bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2661: Targeting endoplasmic reticulum-resident proteins for the treatment of B cell cancer
Authors: Tang Chih-Hang Anthony , Valle Juan R. Del , Hu Chih-Chi Andrew 
Published: August 2019

Abstract
IRE-1 splices XBP-1 mRNAs, leading to activation of the functional XBP-1 transcription factor. We showed that genetic deletion of XBP-1 in chronic lymphocytic leukemia (CLL) cells decelerated malignant progression of CLL in mice. We synthesized and characterized a specific inhibitor, B-I09, which could block the RNase activity of IRE-1 with high potency and efficacy. B-I09 clearly suppressed activation of the IRE-1/XBP-1 pathway, as evidenced by the decreased mRNA and protein levels of XBP-1 in intact cells. B-I09 specifically targeted mouse CLL cells in vivo by inducing apoptosis. Because XBP-1 deficiency could compromise the BCR signaling, a crucial survival signal for CLL, we tested whether pharmacological inhibition of XBP-1 could enhance the effect of inhibitors of the BCR signaling by combining B-I09 with ibrutinib (a Bruton’s tyrosine kinase inhibitor) to treat human CLL cells. A strong pharmacological synergism was determined using the Chou-Talalay combination index method, suggesting that B-I09 could help ibrutinib to achieve higher cytotoxicity at a lower dose, addressing ibrutinib’s toxicity issue. Our studies also led us to discover that IRE-1 interacted with STING, an ER-resident protein critical for cytoplasmic DNA sensing and interferon production. We showed that the IRE-1/XBP-1 pathway was required for the interferon-producing function of STING, and that agonists of STING selectively triggered mitochondria-mediated apoptosis in malignant B cells. Upon stimulation, STING was degraded inefficiently in malignant B cells, implying that prolonged activation of STING could lead to apoptosis. In CLL-bearing mice, injection of the STING agonist, 3'3'-cGAMP, induced apoptosis and regression of leukemia. Similarly efficacious effects were elicited by 3'3'-cGAMP injection in syngeneic or immunodeficient NSG mice grafted with malignant B cells. These data suggested that STING agonists could directly eradicate CLL and other B cell malignancies in vivo. IRE-1 and STING are thus useful ER-resident protein targets for the treatment of B cell cancer.
Citation Format: Chih-Hang Anthony Tang, Juan R. Del Valle, Chih-Chi Andrew Hu. Targeting endoplasmic reticulum-resident proteins for the treatment of B cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2661.
Abstract 2666: ARD1-mediated Hsp70 acetylation protects cancer cells against the cellular stress
Authors: Seo Ji Hae , Shin So-Jin , Kim Jin Young , Lee Seungmee , Chung Hyewon , Cho Chi-Heum 
Published: August 2019

Abstract
The 70 kDa heat shock proteins (Hsp70s) are a family of ubiquitously expressed intracellular proteins that are required for the maintenance of protein homeostasis. Hsp70 is highly induced in response to cellular stressors, including oxidative stress, hyperthermia, hypoxia and changes in pH, contributing to cellular resistance to stress-induced cell death. Most tumor cells, which live under continuous stress conditions, express elevated levels of Hsp70 to combat these harsh conditions and suppress apoptosis. During cellular stress, Hsp70 maintains protein homeostasis through two opposing mechanisms: protein refolding and degradation. However, the mechanisms by which Hsp70 balances these opposing functions under stress conditions remain unknown. Here, we demonstrate that Hsp70 preferentially facilitates protein refolding after stress, gradually switching to protein degradation via a mechanism dependent on ARD1-mediated Hsp70 acetylation. During the early stress response, Hsp70 is immediately acetylated by ARD1 at K77, and the acetylated Hsp70 binds to the co-chaperone Hop to allow protein refolding. Thereafter, Hsp70 is deacetylated and binds to the ubiquitin ligase protein CHIP to complete protein degradation during later stages. In addition, this switch is essential for the maintenance of protein homeostasis and ultimately rescues cancer cells from stress-induced cell death. Therefore, ARD1-mediated Hsp70 acetylation is a key regulatory mechanism that enables Hsp70-expressing cancer cells to be more resistant to proteotoxic stress, and regulation of Hsp70 K77 acetylation might be helpful to cancer treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Ji Hae Seo, So-Jin Shin, Jin Young Kim, Seungmee Lee, Hyewon Chung, Chi-Heum Cho. ARD1-mediated Hsp70 acetylation protects cancer cells against the cellular stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2666.
Abstract 2669: A role for HOXA5 in the transcriptional response of ovarian and fallopian tube surface epithelial cells to norepinephrine
Authors: Dash Sweta , Gjyshi Anxhela , Cen Ling , Cheng Chia-Ho , Zhang Chaomei , Yoder Sean J. , Teer Jamie K. , Armaiz-Pena Guillermo N. , Monteiro Alvaro N. 
Published: August 2019

Abstract
Chronic stress has been suggested to play a role in tumor initiation, progression and patient survival. Studies have shown that activation of the sympathetic nervous system and increased levels of stress-associated hormones such as norepinephrine can enhance migration, invasion and growth of ovarian cancer cells. However, the extent to which stress contributes to tumor initiation remains unknown. The purpose of this study was to explore the effects of norepinephrine on the transcriptional program of immortalized normal cell lines presumed to be the origin of epithelial ovarian cancers. We treated normal immortalized ovarian (iOSE) and fallopian tube (iFTE) surface epithelial cells with 10uM norepinephrine for 15 min, 1h and 4h and generated global transcriptomic profile of treated vs untreated cells by RNA-Seq. The most significant gene expression changes (P(adj) &lt; 0.05) were observed at the 1h time point; with an overlap of 45 differentially expressed genes in both iOSE and iFTE cells. Genes in immune-related and developmental pathways were found to be highly enriched in the norepinephrine treated samples set. By the 4h time point, the number of differentially expressed genes had increased to 313 genes from 234 at 1h in iFTE cells, while it reduced to 34 genes from 53 in iOSE cells. Additionally, the number of differentially expressed genes common to iOSE and iFTE cells had reduced to 14. Gene ontology analysis of the differentially expressed genes revealed ‘transcription factor’ to be the most significantly overrepresented class (based on FDR value) at both 1h and 4h time-points. Promoter enrichment analysis identified HOXA5, GFI1 and FOXI1 transcription factor binding sites to be highly enriched (based on Z-score and Fisher-Score) at both time points. HOXA5 ranked consistently at the top in both cell lines and at both 1h and 4h time points. These observations suggest that HOXA5 may play a central role in regulating the early response to norepinephrine in normal ovarian and fallopian tube cells. We will further assess the function of HOXA5 through ChIP-Seq and shRNA- mediated silencing.
Citation Format: Sweta Dash, Anxhela Gjyshi, Ling Cen, Chia-Ho Cheng, Chaomei Zhang, Sean J. Yoder, Jamie K. Teer, Guillermo N. Armaiz-Pena, Alvaro N. Monteiro. A role for HOXA5 in the transcriptional response of ovarian and fallopian tube surface epithelial cells to norepinephrine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2669.
Abstract 2678: A clonal expression biomarker improves prognostic accuracy: TRACERx lung
Authors: Biswas Dhruva , Birkbak Nicolai J. , Rosenthal Rachel , Hiley Crispin T. , Lim Emilia L. , Papp Krisztian , Krzystanek Marcin , Djureinovic Dijana , Wu Yin , Moore David A. , Skrypski Marcin , Abbosh Christopher , Bakir Maise Al , Watkins Thomas B. , Veeriah Selvaraju , Wilson Gareth A. , Jamal-Hanjani Mariam , Chinnaiyan Arul M. , Micke Patrick , Bartek Jiri , Csabai Istvan , Szallasi Zoltan , Herrero Javier , McGranahan Nicholas , Swanton Charles 
Published: August 2019

Abstract
At the point of cancer diagnosis, molecular biomarkers aim to stratify patients into precise disease subtypes predictive of outcome independent of standard clinical parameters such as tumour stage. Although prognostic gene expression signatures have been derived for many cancer types, seldom have they been shown to improve therapeutic decision making, limiting their clinical use. While intra-tumour transcriptomic heterogeneity (RNA-ITH) has been shown to bias existing biomarkers, efforts to control for this biological parameter have not been considered in biomarker development. Here, we analyse multi-region RNA-seq and whole-exome data for 156 tumour regions from 48 TRACERx patients to explore RNA-ITH in NSCLC. We show that chromosomal instability is a major driver of RNA-ITH, through the generation of heterogeneous copy number events within tumours, and that existing prognostic gene expression signatures are vulnerable to sampling bias. To address this issue, we develop the Outcome Risk Associated Clonal Lung Expression (ORACLE) assay, comprised of genes expressed homogeneously within individual tumours but heterogeneously between patients. These genes are enriched in modules associated with cell proliferation, such as mitosis and nucleosome assembly, that are often selected for through copy number gain events occurring early in tumour evolution. Our approach to identify “clonal” transcriptomic biomarkers in NSCLC overcomes tumour sampling bias, improves survival risk forecasting over current clinicopathological risk factors, and may be generalised to other cancer types, whilst revealing the early evolutionary selection of high risk DNA copy number events driving poor clinical outcome.
Citation Format: Dhruva Biswas, Nicolai J. Birkbak, Rachel Rosenthal, Crispin T. Hiley, Emilia L. Lim, Krisztian Papp, Marcin Krzystanek, Dijana Djureinovic, Yin Wu, David A. Moore, Marcin Skrypski, Christopher Abbosh, Maise Al Bakir, Thomas B. Watkins, Selvaraju Veeriah, Gareth A. Wilson, Mariam Jamal-Hanjani, Arul M. Chinnaiyan, Patrick Micke, Jiri Bartek, Istvan Csabai, Zoltan Szallasi, Javier Herrero, Nicholas McGranahan, Charles Swanton. A clonal expression biomarker improves prognostic accuracy: TRACERx lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2678.
Abstract 268: Engineering of transgenic mice expressing human mesothelin for investigation of mesothelin-targeted therapeutics
Authors: Zhang Xianyu , Hagerty Brendan , Guerin Theresa , O'Sullivan Norene , Kozlov Serguei , Alewine Christine 
Published: August 2019

Abstract
Most monoclonal antibody-based therapeutics are specific for the human isoform of their targets and do not cross-react with orthologous mouse isoforms. This frequently limits pre-clinical modeling to human-derived tumors growing in immune compromised mice and precludes combination studies with immune modulating agents which rely on an active immune system for activity. Although introduction of human cDNA into mouse tumor cells will make these cells susceptible to targeting, a syngeneic mouse may reject or partially reject cells bearing the foreign transgene, impacting anti-tumor efficacy studies. Mesothelin (MSLN) is the target of many cell- and antibody-based therapies that have reached clinical trials due to its lack of expression in critical normal tissues and robust expression in many solid tumors. We have generated two distinct transgenic C57/Bl6 mouse models with compartment-limited expression of human MSLN (hMSLN) for use in pre-clinical testing of MSLN-targeted therapeutics: 1) TPO/hMSLN mice express full-length hMSLN from an insulated rat thyroid peroxidase gene promoter. Analysis by RT-PCR, immunoblot and IHC demonstrate strong thyroid-specific expression hMSLN. 2) In Nor/hMSLN mice, the hMSLN coding region was inserted as a full-length cDNA into the native mMSLN locus via a homologous recombination knock-in technique such that hMSLN is expressed in place of the mouse isoform under the control of endogenous murine MSLN transcription regulatory elements. IHC studies show expected expression of hMSLN in mouse pleura, pericardium and peritoneum. Shed hMSLN can be readily detected in the serum of both transgenic lines using ELISA, similar to human patients. Treatment of either model with MSLN-targeted immunotoxin LMB-100 at the maximum dose tolerated by non-transgenic C57/Bl6 mice resulted in no gross toxicity. Histologic analysis revealed subclinical pericarditis in Nor/hMSLN mice. No post-treatment thyroid damage was observed in TPO/hMSLN mice even upon detailed histologic examination of thyroid tissue. Syngeneic mouse pancreatic cancer cells expressing hMSLN transgene implanted orthotopically into TPO/hMSLN or Nor/hMSLN grew as well or better as those grown in non-transgenic C57/Bl6 mice. We have established two immunologically proficient transgenic mouse models expressing hMSLN that can be used for evaluating immune effect of hMSLN-targeted therapeutics as well as their on-target/off-tumor toxicities.
Citation Format: Xianyu Zhang, Brendan Hagerty, Theresa Guerin, Norene O'Sullivan, Serguei Kozlov, Christine Alewine. Engineering of transgenic mice expressing human mesothelin for investigation of mesothelin-targeted therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 268.
Abstract 2687: Dolasynthen–a novel, homogeneous Auristatin F hydroxypropyl amide antibody-drug conjugate platform
Authors: Toader Dorin , Damelin Marc , Dirksen Anouk , Fesler Shawn P. , Collins Scott D. , Nehilla Barrett J. , Xu Jian , Xu Ling , Cattcott Kalli C. , Uttard Alex , Lee Winnie , Clardy Susan , Stevenson Cheri A. , Qin LiuLiang , Conlon Patrick R. , Kozytska Mariya V. , Chin Chen-Ni , Lee David H. , Lowinger Timothy B. 
Published: August 2019

Abstract
Dolasynthen is a novel, fully synthetic, structurally homogeneous platform that enables the construction of ADCs with tunable drug-to-antibody ratios (DAR), from a low of 2 to a high of 24. The resulting ADCs exhibit excellent physicochemical properties and fully homogeneous conjugates can be created through a variety of bioconjugation chemistries. Analogous to our first platform, Dolaflexin®, Dolasynthen is loaded with the proprietary payload Auristatin F hydroxypropylamide (AF-HPA) with precisely defined numbers of the cytotoxin per Dolasynthen scaffold.Studies that evaluate the tolerability and efficacy of Dolasynthen in preclinical models are described herein. ADCs containing a range of DAR values were generated following conjugation of Dolasynthen to two different monoclonal antibodies. The DAR of the ADCs was achieved by controlled reduction of native disulfide bonds in IgG1 antibodies, chromatographic fractionation, or through use of site-specific conjugation technologies. ADCs with both DAR6 and DAR12 were evaluated in vitro and also in vivo in the mouse, rat and monkey, for efficacy, tolerability and PK. Dolasynthen conjugates had excellent physicochemical properties and displayed the expected cell binding and in vitro cytotoxicities. In vivo pharmacology of Dolasynthen ADCs in in vivo xenograft models showed dose-dependent tumor growth inhibition at low mg/kg mAb doses. Tolerability in the rat at multiple doses was determined, including histopathological evaluation. Dolasynthen ADCs showed excellent PK characteristics in mouse, rat and NHP. Overall, the Dolasynthen platform appears to offer significant potential for clinical application.
Citation Format: Dorin Toader, Marc Damelin, Anouk Dirksen, Shawn P. Fesler, Scott D. Collins, Barrett J. Nehilla, Jian Xu, Ling Xu, Kalli C. Cattcott, Alex Uttard, Winnie Lee, Susan Clardy, Cheri A. Stevenson, LiuLiang Qin, Patrick R. Conlon, Mariya V. Kozytska, Chen-Ni Chin, David H. Lee, Timothy B. Lowinger. Dolasynthen–a novel, homogeneous Auristatin F hydroxypropyl amide antibody-drug conjugate platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2687.
Abstract 269: DNA-PK inhibitor, M3814, as a new combination partner of Mylotarg in the treatment of acute myeloid leukemia
Authors: Zimmermann Astrid , Carr Michael , Zenke Frank T. , Blaukat Andree , Vassilev Lyubomir T. 
Published: August 2019

Abstract
Despite significant advances in the development of new treatments for acute myeloid leukemia (AML) the therapeutic success remains relatively poor. There remains an urgent need for improved therapies with increased tumor potency and selectivity. Mylotarg is the first AML drug from a new generation of antibody drug conjugate (ADC) therapies targeting the acute leukemia cell compartment with increased specificity. This agent targets leukemia cells for apoptosis with a cytotoxic warhead, calicheamicin, carried by a CD33-specific antibody. Calicheamicin induces DNA double strand breaks (DSB) which, if left unrepaired, lead to cell cycle arrest and apoptosis in cancer cells. However, repair of DSBs by the non-homologous end joining pathway driven by DNA-PK (DNA-dependent protein kinase) can reduce the efficacy of calicheamicin. M3814 is a novel, potent and selective inhibitor of DNA-PK protein kinase. This compound effectively blocks DSB repair, strongly potentiates the antitumor activity of ionizing radiation and DSB-inducing chemotherapeutics and is currently under clinical investigation. Suppressing DSB repair with M3814 synergistically enhanced the apoptotic activity of calicheamicin in cultured AML cells. Combination of M3814 with Mylotarg in two AML xenograft models, MV4-11 and HL-60, demonstrated increased efficacy and significantly improved survival benefit without elevated body weight loss. Our results support a new application for pharmacological DNA-PK inhibitors as enhancers of Mylotarg efficacy and a potential new combination treatment option for AML patients.
Citation Format: Astrid Zimmermann, Michael Carr, Frank T. Zenke, Andree Blaukat, Lyubomir T. Vassilev. DNA-PK inhibitor, M3814, as a new combination partner of Mylotarg in the treatment of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 269.
Abstract 2692: Preclinical development of a novel, highly selective PI3Kδ inhibitor, IOA-244, for the treatment of solid malignancies
Authors: Ewings Katherine , MacQueen Amy , Shah Pritom , Tsapara Anna , Papakonstanti Evangelia , Veen Lars van der , Lahn Michael , Johnson Zoe 
Published: August 2019

Abstract
The Class I Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) family is an attractive target class for the treatment of hematological and solid malignancies. In addition to the direct effects of PI3Kδ inhibition on B cell malignancies, inhibiting PI3Kδ preferentially targets regulatory T cells and myeloid derived suppressor cells, thus breaking tumor-induced immune tolerance and restoring anti-tumor immunity. To date, the development of selective inhibitors of the Class I PI3K family has been hampered by the lack of isoform specificity as well as safety issues. IOA-244 is a novel, highly selective, orally bioavailable PI3Kδ inhibitor, with the unique property of being ATP non-competitive; these characteristics make IOA-244 the ideal drug to explore the hypothesis that PI3Kδ inhibition can modulate anti-tumor immunity as a monotherapy and in combination in clinical trials.
In mouse models, IOA-244 inhibited tumor growth when combined with either anti-PD-1 or anti-PD-L1. In the CT26 model the composition of the tumour infiltrating lymphocytes showed a marked decrease in the suppressor cell populations, i.e. Tregs and MDSCs, as well as tumor associated macrophages (TAMs). Conversely a concomitant increase in natural killer cells as well as the ratio of cytotoxic CD8+ T cells: Treg cells was observed. Furthermore, in vitro studies using primary human T cells demonstrated a selective and concentration-dependent suppression of Treg cells by IOA-244 whilst leaving CD8+ T cell proliferation intact.
In addition to effects on the immune system, we are exploring the potential of IOA-244 to mediate direct anti-cancer effects on solid tumors with a high expression of PIK3CD. IOA-244 induced a concentration-dependent inhibition of p-AKT in MDA-MB-231 cells. Furthermore, we demonstrate strong anti-proliferative activity by IOA-244 on hepatocellular tumor lines in vitro. Activity in these and other cell and patient derived lines is being studied, both in xenograft in vivo studies and in vitro models.
Based on GLP toxicology studies, IOA-244 has the potential to be a best-in-class PI3Kδ inhibitor with a safety and pharmacokinetic profile that is amenable for use alone and in combination with immunotherapies for the treatment of solid malignancies. IOA-244 is poised to enter phase I clinical testing in selected cancer indications in the first half of 2019.
Citation Format: Katherine Ewings, Amy MacQueen, Pritom Shah, Anna Tsapara, Evangelia Papakonstanti, Lars van der Veen, Michael Lahn, Zoe Johnson. Preclinical development of a novel, highly selective PI3Kδ inhibitor, IOA-244, for the treatment of solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2692.