bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A60: Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: Therapeutic implications
Authors: Bashari Muhammad Hasan , Fan Fengjuan , Vallet Sonia , Arn M. , Cardone Michael H. , Beckhove Philipp , Schneeweiss Andreas , Sattler Martin , Opferman Joseph T. , Jäger Dirk , Podar Klaus 
Published: May 2016

Abstract
Molecular mechanisms leading to the adaptation of breast cancer (BC) cells to hypoxia are largely unknown. The anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) is frequently amplified in BC; and elevated Mcl-1 levels have been correlated with poor prognosis. Here, we demonstrate for the first time strong correlation between Mcl-1 protein levels and hypoxia, predominantly in Her2-positive BC cells. Surprisingly, genetic depletion of Mcl-1 decreased Her2 and Hif-1α levels followed by inhibition of BC cell survival. In contrast, Mcl-1 protein levels were not downregulated after genetic depletion of Her2 indicating a regulatory role of Mcl-1 upstream of Her2. Indeed, Mcl-1 and Her2 co-localize within the mitochondrial fraction and form a Mcl-1/Her2- protein complex. Similar to genetically targeting Mcl-1 the novel small molecule Mcl-1 inhibitor EU-5346 induced cell death and decreased spheroid formation in Her2-positive BC cells. Of interest, EU-5346 induced ubiquitination of Mcl-1- bound Her2 demonstrating a previously unknown role for Mcl-1 to stabilize Her2 protein levels. Importantly, targeting Mcl-1 was also active in Her2-positive BC cells resistant to Her2 inhibitors, including a brain-primed Her2-positive cell line. In summary, our data demonstrate a critical role of Mcl-1 in Her2-positive BC cell survival under hypoxic conditions and provide the preclinical framework for the therapeutic use of novel Mcl-1- targeting agents to improve patient outcome in BC.
Citation Format: Muhammad Hasan Bashari, Fengjuan Fan, Sonia Vallet, M. Arn, Michael H. Cardone, Philipp Beckhove, Andreas Schneeweiss, Martin Sattler, Joseph T. Opferman, Dirk Jäger, Klaus Podar. Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: Therapeutic implications. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A60.
Abstract A65: A novel regulatory mechanism involving Ras-mediated activation of the zinc-finger transcription factor, SAF-1/MAZ induces EGFR/HER1 expression in breast cancer cells
Authors: Ray Alpana , Havis Brett , Ray Bimal 
Published: May 2016

Abstract
Tumor microenvironment (TME) plays a critical role in tumor growth, invasion and metastasis. In TME, epidermal growth factor receptor (EGFR) family members, including HER1, HER2, HER3 and HER4, are involved in determining aggressive growth of breast cancer due to their ability to transduce the growth promoting functions of growth factors. This activity is potentiated by the over-expression of these receptor molecules in cancer cells. To reduce the activity of EGFR molecules, various inhibitors have been developed. EGFR/HER1 tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show antitumor activity but these drugs have not meet their primary goal of improved survival in the overall patient population. A similar TKI, lapatinib, has shown some limited success in breast cancer. While these therapeutic options focus on reducing the functional activity of EGFR protein, the fundamental and major problem of over-expression of EGFR in cancer cells has not been addressed.
In two-thirds of aggressive breast cancer patients, transcriptional induction of EGFR causes high EGFR/HER1 level. Therefore, the goal of this study is to identify a molecular mechanism by which EGFR is over-expressed in breast cancer cells. To understand how transcriptional induction might occur, we have explored a novel biosynthetic pathway for EGFR over-expression. Our findings reveal that EGFR promoter is significantly more active in MDA-MB-231 cells in comparison to MDA-MB-468 cells. When transcription factor SAF-1 was ectopically expressed in these cells, EGFR promoter activity was further increased in MDA-MB-231 cells. Since MDA-MB-231 cells contain a highly active form of Ras, the data suggested a possible Ras-mediated activation of SAF-1 which in turn induces EGFR expression. Consistent with these findings, inhibition of K- and H-Ras, by using both siRNA and CRISPR/Cas9-mediated knock-out systems, reduced the expression of EGFR in MDA-MB-231 cells. The effect was more profound when K-Ras was targeted for inhibition. Since SAF-1/MAZ is seen to be activated by Ras, our data implicates K-Ras - SAF-1/MAZ - EGFR axis in breast cancer cell growth. Our findings may provide new targets for breast cancer therapy.
Supported by grants from College of Veterinary Medicine Faculty Research Award Grant and MU Center for Botanical Interaction Studies Pilot Project Grant.
Citation Format: Alpana Ray, Brett Havis, Bimal Ray. A novel regulatory mechanism involving Ras-mediated activation of the zinc-finger transcription factor, SAF-1/MAZ induces EGFR/HER1 expression in breast cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A65.
Abstract A68: Design and development of HDAC6-selective inhibitors for hematological cancer treatment and solid tumor immunotherapy
Authors: Shuttleworth Stephen J. 
Published: May 2016

Abstract
Despite its name, HDAC6 is primarily a tubulin deacetylase, not a histone deacetylase, and it has emerged as a particularly interesting - and unique - cancer target as it plays an essential role in stress response and in aggresomal protein degradation: specifically, HDAC6 binds polyubiquitinated misfolded proteins and recruits misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 fail to clear these misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins, which leads to activation of apoptosis. Further, recent evidence has emerged of HDAC6 modulating immune-related pathways in solid tumors, notably regulating PD-L1 expression through STAT3 modulation. In order to explore the clinical potential of HDAC6 in both hematological and solid tumor immunotherapy, we have de novo-designed a class of highly-potent, ultra-selective and orally-active HDAC6 inhibitors with potential in the treatment of multiple tumor types, including through immunotherapeutic mechanisms. Additionally, owing to the selectivity we have achieved for HDAC6 with our lead compounds, much greater opportunities for broader combination modalities can be realized, and we have established potentiation of our leads with other tumor immunotherapeutics in in vivo syngeneic models. The profile of our preclinical development candidate will be presented.
Citation Format: Stephen J. Shuttleworth. Design and development of HDAC6-selective inhibitors for hematological cancer treatment and solid tumor immunotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A68.
Abstract A70: Immunmodulatory effects of the novel HDAC inhibitor resminostat
Authors: Kohlhof Hella , Prenzel Tanja , Hamm Sevetlana , Baumgartner Roland , Borgmann Matthias , Vitt Daniel 
Published: May 2016

Abstract
Introduction:
HDAC inhibitors mediate their anti-cancer activity at least in part via modulation of the immunogenicity of cancer cells and reactivation of effector cells of the immune system. Evaluating possible immunomodulating properties of resminostat which potentially contribute to its overall anti-tumoral effect should be investigated.
Experiments:
Resminostat was tested for its effects on mechanisms affecting the anti-tumoral immune response such as immunosuppression, immunogenicity, immunogenic cell death (ICD) and natural killer (NK) cell recognition in several cancer cell lines.
Results:
Resminostat has the potency to affect the immune response at different levels on tumor as well as immune cells. Resminostat strongly reduced the expression of immunosuppressive enzymes, IDO1 and ARG1, which deplete the tumor microenvironment of amino acids essential for T cell activity. Further, resminostat enhanced the expression of various tumor associated antigens and MHC class I molecules leading to enhanced tumor immunogenicity. This was further enhanced by upregulation of the ICD marker and dendritic cell engulfment signal Calreticulin. The additional upregulation of MHC class II molecules and co-stimulatory molecules by resminostat lead to convertion of tumor cells into so called unprofessional antigen presenting cells. Furthermore, by upregulation of NK cell activating ligands on tumor cells, resminostat increased NK cell-mediated tumor cell cytotoxicity.
Conclusion:
Resminostat displayed promising immunomodulatory effects and immune priming capacity. Thus, this novel HDAC inhibitor demonstrates potential synergistic effects with immunotherapeutics such as opsonizing antibodies (e.g. rituximab), immunostimulating agents (e.g. cytokines and TLR ligands) and immune checkpoint blockers (such as PD1/PDL1 and CTLA-4 inhibitors) which will be analyzed on functional assays and in vivo models.
Citation Format: Hella Kohlhof, Tanja Prenzel, Sevetlana Hamm, Roland Baumgartner, Matthias Borgmann, Daniel Vitt. Immunmodulatory effects of the novel HDAC inhibitor resminostat. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A70.
Abstract A73: Antisense oligonucleotides targeting ENO2 have selective anti-proliferative effects in glioblastoma cell with 1p36 genomic loss
Authors: Shahmoradgoli Maria , Mazur Curt , Kim Youngsoo , Monia Brett P , Macleod A. Robert , Muller Florian M , Hart Christopher E 
Published: May 2016

Abstract
Essential cellular processes are often supported by redundant genes and pathways. Cancer cells frequently harbor deletions or mutations in essential genes and survive because of this functional redundancy. Identification of recurrent events that leave cancer cells selectively sensitive to inhibition of a particular pathway or gene can provides the opportunity to develop therapeutics with a high degree of selectivity for cancer cells over normal cells. In Glioblastoma Multiform (GBM), one of the most malignant brain cancers, roughly 3-5% of tumors have loss of the chromosome locus 1p36. Among the genes lost at this locus, is enolase1 (ENO1). Loss of ENO1 is tolerated by the cancer cells and is not required for cancer initiation or progression; likely because of functional redundancy with the closely related paralog, ENO2. However, it has been recently demonstrated that cancer cells with homozygous ENO1 loss are selectively sensitive to ENO2 inhibition. Here we investigate the potential of Antisense Oligonucleotides (ASO) targeted to ENO2 as a therapeutic approach to treat GBM with 1p36 loss of ENO1.We show that constrained ethyl (cET) modified ASOs targeting ENO2 produced dose dependent inhibition of ENO2 RNA and protein levels in GBM cells when delivered by free uptake. ASO-mediated ENO2 depletion led to the selective inhibition of ENO1-null cells and not the isogenic cells engineered to express ENO1. Moreover, cell cycle analysis is demonstrated that ENO2 depletion resulted in impaired proliferation due to unsuccessful transition of cells from G1 to S phase of the cell cycle. These findings support the application of ASO to elicit synthetic lethality in GBM tumors with 1p36 loss.
Citation Format: Maria Shahmoradgoli, Curt Mazur, Youngsoo Kim, Brett P Monia, A. Robert Macleod, Florian M Muller, Christopher E Hart. Antisense oligonucleotides targeting ENO2 have selective anti-proliferative effects in glioblastoma cell with 1p36 genomic loss. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A73.
Abstract A75: Pan-cancer identification of fusion genes as therapeutic targets in cancer
Authors: Edgren Henrik , Ojala Kalle , Ruusulehto Anja 
Published: May 2016

Abstract
Fusion genes are a well established category of oncogenic mutations, in which a chromosomal rearrangement brings together parts of two different genes to create a novel gene with oncogenic potential. Originally identified mostly in hematologic malignancies (e.g. BCR-ABL1 in CML), over the last years fusion genes have been shown to occur in practically all types of cancers examined. Some of the best known examples of these are ETS-family gene fusions (e.g. TMPRSS2-ERG) in prostate cancer and EML4-ALK fusions in non-small cell lung cancer. Although the prevalence of a specific gene fusion in a single cancer is often low, the example of treating e.g. EML4-ALK fusion positive NSCLC cancers with ALK inhibitors, such as crizotinib and ceritinib, has shown gene fusions to have significant value as targets of drug development.
In this study, we describe a comprehensive survey of gene fusions in 7428 cancer samples from 27 different cancer types, using paired-end RNA-seq data created by the TCGA project. At least one fusion gene was identified in 3801/7428 samples, with over 9000 genes taking part in a total of ∼11000 fusion gene events. The number of gene fusions per tumor is highly variable, with the largest number of fusions typically identified in tumors with high level amplifications. This suggests many of the fusion genes identified here may arise as byproducts of amplicon formation, making them likely passenger events.
Several potentially targetable genes take part in gene fusions across different cancer types. For instance, we identified a total of 12 gene fusions involving ALK in 5 different cancer types. Strikingly, only 5 of these involve EML4 as 5' partner gene. NTRK fusions were identified in 24 samples from 9 cancer types, FGFR fusions in 39 samples from 14 cancer types and MAST family kinase fusions in 14 samples from 7 cancer types.
In summary, our analysis of fusion gene occurrence across a wide variety of cancer types identifies several interesting and potentially targetable gene fusions. Furthermore, it illustrates that many of these are found across several different cancer types, as well as involve a large number of different fusion partner genes, suggesting this may need to be taken into account in diagnostics of fusion genes as well as selection of patients for clinical trials.
Citation Format: Henrik Edgren, Kalle Ojala, Anja Ruusulehto. Pan-cancer identification of fusion genes as therapeutic targets in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A75.
Abstract A90: Combination therapy of chemokine receptor inhibition plus PDL-1 blockade potentiates anti-tumor effects in a murine model of breast cancer
Authors: Jung Heiyoun 
Published: May 2016

Abstract
Trafficking and expansion of myeloid derived suppressor cells (MDSCs) plays a major role in immune suppression of tumor. MDSCs express chemokine receptors which likely mediate their recruitment to the tumor microenvironment. Suppression of T cells is also mediated by the interaction of programmed death-1 (PD-1) and its ligands which are abundantly expressed in cancer cells and immune infiltrates, including MDSCs. Here, we show that targeting both pathways through administration of a small molecule chemokine receptor antagonist (CCX9588 which blocks CCR1) and an anti-PDL1 antibody significantly reduced tumor burden in an orthotopic breast cancer mouse model. Primary tumor growth and lung metastasis were modestly reduced by either agent (anti-PDL-1 or CCR1 inhibitor) alone, but the combination of CCR1 inhibitor plus anti-PDL1 antibody resulted in significantly reduced tumor burden as compared to either of the single agents. Orthotropic breast cancer cell engraftment induces robust expansion of CD11b+Ly6Ghi Ly6Chi MDSCs, a subpopulation of which express CCR1. Analysis of the tumor infiltrating cells revealed that CCX9588 significantly reduced the number of MDSCs in primary tumors, showing that CCR1 blockade of MDSC trafficking translates into reduced tumor burden. Analysis of human breast cancer patient samples from The Cancer Genome Atlas (TCGA) database revealed that the CCR1 ligands, MCP-7 (CCL7) and RANTES (CCL5) are present at significantly higher levels in breast cancers as compared to normal breast tissue. Furthermore, CCR1 and its ligands, as well as PDL-1 are significantly higher in triple negative breast cancer samples than in the other breast cancer subtypes. These data are the first to show that CCR1 chemokine receptor antagonists can act synergistically with PDL-1 inhibitors, and suggest a novel approach for potentiating the activity of immune cell checkpoint inhibitors in the most aggressive forms of breast cancer.
Citation Format: Heiyoun Jung. Combination therapy of chemokine receptor inhibition plus PDL-1 blockade potentiates anti-tumor effects in a murine model of breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A90.
Abstract A91: BGB-283 exhibits potentials in enhancing tumor immune sensitization and lymphocyte function
Authors: Yuan Xi , Lian Mi , Wu Xiaoran , Luo Lusong 
Published: May 2016

Abstract
Oncogenic B-RAF, which drives cell transformation and proliferation, has been detected in a variety of human malignancies. Prior studies suggested that B-RAF-targeting therapies could increase antigen expression, decrease immune suppressive factors in tumor microenvironment, and improve homing of T effector cells to the tumors. Thus, selective BRAF inhibitors were suggested to possess immunosensitization properties and could be used in combination with immunotherapies to achieve more durable disease control/response in treating BRAF V600E melanomas. BGB-283 is a novel inhibitor of the RAF dimer with potent and reversible inhibitory activities against RAF family kinases including wild type A-RAF, B-RAF, C-RAF and B-RAF V600E. In addition, BGB-283 has potent inhibitory activity against EGFR (Mol. Can. Ther. onlinefirst 2015; doi: 10.1158/1535-7163). BGB-283 is currently under Phase 1 clinical investigations. In the present study, BGB-283 showed significant stimulation of melanocyte-differentiation antigens and HLA-A expression in BRAF V600E melanoma cell lines. Intermediate level of BGB-283 was found to stimulate proliferation of human peripheral blood mononuclear cell (PBMC) and isolated human CD4+ and CD8+ T cells. In addition, BGB-283 potentiated IFNγ releasing from PBMCs at concentration range of 30∼300 nM. In newly developed the 3D tumor spheroid/PBMC co-culture system, BGB-283 improved PBMC function as measured by cell proliferation and IFNγ production. The presence of PBMC also enhanced the anti-proliferation activity of BGB-283 on A375 BRAF V600E mutant melanoma cells in the co-culture system. Further studies have shed light on the mechanistic underpinning of the immunomodulation effect of BGB-283 and its potential differentiation from vemurafenib. These findings support BGB-283 as a promising clinical stage antitumor drug that could potentially combine with immunotherapies by enhancing immune sensitization and T cell function.
Citation Format: Xi Yuan, Mi Lian, Xiaoran Wu, Lusong Luo. BGB-283 exhibits potentials in enhancing tumor immune sensitization and lymphocyte function. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A91.
Abstract A92: Effects of lenvatinib on tumor-associated macrophages enhance antitumor activity of PD-1 signal inhibitors
Authors: Kato Yu , Tabata Kimiyo , Hori Yusaku , Tachino Sho , Okamoto Kiyoshi , Matsui Junji 
Published: May 2016

Abstract
[Background]
Lenvatinib mesylate (lenvatinib) is an orally administrated multiple receptor tyrosine kinase inhibitor that selectively inhibits the kinase activities of VEGFR1-3, FGFR1-4, KIT, PDGF-Rα and RET, which are involved in tumor angiogenesis and proliferation of several cancer types such as thyroid cancer. In order to investigate whether lenvatinib has effects on immune cell population in tumors, we examined antitumor effects and immune modulating abilities of lenvatinib in syngeneic murine tumor models.
[Materials and methods]
We examined antitumor activity of lenvatinib against BNL 1ME A.7R.1 murine hepatocellular carcinoma cell line in syngeneic and immune-deficient mice model. Combination treatment with lenvatinib at 10mg/kg (qd) plus anti-PD-1 mAb at 500μg/ml (twice weekly) was conducted in LL/2 murine Lewis lung carcinoma cell line syngeneic model. For immune population analyses, lenvatinib at 10mg/kg was orally administrated in BNL 1ME A.7R.1 or LL/2 mice model. On Day 7 after starting treatment, percentages of immune populations were analyzed by flow cytometer. For cytokine analysis, IFNγ in CD8+ T cells was intracellularly stained and analyzed by flow cytometer. The expression of immune related molecules in tumors was analyzed by quantitative PCR.
[Results]
Lenvatinib showed more potent inhibition of BNL 1ME A.7R.1 tumor growth in immune functional mice than in immune-deficient mice when given the same dose. A flow-cytometry analysis of immune populations in both BNL 1ME A.7R.1 and LL/2 tumors indicated that lenvatinib significantly decreased the percentage of tumor associated macrophages (TAM) with CD45+CD11b+Ly6GlowLy6ClowF4/80+ markers. In addition, immune inhibitory molecules were downregulated in tumors. Lenvatinib significantly increased the percentage of IFNγ-secreting CD8+ T cells in regional lymph node. In LL/2 tumor model, the combination effect of lenvatinib with anti-PD-1 mAb showed a superior antitumor activity to each monotherapy.
[Conclusion]
These results indicate that lenvatinib has more potent antitumor effect in immune functional environment. It was noteworthy that lenvatinib decreased TAM population in tumors. Furthermore, lenvatinib enhanced antitumor activity of PD-1 signal inhibitors with combination treatment.
Citation Format: Yu Kato, Kimiyo Tabata, Yusaku Hori, Sho Tachino, Kiyoshi Okamoto, Junji Matsui. Effects of lenvatinib on tumor-associated macrophages enhance antitumor activity of PD-1 signal inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A92.