bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2581: Plasma HPV cell free DNA as an earlier predictor of treatment response in advanced oropharyngeal cancer
Authors: Hanna Glenn J. , Supplee Julianna G. , Kuang Yanan , Geary Kate , Janne Pasi A. , Haddad Robert I. , Paweletz Cloud P. 
Published: August 2018

Abstract
Purpose: Human papillomavirus (HPV) is associated with the majority of oropharyngeal squamous cell carcinomas (OPSCC), with a rising incidence of OPSCC predominantly among middle-aged men. Tumor-derived HPV cell-free (cf)DNA can be detected and quantified in circulation with high sensitivity and specificity. Although cfDNA has limited clinical application in monitoring locoregional spread of these tumors, up to 10% of HPV+ OPSCC patients present or recur with distant, metastatic disease. The potential of HPV DNA monitoring in this setting remains largely unexplored.
Methods: We present a proof-of-concept prospective observational cohort of recurrent, metastatic (R/M) HPV+ OPSCC patients treated with standard systemic therapies. We utilized droplet digital (dd)PCR to identify and quantify HPV cfDNA (strains 16, 18, 31, 33 and 45) at multiple time points throughout treatment. We then compared HPV cfDNA concentration at various timepoints with clinical parameters such as disease burden and treatment response.
Results: Clinicopathologic data from 12 R/M patients revealed a predominantly male cohort (11/12, 92%) with a median age of 55 at diagnosis. Eight (67%) were on immunotherapy treatments and the other four on standard chemotherapy during the study period (2.5 months). Plasma HPV cfDNA was detected in 6/12 (50%) samples (range 0-4460 copies/mL) in at least one timepoint during the study. All patients with undetectable HPV cfDNA had evidence of stable, low burden disease or no measurable lesions (near-complete response) on their current therapy. HPV cfDNA levels strongly correlated with both disease burden (p &lt; 0.01) and distant disease sites (p &lt; 0.01). In three cases, HPV DNA levels declined prior to contrast enhanced imaging findings which later confirmed treatment response (up to 14 days prior to planned imaging).
Conclusion: Our results suggest that high sensitivity plasma HPV cfDNA levels can be an early indicator of treatment response. HPV cfDNA monitoring could significantly impact clinical decision-making and improve patient outcomes by informing treatment response or failure. Further studies are underway to validate these findings and determine how early cfDNA can detect metastatic disease.
Citation Format: Glenn J. Hanna, Julianna G. Supplee, Yanan Kuang, Kate Geary, Pasi A. Janne, Robert I. Haddad, Cloud P. Paweletz. Plasma HPV cell free DNA as an earlier predictor of treatment response in advanced oropharyngeal 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 2581.
Abstract 2648: Prognostic significance of thyroid hormone receptor-alpha-2 (THRα2) expression in triple-negative breast cancer: A TCGA study
Authors: Jerzak Katarzyna J. , Dvorkin-Gheva Anna , Cockburn Jessica G. , Bane Anita , Hassell John A. 
Published: August 2018

Abstract
Background: Thyroid hormones promote breast cancer cell proliferation and expression of their cognate nuclear receptors has shown prognostic potential in small cohort studies. Among two isoforms of thyroid hormone receptor alpha (THRα), the alpha1 splice variant (THRα1) promotes thyroid hormone mediated cell proliferation whereas the alpha2 variant (THRα2) opposes it. Hence, THRα2 expression may be a favorable prognostic biomarker in breast cancer.
Methods: A publicly available database of breast tumors archived by The Cancer Genome Atlas (TCGA) was employed for this study. We analyzed RNA expression of THRα1 and THRα2 in 106 triple negative breast cancers (TNBCs) and correlated it with tumor stage (I vs II vs III) and nodal involvement (positive vs negative). Tumor grade was not uniformly reported. Univariate Cox proportional hazards regression models were fitted to determine the prognostic impact of THRα1 and THRα2 expression on overall survival (OS) and multivariate models were adjusted for age, tumor stage and radiation treatment.
Results: The median age of women was 54 (range 29-90) and 12.3% died. The majority (62.3%) of patients presented with stage II disease; 16.0% were stage III and 17.9% were stage I at diagnosis. There was no significant correlation between THRα1 or THRα2 expression and tumor stage or nodal involvement. Expression of THRα2 was associated with improved OS in both uni- and multi-variate models (Table).
Conclusions: In this study, THRα2 expression was independently prognostic for improved OS in TNBC. We previously demonstrated similar results in 158 TNBCs via immunohistochemistry but differentiation between RNA (as opposed to protein) splice variants is more precise. These results support investigation of THRα2 up-regulation or THRα1 inhibition as therapeutic strategies.
Table. Prognostic associations of THRα2 expression in TNBCVariableUnivariate HR (95%CI)p valueMultivariate HR (95%CI)p valueLog (THRα2)0.46 (0.26-0.81)&lt;0.010.28 (0.09-0.84)0.02Log (THRα1)0.54 (0.31-0.94)0.031.38 (0.53-3.62)0.51Age (years)0.98 (0.94-1.02)0.370.92 (0.84-1.01)0.10Stage (I vs II vs III vs IV)6.14 (2.19-17.22)&lt;0.0126.03 (4.05-167.14)&lt;0.01Radiation therapy (yes vs no)0.23 (0.04-1.22)0.080.10 (0.02-0.73)0.02
Citation Format: Katarzyna J. Jerzak, Anna Dvorkin-Gheva, Jessica G. Cockburn, Anita Bane, John A. Hassell. Prognostic significance of thyroid hormone receptor-alpha-2 (THRα2) expression in triple-negative breast cancer: A TCGA study [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 2648.
Abstract 267: Nonsteroidal anti-inflammatory drugs induce ER stress- and BID-dependent immunogenic cell death to suppress colorectal tumorigenesis
Authors: Fletcher Rochelle Elayne , Leibowitz Brian , Wang Yijun , Concha-Benavente Fernando , Ferris Robert , Schoen Robert , Yu Jian , Zhang Lin 
Published: August 2018

Abstract
Prevention or early detection represents a key approach for reducing the mortality and morbidity of CRC. Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with decreased risk of CRC in numerous epidemiological studies, clinical trials, and animal model studies. However, the mechanism by which NSAIDs suppress colorectal tumorigenesis has remained unclear. We previously demonstrated that the chemopreventive effect of NSAIDs is mediated by a synthetic lethal interaction between death receptor signaling and loss of the gatekeeper APC tumor suppressor, which is dependent on the BH3-only Bcl-2 family member BID. In this study, we found a critical role of endoplasmic reticulum (ER) stress upstream of death receptor signaling and BID activation. Elevated levels of ER stress and cell death markers were detected in advanced adenomas from patients taking NSAIDs including aspirin. Inhibiting ER stress using a pharmacological approach abolished the apoptotic effect of NSAIDs in CRC cells and normal colonic epithelial cells with APC loss and also suppressed the chemopreventive activity of the NSAID sulindac in APCMin/+ mice. Importantly, our results unveiled a critical role of ER stress and BID-dependent cell death in triggering immune-mediated elimination of nascent cells that lose APC. Markers of immunogenic cell death (ICD), including plasma membrane translocation of calreticulin and phagocytosis by dendritic cells, were suppressed in cells with BID knockout or ER stress inhibition. BID knockout or ER stress inhibition also reduced tumor infiltrating lymphocytes (TILs) in sulindac-treated APCMin/+ mice. Collectively, our results suggest that NSAIDs suppress colorectal tumorigenesis by enhancing immunosurveillance through ER stress and BID-dependent ICD. These results provide novel insight into the chemopreventive mechanism of NSAIDs, which may help design more effective chemopreventive strategies and agents.
Citation Format: Rochelle Elayne Fletcher, Brian Leibowitz, Yijun Wang, Fernando Concha-Benavente, Robert Ferris, Robert Schoen, Jian Yu, Lin Zhang. Nonsteroidal anti-inflammatory drugs induce ER stress- and BID-dependent immunogenic cell death to suppress colorectal tumorigenesis [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 267.
Abstract 2671: 17beta-hydroxywithanolides inhibit the proliferation of castration-resistant prostate cancer cells by reducing levels of cFLIP
Authors: Brooks Alan D. , Wright Nicola E. , Xu Ya-ming , Wijeratne Kithsiri , Tewary Poonam , Cross Neil , Gunatilaka A. A. Leslie , Sayers Thomas J. 
Published: August 2018

Abstract
Using a high throughput gene expression profiling assay directly targeting genes of the androgen receptor pathway, we previously identified the 17beta-hydroxywithanolide (17-BHW), physachenolide C (PCC), as a potent inhibitor of prostate cancer cell growth. Using a panel of prostate cancer cell lines, PCC at low concentrations (IC50 20-50 nM) reduced prostate cancer cell numbers under both standard and 3D in vitro growth conditions. This reduction in cell number was due to growth inhibition and not apoptosis, with PCC causing reductions in the levels of cyclin D, an increase in p21 and arrest of cells in the G1 phase of the cell cycle. Subsequently over 150 natural and semi-synthetic withanolides were evaluated for their ability to inhibit prostate cancer cell growth. All highly active withanolides were 17-BHWs, and some were up to 4-fold more active than PCC. Preliminary structure-activity relationship (SAR) studies suggested that the enone moiety in ring A was essential for activity. In addition, acetoxylation at C-18, an alpha orientation of the side-chain lactone group and the double bond at C-24(25) of the lactone ring played important roles in determining the activity of 17-BHWs as inhibitors of prostate cancer cell growth. Interestingly highly active 17-BHWs rapidly reduced levels of both antiapoptotic cFLIPL and cFLIPS proteins in 22Rv1 prostate cancer cells. However, this reduction did not sensitize 22Rv1 cells to apoptosis. Nonetheless specific reduction of cFLIPL in the castration-resistant 22Rv1 cells using siRNA significantly inhibited their proliferation. This suggests that cFLIPL plays a critical role in the proliferation of some castration-resistant prostate cancer cells. Since the 17-BHW scaffold is amenable to optimization by a medicinal chemistry approach, this could lead to the identification of highly active natural product-based inhibitors of castration-resistant prostate cancer cell proliferation. The cellular molecular target(s) of active 17-BHWs that promote cFLIP reduction are currently under further investigation.
Funded by FNLCR Contract HHSN261200800001E and the University of Arizona.
Citation Format: Alan D. Brooks, Nicola E. Wright, Ya-ming Xu, Kithsiri Wijeratne, Poonam Tewary, Neil Cross, A. A. Leslie Gunatilaka, Thomas J. Sayers. 17beta-hydroxywithanolides inhibit the proliferation of castration-resistant prostate cancer cells by reducing levels of cFLIP [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 2671.
Abstract 2674: Novel tubulin polymerization inhibitors repress tumor xenografts in nude mice and leukemia in zebrafish
Authors: Xie Yanqi , Kril Liliia , Zhang Wen , Frasinyuk Mykhaylo , Bondarenko Svitlana , Hausman Elizabeth , Martin Zachary , Wyrebek Przemyslaw , Yu Tianxin , Zhan Changguo , Sviripa Vitaliy , Blackburn Jessica , Watt David , Liu Chunming 
Published: August 2018

Abstract
In an effort to screen natural compounds and their derivatives as novel agents for cancer treatment, we developed two semisynthetic nature compounds, A14 and A52, which have potencies in an in vitro cell proliferation studies against LS174T and PC-3 cells in the mid-nanomolar range. A14 inhibited more than 90% of in vitro cancer cell proliferation around 300 nM and also inhibited in vivo PC-3 prostate cancer xenografts in nude mice. Cell morphology studies and comparisons with known antineoplastic agents suggested that A14 disrupted microtubule organization. In vitro tubulin polymerization assay suggested that A14 inhibited this process. Based on molecular docking, A14 fits very well in the colchicine-binding site at the interface between the alpha-tubulin and beta-tubulin. Further analyses suggest that A14 sensitivity may correlate with CDK/cyclin activity. A14 inhibited PC-3 prostate cancer xenografts in nude mice. In addition to solid tumors, A14 and its analog A52 strongly inhibited a panel of human leukemia cancer cell lines. Furthermore, these compounds inhibited Myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model. Although many tubulin inhibitors were available, there is no compound that targeting the colchicine-binding site has been approved by FDA for cancer treatment. This new family of tubulin polymerization inhibitors could be further developed for the treatment of both solid and liquid tumors.
Citation Format: Yanqi Xie, Liliia Kril, Wen Zhang, Mykhaylo Frasinyuk, Svitlana Bondarenko, Elizabeth Hausman, Zachary Martin, Przemyslaw Wyrebek, Tianxin Yu, Changguo Zhan, Vitaliy Sviripa, Jessica Blackburn, David Watt, Chunming Liu. Novel tubulin polymerization inhibitors repress tumor xenografts in nude mice and leukemia in zebrafish [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 2674.
Abstract 2688: ZB716 is orally efficacious in blocking tumor growth in mouse xenograft models
Authors: Guo Shanchun , Zhang Changde , Liu Jiawang , Zheng Shilong , Yang Lin , Wang Guangdi 
Published: August 2018

Abstract
Advances in oral SERDs development so far have been confined to nonsteroidal molecules such as those containing a cinnamic acid moiety, which are in early-stage clinical evaluation. ZB716 was previously reported as an orally bioavailable SERD structurally analogous to fulvestrant. In this study, we examined the binding details of ZB716 to the estrogen receptor alpha (ERα) by computer modeling to reveal its interactions with the ligand binding domain as a steroidal molecule. The ability of ZB716 to inhibit cell growth and downregulate ER expression in endocrine resistant, ERα mutant breast cancer cells was demonstrated. Moreover, in the MCF-7 xenograft and two patient derived xenograft models, orally administered ZB716 showed superior efficacy in blocking tumor growth when compared to fulvestrant. Importantly, such enhanced efficacy of ZB716 was shown to be attributable to its markedly higher bioavailability, as evidenced in the final plasma and tumor tissue concentrations of ZB716 in mice where drug concentrations were found significantly higher than in the fulvestrant treatment group.
Citation Format: Shanchun Guo, Changde Zhang, Jiawang Liu, Shilong Zheng, Lin Yang, Guangdi Wang. ZB716 is orally efficacious in blocking tumor growth in mouse xenograft models [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 2688.
Abstract 2697: Alterations in the HSP70 interactome are induced by overexpression of MUC1 in pancreatic cancer
Authors: Nitika . , Wolfgeher Donald J. , Mukherjee Pinku , Truman Andrew W. 
Published: August 2018

Abstract
Heat Shock Protein 70 (HSP70) is an evolutionarily well-conserved molecular chaperone involved in several cellular processes such as folding of proteins, modulating protein-protein interactions and transport of proteins across membranes. HSP70 works synergistically with a series of chaperones, co-chaperones, adaptors, and folding enzymes known as the HSP70 “interactome”. Previous work has demonstrated that HSP70 interactome changes can be promoted by overexpression of oncoproteins. An important “client” of HSP70 is the oncoprotein MUC1. MUC1 is overexpressed and promotes drug resistance in pancreatic cancer. We applied quantitative affinity-purification mass spectrometry (AP-MS) to characterize the HSP70 interactome differences between PC3/NEO and PC3/MUC1 cell lines. 439 HSP70-interacting proteins were identified and quantified via LC-MS/MS. Interestingly while 53% of HSP70 interactions remained constant upon MUC1 overexpression, 29% significantly increased and 18% decreased. Many of the altered proteins were key co-chaperones that regulate and maintain HSP70 activity. High levels of MUC1 promoted HSP70 association with 15 co-chaperones (HSPA5, DNAJB1, STIP1, TXNDC5, HSPB1, CCT2, TCP1, P4HB, CCT6A, CCT8, PDIA3 and HSP90B). Conversely, MUC1 overexpression triggered the loss of HSP70 interaction with only 2 co-chaperones (PPIB and DNAJA2). We are currently validating these altered interactions using an array of biochemical techniques. Our hope is that by understanding these HSP70 interactome changes, we may be able to uncover novel ways to inhibit MUC1 function in pancreatic cancer.
Citation Format: . Nitika, Donald J. Wolfgeher, Pinku Mukherjee, Andrew W. Truman. Alterations in the HSP70 interactome are induced by overexpression of MUC1 in pancreatic 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 2697.
Abstract 2713: Preclinical development of first-in-class antibodies targeting Siglec-9 immune checkpoint for cancer immunotherapy
Authors: Bénac Olivier , Gaudin Marion , Ors Mélody , Roy Aude Le , Blanc Hélène Rispaud , Soulas Caroline , Chanteux Stéphanie , Rossi Benjamin , Gauthier Laurent , Paturel Carine , Morel Yannis , Perrot Ivan , Cornen Stéphanie 
Published: August 2018

Abstract
Siglec-9 is a MHC class I-independent inhibitory receptor expressed on NK and myeloid cells (including dendritic cells, monocytes and neutrophils). Its ligands are sialic acid-containing carbohydrates which are over-expressed on various tumor types compared to normal tissues (1). Sialylation of tumor cells is involved in tumor cell malignancy and is reported for decades as a mechanism of escape from immune surveillance (2). The loss of beta-2-microglobulin, an essential component of MHC class I antigen presentation, was recently described as a common mechanism of resistance to checkpoint blockade in clinical trials and revealed the need for MHC class I-independent therapies (3-4). Thus, Siglec-9-sialic acid interaction disruption may promote anti-tumor immunity independently of MHC class I expression by tumors. Here, we describe the discovery and characterization of first-in class anti-human Siglec-9 antibodies as new checkpoint blockade therapy in a wide range of cancers. Antibodies were discovered that efficiently block the interaction between Siglec-9 and its ligands. Epitope mapping revealed that antibodies bind to distinct epitopes on Siglec-9 near the sialic acid binding site. In vitro assays showed that they potently reverse inhibitory functions of Siglec-9 on NK cells leading to subsequent sialic acid-expressing tumor cell killing. Interestingly, Siglec-9 is enhanced on both CD4+ and CD8+ T cells from RCC, melanoma and NSCLC PBMC patients suggesting a putative additional role on adaptive immunity. Siglec-9 was also co-expressed with other inhibitory receptors on NK cells and combination with other immune checkpoint blockers in in vitro assays is ongoing. The antibodies displaying the most interesting features were successfully humanized. (1) Pathol Oncol Res. 2016 Jul;22(3):443-7 (2) Nature. 1968 Jun 29;218(5148):1254-5 (3) Nat Commun. 2017 Oct 26;8(1):1136 (4) N Engl J Med. 2016 Sep 1;375(9):819-29
Citation Format: Olivier Bénac, Marion Gaudin, Mélody Ors, Aude Le Roy, Hélène Rispaud Blanc, Caroline Soulas, Stéphanie Chanteux, Benjamin Rossi, Laurent Gauthier, Carine Paturel, Yannis Morel, Ivan Perrot, Stéphanie Cornen. Preclinical development of first-in-class antibodies targeting Siglec-9 immune checkpoint for cancer immunotherapy [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 2713.
Abstract 273: Upregulation of 15-hydroxyprostaglandin dehydrogenase expression by 15-Deoxy-Δ12,14-prostaglandin J2 through inactivation of DNA methyltransferase 1
Authors: Jang Hye-Ok , Kim Hye-Rim Kim , Lee Ha-Na , Kim Do-Hee , Surh Young-Joon , Na Hye-Kyung 
Published: August 2018

Abstract
15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of prostaglandin E2 (PGE2) to a biologically inactive keto metabolite 15-keto-PGE2. However, the molecular mechanisms underlying regulation of 15-PGDH expression remain largely elusive. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor γ, has been reported to have anti-inflammatory and anti-carcinogenic activities. In the present study, we have found that 15-PGJ2 upregulates expression and catalytic activity of 15-PGDH in human breast cancer (MDA-MB-231) cells. 15d-PGJ2 treatment decreased the CpG methylation in the 15-PGDH promoter in MDA-MB-231 cells as determined by the bisulfite genome sequencing and methyl-specific PCR. 15d-PGJ2 inhibited catalytic activity of methyltransferase 1 (DNMT1) but did not influence DNMT expression. 15d-PGJ2 increased the expression of c-Fos which is a functional subunit of AP-1. Chromatin-immunoprecipitation analysis revealed that 15d-PGJ2 significantly attenuated DNMT1 binding to the site for AP-1 transcription factor present in the 15-PGDH promoter regions, while increasing c-Fos binding. Biotin-tagged 15d-PGJ2 directly bound to DNMT1, and reduced its catalytic activity. A non-electrophilic analogue 9,10-dihydro-15d-PGJ2 failed to suppress the methylation of CpG islands present in 15-PGDH promoter and did not affect both DNMT1 activity and 15-PGDH expression. This findings suggests that the α,β-unsaturated carbonyl group of 15d-PGJ2 is essential for its inactivation of DNMT1 and expression of 15-PGDH. In conclusion, 15d-PGJ2 directly interacts with DNMT1 and consequently suppresses DNMT1-mediated hypermethylation of 15-PGDH promoter, leading to upregulation of 15-PGDH expression.
Citation Format: Hye-Ok Jang, Hye-Rim Kim Kim, Ha-Na Lee, Do-Hee Kim, Young-Joon Surh, Hye-Kyung Na. Upregulation of 15-hydroxyprostaglandin dehydrogenase expression by 15-Deoxy-Δ12,14-prostaglandin J2 through inactivation of DNA methyltransferase 1 [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 273.