bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5857: Isorhapontigenin inhibits triple-negative breast cancer via activating NRF2-mediated pathway
Authors: Zhu Yusha , Murphy Anthony , Kluz Thomas , Li Bo , Costa Max , Huang Chuanshu , Sun Hong 
Published: August 2018

Abstract
Breast cancer is the most prevalent cancer among women worldwide, and is the second leading cause of cancer mortality among women. Triple-negative breast cancers (TNBCs; ER-/PR-/HER2-) are highly aggressive tumors with poor prognosis. Due to lack of these specific receptors, TNBCs cannot be treated with hormone therapies or anti-HER2 targeted therapies. Chemotherapy, combined with surgery and radiation therapy, is the primary strategy for treating TNBCs. Thus, discovery and evaluation of new alternative medications targeting triple-negative breast cancer is of tremendous importance for reducing breast cancer mortality. Isorhapontigenin (ISO), a new derivative of stilbene isolated from Chinese herb Gnetum Cleistostachyun, exhibits a strong inhibitory effect on human bladder cancers. However, its anticancer activity with respect to breast cancer remains unclear. In the present study, we investigated the potential anticancer effect of ISO on TNBCs. ISO treatment inhibited the proliferation and anchorage-independent growth of 4T1 cells, a murine triple-negative breast cancer cell line, in a dose-dependent manner. In addition, the results from wound healing and Transwell invasion assay indicated significantly reduced cell migration and invasion in ISO-treated cells. Moreover, we performed the whole transcriptome analysis using RNA-seq to elucidate the molecules and pathways that mediate ISO's anticancer activity. A total of 1972 differentially expressed genes were identified in ISO-treated cells. IPA analysis revealed that the top canonical pathway altered by ISO is NRF2-mediated pathway. ISO-induced NRF2 activation was further confirmed by nuclear translocation of NRF2 protein and upregulation of NRF2 downstream target genes (GSTA1, GSTM1, HMOX1, and NQO1). In summary, our study is the first to demonstrate that ISO inhibits breast cancer cell growth and invasion, in part, by activating NRF2-mediated signaling pathway. Our results provide a novel mechanism for ISO-induced anticancer effect, and strongly support ISO as a promising therapeutic agent for triple-negative breast cancers.
Citation Format: Yusha Zhu, Anthony Murphy, Thomas Kluz, Bo Li, Max Costa, Chuanshu Huang, Hong Sun. Isorhapontigenin inhibits triple-negative breast cancer via activating NRF2-mediated pathway [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 5857.
Abstract 5873: BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors
Authors: Lemos Clara , Schulze Volker K. , Bader Benjamin , Christ Clara D. , Briem Hans , Politz Oliver , Prinz Florian , Holton Simon , Heinrich Tobias , Lefranc Julien , Lienau Philip , Scholz Arne , Nussbaum Franz von , Nising Carl Friedrich , Mumberg Dominik , Bauser Marcus , Hägebarth Andrea 
Published: August 2018

Abstract
The AMP-activated protein kinase (AMPK) is a sensor of the energy status in the cells, playing a key role in controlling their metabolism. For many years, AMPK was mainly perceived as a tumor suppressor in agreement with being a component of the LKB1 tumor suppressor cascade, which inhibits mTORC1. However, in the last few years, some studies suggested that AMPK might actually exert a pro-tumorigenic role in certain contexts. For instance, Liu and colleagues demonstrated that dysregulated MYC expression renders tumor cells sensitive to AMPK depletion (Liu et al, 2012. Nature). The authors showed that, due to their increased anabolism, MYC-dependent cells rely on AMPK to restore ATP levels and to prevent an energy crisis that results in apoptosis and cell death. Here we report the discovery of a new lead structure for the inhibition of AMPK by biochemical high throughput screening. The optimization of this lead structure towards potency and selectivity led to the probe compound BAY-3827 and the use of this tool compound to evaluate the therapeutic potential of AMPK inhibition in MYC-dependent tumors. To demonstrate a cellular effect of BAY-3827 an HRTF® assay (Homogeneous Time Resolved Fluorescence, cisbio) for phospho-Acetyl-CoA carboxylase (p-ACC, Ser79), a direct substrate of AMPK, was used. ACC phosphorylation was strongly inhibited by BAY-3827 in COLO 320DM and IMR-32 cells. However, despite its high potency, BAY-3827 failed to inhibit the proliferation of cells with dysregulated c-MYC or N-MYC. In conclusion, we have identified a potent and selective AMPK inhibitor. Despite demonstrated inhibition of AMPK kinase activity, BAY-3827 treatment did not translate into antiproliferative activity in MYC-dependent cells. While we could not confirm our initial hypothesis, one might speculate that inhibition of AMPK might be of therapeutic utility in other biological contexts. Therefore, the availability of potent and selective inhibitors, as described here, will contribute to further insight into the potential of AMPK inhibition as a therapeutic target in cancer.
Citation Format: Clara Lemos, Volker K. Schulze, Benjamin Bader, Clara D. Christ, Hans Briem, Oliver Politz, Florian Prinz, Simon Holton, Tobias Heinrich, Julien Lefranc, Philip Lienau, Arne Scholz, Franz von Nussbaum, Carl Friedrich Nising, Dominik Mumberg, Marcus Bauser, Andrea Hägebarth. BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors [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 5873.
Abstract 892: Doxorubicin-induced cardiotoxicity in iPSC-cardiomyocytes: Altered mitochondrial gene expression and function
Authors: Reyes Monica E. , Callender Rashida , Ma Jianzhong , Grove Megan L. , Morrison Alanna C. , Hildebrandt Michelle A. 
Published: August 2018

Abstract
Introduction: Cardiomyocytes are highly vulnerable to anthracycline-induced toxicity, which may lead to heart failure. This includes doxorubicin, which is a commonly used chemotherapeutic agent. Although mitochondrial function has been implicated as a mechanism of anthracycline-induced toxicity in rodent heart cells, the precise genes that regulate this response in humans remain to be elucidated. We hypothesized that doxorubicin significantly alters expression of mitochondrial genes in human cardiomyocytes, which impairs mitochondrial function.
Methods: Human inducible pluripotent stem cell (iPSC)-derived cardiomyocytes were treated with doxorubicin or left untreated for control to assess changes in gene expression using RNAseq. A total of 169 genes involved in mitochondrial function, as defined by Ingenuity Pathway Analysis and KEGG, were analyzed for significant differences between untreated and treated conditions using DESeq2 and GenePattern 2.0. Mitochondrial respiration was measured in control and doxorubicin-treated cells using the Seahorse Bioscience XFe96 Cell Mito Stress Test kit. We used a Spearman's partial correlation coefficient analysis to correlate gene expression levels with mitochondrial basal respiration, ATP production, maximal respiration, and spare respiratory capacity for untreated and doxorubicin-treated iPSC-cardiomyocytes.
Results: Of the 169 mitochondrial genes analyzed, we identified 25 genes that were significant in our global differential expression analysis across all conditions (P&lt;0.05). Seven of these genes (ATP5D, COX5A, CYC1, HSD17B10, NDUFB10, NDUFS8, UQCRC1) remained significant in pairwise analyses between control and doxorubicin treated cells. We observed a decrease in mitochondrial respiration following treatment with doxorubicin. Maximal respiration (r=-0.929; P=0.022) and spare respiratory capacity (r=-0.98;P=0.0025) negatively correlated with NDUFS8 expression in doxorubicin-treated iPSC-cardiomyocytes.
Conclusion: Our findings underscore a role for mitochondrial function in the development of doxorubicin-induced cardiotoxicity and implicate specific genes in this process. Doxorubicin-altered gene expression in cardiomyocytes may provide insight into how impaired mitochondrial function leads to heart failure in cancer survivors.
Citation Format: Monica E. Reyes, Rashida Callender, Jianzhong Ma, Megan L. Grove, Alanna C. Morrison, Michelle A. Hildebrandt. Doxorubicin-induced cardiotoxicity in iPSC-cardiomyocytes: Altered mitochondrial gene expression and function [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 892.
Abstract 982: Pharmacological DNA-PK inhibition induces ATM/p53 dependent premature senescence with immunomodulatory phenotype in irradiated cancer cells
Authors: Guo Yige , Sun Qing , Liu Xiaohong , Puc Janusz , Czauderna Frank , Zenke Frank , Blaukat Andree , Vassilev Lyubomir T. 
Published: August 2018

Abstract
A new generation, clinical-stage DNA-PK inhibitor, M3814, potently and selectively blocks one of the two major pathways for repair of DNA double strand breaks (DSB) and synergizes with ionizing radiation (IR) and DSB-inducing chemotherapy. We show that by inhibiting DNA-PK catalytic activity in the presence of DNA DSBs, M3814 simultaneously suppresses DNA repair and a negative regulatory signal to ATM, leading to enhanced activation of the ATM dependent signaling, including CHK2 and p53-dependent cell cycle arrest. Combination treatment of proliferating p53 wild-type cancer cells (A549, A375, H460) with a single dose of ionizing radiation (2-5Gy) and sustained exposure to M3814 induced a complete G1/S and G2/M cell cycle block. Within 4-7 days of treatment cells acquired a typical senescence phenotype with large/flat morphology and β-Gal staining. Live cell imaging and BrdU labeling in A549 cells demonstrated that this phenotype is not reversible following M3814 removal, in contrast to a fully reversible senescence-like phenotype caused by selective p53 activation by MDM2 inhibitor Nutlin-3a. Isogenic p53-null A549 cells lost the ability to fully arrest their cell cycle, confirming the role of p53 in senescence induction. Analysis of mRNA from IR/M3814 induced senescent A549 and A375 cells by the Nanostring PanCancer Immune profiling panel revealed activation of a large group of genes from several immune response pathways, including interferon, cytokine/chemokine, and complement. Eighteen genes were commonly upregulated &gt;3-150 fold compared to controls. These substantial changes in gene expression were built gradually and correlated with the development of senescence phenotype. Several proteins from the induced subset were measured in the cell media (MesoScale Discovery) and confirmed that they are secreted by senescent cells in the absence of M3814. Culture media from M3814-induced senescent cells showed increased immunomodulatory effect on human PBMC-derived immune cells, suggesting increased probability for clearance of IR+M3814 induced senescent cancer cells by the immune system.
Citation Format: Yige Guo, Qing Sun, Xiaohong Liu, Janusz Puc, Frank Czauderna, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev. Pharmacological DNA-PK inhibition induces ATM/p53 dependent premature senescence with immunomodulatory phenotype in irradiated cancer 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 982.
Abstract LB-080: Discovery of an unconventional form of cell-death in colorectal cancer
Authors: Tiwari Amit K. , Amawi Haneen , Chandrabose Karthikeyan , Erhardt Paul , Trivedi Piyush 
Published: August 2018

Abstract
We recently discovered unique, structurally constrained 4-pyridinyl - containing compounds that induce a form of caspase-independent cell death in colorectal cancer (CRC) cells. This was characterized by the simultaneous induction of dysregulated macropinocytosis and macroautophagy, a type of cell death we have termed ‘methuophagy' (this neologism arises from the Greek ‘methuo', to drink to intoxication and ‘phagy', self-eating). Our new class of small molecular probes (BAPT analogues) do not induce cell death via activation of the well characterized classical apoptotic pathways. In contrast, our BAPT compounds cause methuophagy by inducing the formation and accumulation of fluid-filled, heterogeneous vacuoles and autophagosomes, resulting in metabolic failure, loss of membrane integrity, and detachment of cells from the substratum. Methuophagy produces extensive autophagy without cell shrinkage, chromatin condensation, alteration of mitochondrial membrane potential or nuclear membrane damage. The optimization of the BAPT structure led to the discovery of BAPT-27, which has nanomolar potency in inducing methuophagy in broad spectrum of CRC cell lines and may serve as a prototype for a new class of drugs. BAPT-27 produces methuophagy and surmounts MDR in CRC cells independent of Ras, p53 or other apoptotic protein (i.e. Bax, Bak) or expression of ATP-binding cassette (ABC) transporters. Furthermore, BAPT-27 is non-toxic in normal cells and zebrafish. Based on our findings, we postulate that the induction of methuophagy by BAPT-27 produces endolysosomal trafficking defects that prevent recycling of lysosomes and cause lysosome-to-nucleus signaling defect, a mechanism that disturb cellular clearance and energy metabolism. The selected compounds will allow us to understand the biology of methuophagy-induced cell death and will be particularly beneficial for treatment of patients with apoptotic-resistant and aggressive CRCs.
Citation Format: Amit K. Tiwari, Haneen Amawi, Karthikeyan Chandrabose, Paul Erhardt, Piyush Trivedi. Discovery of an unconventional form of cell-death in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-080.
Abstract LB-296: Discovery and development of MEDI7247, a novel Pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2, for treating hematological and solid cancers
Authors: Pore Nabendu , Borrok M Jack , Rebellato Marlon , Hinrichs MaryJane , Schifferli Kevin P. , Monks Noel R. , Tammali Ravinder , Herbst Ronald , Coats Steven R. , Tice David A. 
Published: August 2018

Abstract
The sodium dependent neutral amino acid transporter, ASCT2/SLC1A5 is frequently overexpressed in cancer to sustain “glutamine addiction” of cancer cells and to meet their increased demand for energy and nutrients. High expression of ASCT2 is often associated with poor disease prognosis. Immuno-histochemistry (IHC) data from 600+ tumor samples suggest ASCT2 expression in hematologic and solid cancers, including MM, AML, and DLBCL (≥ 95% positive in respective tumor samples), as well as squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), prostate, pancreatic, and colorectal cancer (66% to 95% positivity in respective tumors). Broad expression across various cancers and restricted expression in normal tissues warrant ASCT2 as an attractive candidate for an antibody drug conjugate. MEDI7247 is a novel investigational antibody-drug conjugate (ADC) comprising an anti-ASCT2 human monoclonal antibody site-specifically conjugated to pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker, with a drug to antibody ratio (DAR) of 2. MEDI7247 specifically binds to cell surface ASCT2 while exhibiting no affinity to the other members of the family, including ASCT1. Following binding, MEDI7247 is internalized and trafficked to the lysosomes to subsequently release the PBD warhead. PBD enters the nucleus where it induces DNA damage and results in tumor cell death. MEDI7247 shows potent in vitro cytotoxicity in several human cancer cell lines expressing variable levels of ASCT2. Dose dependent in vivo efficacy of MEDI7247 was determined in solid tumor xenografts and disseminated hematological malignancy models. MEDI7247 is cross-reactive with cynomolgous monkey ASCT2 and shows similar binding and killing with cyno ASCT2 expressing cells. MEDI7247 demonstrated acceptable safety profile in toxicity studies with non-human primates to support first in human trials. Based on its combined efficacy and safety, MEDI7247 is in clinical development for the treatment of ASCT2 positive cancers.
Citation Format: Nabendu Pore, M Jack Borrok, Marlon Rebellato, MaryJane Hinrichs, Kevin P. Schifferli, Noel R. Monks, Ravinder Tammali, Ronald Herbst, Steven R. Coats, David A. Tice. Discovery and development of MEDI7247, a novel Pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2, for treating hematological and solid cancers [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-296.
Abstract LB-298: MEDI7247: A first in class antibody drug conjugate targeting ASCT2 in a range of solid tumors
Authors: Schifferli Kevin P. , Monks Noel R. , Tammali Ravinder , Borrok M Jack , Flynn Matthew G. , Hurt Elaine M. , Coats Steven R. , Herbst Ronald , Tice David A. , Pore Nabendu 
Published: August 2018

Abstract
MEDI7247 is a first in class ADC consisting of a human anti-ASCT2 monoclonal antibody, site specifically conjugated to highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimers (DAR of 2) via a protease-cleavable linker. ASCT2 (SLC1A5) is a multi-pass, Na+-dependent, neutral amino acid transporter that mediates the uptake of amino acids required for tumor growth and progression. ASCT2 over-expression has been identified on numerous solid tumor indications including pancreatic (94% Positive), small cell (SCLC) and non-small cell (NSCLC) lung cancer (65% positive), colorectal (73% positive), squamous cell carcinoma of the head and neck (SCCHN - 94% positive) and prostate (65% positive). MEDI7247 binds to ASCT2 facilitating internalization and ultimately cell death. We have evaluated the in vivo anti-tumor activity of MEDI7247 in both cell line-derived xenografts (CDX) and patient-derived xenografts (PDX). Cell line-derived xenografts were utilized to examine the anti-tumor activity in colorectal (WiDR), small cell lung cancer (H69) and squamous head and neck (FADU) tumors. Expression of ASCT2 was determined to be high in WiDR and low in both H69 and FADU. Regardless of ASCT2 expression level MEDI7247 controlled tumor growth in each of these models. MEDI7247 was further examined in numerous PDX models of pancreatic, NSCLC and colorectal tumors. Activity was observed across all the PDX models tested. Two pancreatic cancer PDX with both low and high ASCT2 expression levels showed anti-tumor responses to MEDI7247 at all dose levels tested (0.1, 0.2, 0.3 and 0.4 mg/kg). In both models, tumor regressions were observed with durable responses observed beyond 100 days. Flow cytometry analyses reveal high ASCT2 expression of cancer stem cells (CSCs) in Patient Derived Xenografts(PDX). Additionally, MEDI7247 ablates CSCs in vivo in PDX tumors, which may yield opportunity for more durable clinical responses. In summary, preclinical in vivo evaluation of MEDI7247 demonstrates target dependent anti-tumor activity across all the solid tumor indications evaluated and may be important in tumor initiating cell populations. MEDI7247 is currently in Phase I clinical trials.
Citation Format: Kevin P. Schifferli, Noel R. Monks, Ravinder Tammali, M Jack Borrok, Matthew G. Flynn, Elaine M. Hurt, Steven R. Coats, Ronald Herbst, David A. Tice, Nabendu Pore. MEDI7247: A first in class antibody drug conjugate targeting ASCT2 in a range of solid tumors [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-298.
Abstract A45: Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer
Authors: Donnella Hayley , Webber James , Shokat Kevan , Goga Andrei , Gordan John , Bandyopadhyay Sourav 
Published: August 2018

Abstract
Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest. We hypothesized that dynamic changes in signaling, including adaptation and feedback, limit drug efficacy. Using a quantitative proteomics approach, we mapped dynamic changes in the kinome in response to various agents and identified signaling changes that correlate with drug sensitivity. Measurement of dynamics across a panel of breast cancer cell lines identified that maintenance of CDK4 and AURKA activity was associated with drug resistance. We tested whether incomplete inhibition of CDK4 or AURKA was a source of therapy failure and found that inhibition of either was sufficient to sensitize most breast cancer cells to PI3K, AKT, and mTOR inhibitors. In particular, drug combinations including the AURKA inhibitor MLN8237 were highly synergistic and induced apoptosis through enhanced suppression of mTOR signaling to S6 and 4E-BP1 leading to tumor regression in vivo. This approach identifies survival factors whose presence limits the efficacy of target therapy and suggests that Aurora kinase coinhibition could unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.
Citation Format: Hayley Donnella, James Webber, Kevan Shokat, Andrei Goga, John Gordan, Sourav Bandyopadhyay. Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A45.