulesza, Nicolas Boutard, David Schultz, Justyna Wujkowska, Karolina Pyziak, Agnieszka Sroka-Porada, Agnieszka Przybylowicz, Agnieszka Adamus, Magdalena Sieprawska-Lupa, Przemyslaw Golik, Piotr Kowalczyk, Krzysztof Brzozka, Tomasz Rzymski, Mateusz Nowak. Discovery of novel SHMT small molecule inhibitors for cancer treatment [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 3516.
Abstract SY18-03: Cross-presenting DC in the TME
Authors: Matthew F. Krummel
Journal: Cancer Research (2018)

Abstract The immune response to tumors is malleable as we have learned from the various success of immunotherapies, across a diversity of tumor types. What are the foundations for a solid immune response, particularly one executed by T cells? Imaging and single-cell approaches provide key insights into immune cell types that can be unleashed on tumors, identifying both their identity and the immune interactions that are to be fostered. In considering this, we consider the concepts of seeking "allies" for tumor therapies as well as for understanding the balance of push/pull signals that likely contribute to determine the consensus immune response.We discuss a few of these with particular emphasis on the diversity of the innate immune system and how its component parts can contribute toward antitumor immunity. Citation Format: Matthew F. Krummel. Cross-presenting DC in the TME [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 SY18-03.
Abstract 3937: Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib
Authors: Deniz C. Kahraman, Tamer Kahraman, Rengul Cetin Atalay
Journal: Cancer Research (2018)

Abstract Liver cancer stem cells (LCSCs) are derived from damaged and transformed hepatic progenitor cells (HPCs) during precancerous cirrhosis stage. Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are significantly deregulated in liver cancer. The activation of PI3K/AKT/mTOR pathway in LCSC population is one of the reasons for acquired resistance to sorafenib in advanced hepatocellular carcinoma (HCC) patients. Therefore, identifying novel inhibitors targeting this pathway acting on LCSCs is highly essential. We, therefore, elucidated the bioactivities of small-molecule kinase inhibitors on LCSCs acting through PI3K/Akt/mTOR pathway in comparison with DAPT (CSC inhibitor), DNA intercalators and sorafenib. For this purpose, CD133+/EpCAM+ cells originated from HCC cells were analyzed by flow cytometry and effective inhibitors on LCSCs were further tested for their potential combinatorial effects. Treatment of cells with sorafenib and DNA intercalators resulted in enrichment of CD133+/EpCAM+ cells. Yet, rapamycin, LY294002 and DAPT significantly reduced CD133/EpCAM positivity. Combination studies revealed that sequential treatment strategy decreased the ratio of LCSCs as opposed to sorafenib treatment alone. The effects of the inhibitors were also demonstrated with LCSC sphere formation. Additionally, a large panel of genes involved in cancer pathways was analyzed using Nanostring® nCounter® Technology to identify the differentially expressed genes in rapamycin, sorafenib or DAPT treated cells. Systematic pathway analysis using Cytoscape ScoreFlow algorithm application allowed us to identify differential response genes involved in stemness. While the stemness genes were downregulated in cells treated with rapamycin or DAPT, JAG1 gene was found to be upregulated in sorafenib-treated cells. Interleukin 8 (IL-8) was downregulated upon treatment with DAPT, yet upregulated upon sorafenib treatment. Following IL-8 inhibition with repaxirin, CD133/EpCAM positivity of cells decreased significantly, indicating that IL-8 signaling is crucial for the conservation of stemness features of cancer cells. The combination of sorafenib and reparixin resulted in lower levels of SOX2 and Nanog proteins. Conclusion: PI3K/Akt/mTOR pathway inhibitors alter hepatic CSC composition and gene expression in favor or to the detriment of cancer stem cell survival. Blockade of IL-8 signaling provides a promising therapeutic approach for prevention of LCSC enrichment. Citation Format: Deniz C. Kahraman, Tamer Kahraman, Rengul Cetin Atalay. Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib [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 3937.
Inhibition of Vascular Smooth Muscle Cell Proliferation and Neointimal Formation in Injured Arteries by a Novel, Oral Mitogen-Activated Protein Kinase/Extracellular Signal–Regulated Kinase Inhibitor
Authors: GiuseppaGennaro, CatherineMénard, Sophie-ÉliseMichaud, DenisDeblois, AlainRivard
Journal: Circulation (2004)

Background— Mitogen-activated protein kinases (MAPKs) are rapidly induced after arterial injury in different animal models. However, their precise role in vascular smooth muscle cell (VSMC) proliferation and neointimal formation in vivo remains to be determined. Methods and Results— We investigated the properties of a novel, selective inhibitor of the upstream kinase, MAPK/extracellular signal–regulated kinase, that is orally active (PD0185625). In vitro, PD0185625 was shown to abrogate p44/p42 MAPK activation in VSMCs after serum stimulation. This was associated with a dose-dependent inhibition of VSMC proliferation. In vivo, PD0185625 was administered orally to rats (200 mg · kg−1 · d−1) beginning 2 days before balloon injury of the left carotid artery and for 2 weeks thereafter. Treatment with PD0185625 led to nearly complete inhibition of p44/p42 MAPK activation after balloon injury. This resulted in a significant decrease in VSMC proliferation (BrdU incorporation) at day 7 after injury. Moreover, neo...
Abstract 4955: Heterogeneous nuclear ribonucleoprotein C as a novel therapeutic target for acute myeloid leukemia
Authors: Vindhya Vijay, Amy Meacham, Jesse Terrell, Lauren Katzell, Leylah Drusbosky, Christopher Cogle
Journal: Cancer Research (2018)

Abstract Acute myeloid leukemia (AML) is a highly refractory cancer despite conventional treatment. Previously, we found that blood vessels are sanctuary sites for chemo-refractory AML cells. To target AML cells sequestered in the vascular niche, we developed an in vitro co-culture assay consisting of AML cells on bone marrow- derived endothelial cells (BMECs), mimicking the chemo-protective effect of the vascular niche in the bone marrow microenvironment. Using this assay, we performed high-throughput chemical-phenotypic screening of 31 million compounds and identified a novel polyamine sulfonamide (2470-51) that selectively killed AML cells, while sparing the underlying BMECs. 2470-51 was also cytotoxic to CD34+CD38-CD123+ AML stem cells; however, the compound was non-toxic to hematopoietic stem/progenitor cells and T lymphocytes from healthy volunteers. In vivo AML patient-derived xenograft modeling further validated the efficacy of 2470-51 as a selective anti-leukemic agent compared to cytarabine (conventional control) and vehicle control. Protein target identification experiments using unbiased label-free shotgun proteomic analysis in combination with targeted selected ion monitoring revealed heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) as the covalent target of 2470-51. These findings were further validated by shRNA mediated knock-down of HNRNPC (HNRNPC-kd) in AML cell lines THP-1 and K562. HNRNPC-kd significantly reduced AML cell proliferation as well as AML cell viability by inducing apoptosis, compared to scramble controls. HNRNPC-kd also significantly reduced the clonogenic potential of both AML cell lines. In contrast, normal mesenchymal/fibroblastic (HS5) and endothelial cells (BMECs) were unaffected by HNRNPC-kd, indicating the selective dependence of AML cells on hnRNPC. RNA-Seq analyses revealed alternative splice events associated with HNRNPC-kd. Functional enrichment analyses followed by pathway analyses indicated the involvement of hnRNPC in key oncogenic and cell survival pathways. Depleting hnRNPC significantly altered the post-transcriptional landscape, leading to induction of apoptosis. Clinical studies using TCGA AML datasets showed significant survival advantage associated with lower HNRNPC expression. Collectively, our data indicate that hnRNPC is a critical factor in AML and that inhibiting this splicing repressor may be a new therapeutic strategy. Citation Format: Vindhya Vijay, Amy Meacham, Jesse Terrell, Lauren Katzell, Leylah Drusbosky, Christopher Cogle. Heterogeneous nuclear ribonucleoprotein C as a novel therapeutic target for acute myeloid leukemia [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 4955.
Rho Family Small G Proteins Play Critical Roles in Mechanical Stress–Induced Hypertrophic Responses in Cardiac Myocytes
Authors: RyuichiAikawa, IsseiKomuro, TsutomuYamazaki, YunzengZou, SumiyoKudoh, WeidongZhu, TakashiKadowaki, YoshioYazaki
Journal: Circulation Research (1999)

Abstract—Mechanical stress induces a variety of hypertrophic responses, such as activation of protein kinases, reprogramming of gene expression, and an increase in protein synthesis. In the present study, to elucidate how mechanical stress induces such events, we examined the role of Rho family small GTP-binding proteins (G proteins) in mechanical stress–induced cardiac hypertrophy. Treatment of neonatal rat cardiomyocytes with the C3 exoenzyme, which abrogates Rho functions, suppressed stretch-induced activation of extracellular signal–regulated protein kinases (ERKs). Overexpression of the Rho GDP dissociation inhibitor (Rho-GDI), dominant-negative mutants of RhoA (DNRhoA), or DNRac1 significantly inhibited stretch-induced activation of transfected ERK2. Overexpression of constitutively active mutants of RhoA slightly activated ERK2 in cardiac myocytes. Overexpression of C-terminal Src kinase, which inhibits functions of the Src family of tyrosine kinases, or overexpression of DNRas had no effect on str...