bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2879: Dj-1 confers maintenance of stemness and radioresistance by regulating EGFRvIII expression in glioma stem cells
Authors: Park Myung-Jin , Kim Jeong-Yub , Kim Hee-Jin , Kim Ji-Soo , Kim Jeong-Chul , Lee Dea-Hee , Na Yoo-Jin 
Published: July 2017

Abstract
DJ-1 is involved in many key cellular processes including cell proliferation, transcriptional regulation, differentiation, oxidative stress protection, and mitochondrial function maintenance. Deregulation of DJ-1 has been implicated in the pathogenesis of many human diseases such as Parkinson's disease, amyotrophic lateral sclerosis, infertility, and cancer. DJ-1 was initially identified as an oncogene product involved in human tumorigenesis in numerous cancer types. Alteration in expression of DJ-1 is associated with tumorigenesis in several types of cancers. Herein, we aimed to clarify the effect of DJ-1 on stemness and radioresistance of glioma stem cells (GSCs). Firstly, we found that the reduction in expression of DJ-1 in brain tumor tissues when compared with tumor adjacent normal brain tissues, as indicated by reduced DJ-1 staining. Knock-down of DJ-1 inhibited self-renewal activity of GSCs in vitro as evidenced by neurosphere formation, limiting dilution, and soft agar clonogenic assays. DJ-1 knock-down suppressed maintenance of stemness by suppressing the expression of Notch intracellular domain, Sox2, and phosphorylated STAT3 proteins. Intriguingly, DJ-1 knock-down inhibited the expression of EGFRvIII in GSCs which might be the cause of suppression of stemness pathways. In addition, knockdown of DJ-1 induced apoptosis, reduced cell invasiveness, and sensitized GSCs to ionizing radiation. Based on these data, we propose that DJ-1 could be considered as a crucial diagnostics and therapeutics target for malignant glioma.
Note: This abstract was not presented at the meeting.
Citation Format: Myung-Jin Park, Jeong-Yub Kim, Hee-Jin Kim, Ji-Soo Kim, Jeong-Chul Kim, Dea-Hee Lee, Yoo-Jin Na. Dj-1 confers maintenance of stemness and radioresistance by regulating EGFRvIII expression in glioma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2879. doi:10.1158/1538-7445.AM2017-2879
Abstract 2903: 1-Methoxyphaseollidin: Novel gamma secretase inhibitor targeting notch-1 signaling in breast cancer stem cells
Authors: Kolluru Venkatesh , Pal Deeksha , Baby Becca , Alatassi Houda , Sharma Arun Kumar , Ankem Murali , Damodaran Chendil 
Published: July 2017

Abstract
We recently showed that two different ALDH+ and CD44+/CD24-/low breast cancer stem cells (BSCSs) exhibited stem cell characteristics that include self-renewal, extensive proliferation, the ability to form non-adherent spherical clusters, chemotherapy resistance and high Notch1 expression. We have identified a compound compound: 6-(3-methylbut-2-enyl) coumestrol (Pso) and treatment with Pso resulted in growth inhibition and an EMT phenotype in both BCSCs and BC cells. Oral Pso administration at physiologically achievable doses (25 mg/kg/BW) suppressed the growth of BCSCs and BC xenografts without toxicity. In the current studies, we identified several novel Pso-derived analogs that may be more potent than the parent compound. One such compound, 1-methoxyphaseollidin (1MP), obtained via three main functional group changes: (i) translocation of the isoprenyl moiety from the phenyl ring fused to the pyran ring (as in Pso) to the phenyl ring adjacent to the furan ring, (ii) removal of the carbonyl group from the pyran ring, and (iii) introduction of a methoxy group at the 1-position, inhibited Notch1 activity and growth of both BSCS and BC cells at nM concentration (IC50: 300nM), which is 100 times more potently than Pso in cell culture models. Molecular studies suggest that 1MP inhibits Notch signaling pathways (Hes1, Hey1 and Presenilin) in both BCSC and BC cells. Further, downregulation of AKT signaling (pAKT (S473), p65 and BCl-2 were seen in 1MP treated cells. Docking studies suggest that 1MP binds outside of the catalytic unit of γ-secretase and induces a conformational change, resulting in Notch1 inhibition in both BCSCs and BC cells. More importantly, administration of 1MP significantly inhibited the growth of BCSC and BC tumors without causing gastrointestinal toxicity in tumor-bearing mice. H&E staining suggests that 1MP treated tumors show infiltrate to margins are less as compared to vehicle treated mice’s. We believe targeting notch1 signaling and optimizing 1MP could be an effective therapeutic strategy for treating breast cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Venkatesh Kolluru, Deeksha Pal, Becca Baby, Houda Alatassi, Arun Kumar Sharma, Murali Ankem, Chendil Damodaran. 1-Methoxyphaseollidin: Novel gamma secretase inhibitor targeting notch-1 signaling in breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2903. doi:10.1158/1538-7445.AM2017-2903
Abstract 291: Sequential treatment with the Wee1 inhibitor, AZD1775, enhances the effect of trabectedin in the L-sarcomas
Authors: Musi Elgilda , Ambrosini Grazia , Schwartz Gary K. 
Published: July 2017

Abstract
Soft tissue sarcomas are heterogeneous mesenchymal neoplasms and account for 1% of all cancers in adults. Over 50 sarcomas subtypes have been classified and many have very limited treatment options. Chemotherapies such as doxorubicin, dacarbazine and gemcitabine have had very low response rates. Two of the most common subtypes of sarcomas are liposarcoma and leiomyosarcoma, also referred to as the L-sarcomas. Trabectedin, a marine derived compound from the sea sponge, Ecteinascidia turbinate, has recently been approved for the treatment of L-sarcomas which has shown a modest effect over common therapies. As a DNA damaging agent, we hypothesized that trabectedin would induce a G2 cell cycle arrest and subsequent inhibition of Wee1 would abrogate this cell cycle checkpoint and induce apoptosis. We therefore examined the effects of trabectedin followed by AZD1775, a Wee1 inhibitor, in a panel of 6 sarcoma cell lines including liposarcoma (LS141, DDLS) and leiomyosarcoma (SK-LMS, SK-UT1, SK-UT1b). IC50s concentrations of trabectedin were determined to be between 0.5 to 2nM, while IC50s for AZD1775 were in the range of 100-200 nM. In vitro results have shown an enhanced inhibition of cell viability with combination treatment in all cell lines at concentrations of 1nM trabectedin for 24hrs followed by 100nM AZD1775 for 48hrs. We also examined biochemical effects with sequential drug treatment (24hrs trabectedin followed by 24hrs AZD1775) which presented an increase of cyclin A1 and cyclin B1 indicative of G2 cell cycle arrest along with increase of phospho-H2AX, indicative of DNA damage by trabectedin, while subsequent treatment with the Wee1 inhibitor showed decrease of phosphorylation of CDC2 (Tyr15). Flow cytometric analysis indicated G2/M cell cycle arrest with trabectedin and abrogation of G2/M with AZD1775. These observations correlated with enhanced apoptosis as measured by biochemical PARP cleavage and DNA content (sub-G1 population). Taken together these results provide a foundation for the development of the sequential treatment of trabectedin followed by the Wee1 inhibitor, AZD775, in the L-sarcomas.
Citation Format: Elgilda Musi, Grazia Ambrosini, Gary K. Schwartz. Sequential treatment with the Wee1 inhibitor, AZD1775, enhances the effect of trabectedin in the L-sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 291. doi:10.1158/1538-7445.AM2017-291
Abstract 2915: The timing of mutational burst events impact the growth of tumors in the colon
Authors: Sievers Chelsie K. , Vo Tien N. , Pickhardt Perry J. , Pooler Bryan D. , Matkowskyj Kristina A. , Albrecht Dawn M. , Rosemarie Quincy , Newton Michael A. , Halberg Richard B. 
Published: July 2017

Abstract
Basic and clinical scientists believe that benign polyps in the colon progress to cancers through the slow, stepwise accumulation of mutations. Interestingly, only a small percentage of all tumors progress, whereas a significant number remain static in size, regress, or resolve completely. The mechanisms underlying these differential fates are unknown, and mechanisms of tumor evolution during this premalignant phase are still under investigation and continued debate. We previously reported that sub-clonal diversity arises early in small human adenomas and contributes to the growth of tumors in the colon. An emerging hypothesis is that colorectal tumors form and progress via a process of punctuated equilibrium, where multiple copy number alterations and mutational events happen simultaneously in a burst-like fashion. In this study, we prospectively test this concept using a mouse model in which tumor induction is spatially and temporally controlled via a non-surgical delivery of adenovirus expressing CRE recombinase and a temporally controlled mutational burst via administration of the carcinogen Azoxymethane. Tumors are induced at a similar rate regardless the timing of the burst relative to tumor induction with a mean tumor incidence of 62% at three weeks post induction. However, tumor growth may be affected by the timing of the burst. Animals that had a mutational burst event prior to tumor induction or those that had a late mutational burst event had a lower average in vivo growth rate compared to controls and those with an early burst event, but the average in vivo tumor size was comparable across all groups. Taken together, these preliminary data provide evidence that the timing of a mutational burst event contributes to tumor growth. This prospective experiment is being extended through computer modeling and statistical inference to compare in silico mutational landscapes to a cohort of colon polyps removed from patients at normal screening. The findings will provide new insights into the earliest stages of tumorigenesis.
Citation Format: Chelsie K. Sievers, Tien N. Vo, Perry J. Pickhardt, Bryan D. Pooler, Kristina A. Matkowskyj, Dawn M. Albrecht, Quincy Rosemarie, Michael A. Newton, Richard B. Halberg. The timing of mutational burst events impact the growth of tumors in the colon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2915. doi:10.1158/1538-7445.AM2017-2915
Abstract 2917: High complexity molecular indexing reveals that time-dependent cell plasticity underpins response to EGFR targeted therapy
Authors: Boudreau Aaron , Bourgon Richard , Evangelista Marie 
Published: July 2017

Abstract
Non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)-mutant tumors often receive erlotinib, a 1st generation EGFR inhibitor, as a frontline therapy. Although many patients initially experience positive response with erlotinib treatment, resistance invariably occurs in the majority of cases - however, it remains unclear the full extent by which resistance is pre-determined by genomic aberration, stochastic by potentially epigenetic mechanisms, or a combination thereof. Using a lentiviral DNA barcode library to molecularly index PC-9, an EGFR mutant (exon 19 del. E746-A750) cell line model, we used next-generation DNA sequencing to trace the fate of over 1.6 million individual cells following erlotinib treatment. Similar to previous reports, we show that multiple subpopulations are present in PC-9 cells - those that are exquisitely sensitive to erlotinib, and those that are inherently resistant, representing ~2% of the population. Surprisingly, in the absence of erlotinib treatment, we show that cells cultured over time transitioned between these two states while maintaining population equilibrium. Using mathematical modeling, we identified several parameters of state switching or flux that were required to maintain this dynamic equilibrium. Understanding the molecular basis by which cells maintain cell state plasticity may enable new strategies to limit intra-tumor heterogeneity and may ultimately improve recurrence-free survival in NSCLC following erlotinib therapy.
Citation Format: Aaron Boudreau, Richard Bourgon, Marie Evangelista. High complexity molecular indexing reveals that time-dependent cell plasticity underpins response to EGFR targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2917. doi:10.1158/1538-7445.AM2017-2917
Abstract 2999: NKG2A checkpoint receptor expression on tumor-infiltrating CD8+ T cells restrains efficacy of immunotherapy
Authors: Hall Thorbald van , Montfoort Nadine van , Piersma Sytse , Sluijter Marjolein , Welters Marij J. , André Pascale , Wagtmann Nicolai , Burg Sjoerd H. van der 
Published: July 2017

Abstract
The inhibitory receptor CD94-NKG2A is expressed on subsets of NK cells and cytotoxic CD8+ T cells, but not CD4+ T helper cells. It’s ligand is the non-classical MHC class I molecule HLA-E, commonly over-expressed in human cancers. We previously demonstrated that high HLA-E expression in ovarian carcinoma and NSCLC may neutralize the survival benefit of T cell infiltration, suggesting that NKG2A could represent an immune checkpoint that tumors may exploit for immune evasion. We thus examined NKG2A expression on human and mouse Tumor Infiltrating Lymphocyte (TIL) populations and tested blockade of this receptor in mouse tumor models. Multicolor flow cytometry analysis showed higher frequency of NKG2A+CD8+ T cells in TIL samples obtained from biopsies of human head- and neck- carcinomas (n=17) compared to peripheral blood CD8+ T cells. Frequency of NKG2A+ TIL was higher in patients with measurable immune reactivity to HPV16-viral antigens than in patients without tumor immunity (14.8% vs 4.7%, respectively). Interestingly, only subsets of the NKG2A+ T cells co-expressed other inhibitory receptors, including PD-1 and TIM3, suggesting the existence of a ‘dedicated’ T cell subset for NKG2A. In our mouse tumor models we observed similar findings and, moreover, demonstrated that therapeutic vaccines comprising tumor antigens increased the frequency of NKG2A+-positive CD8+ TIL up to 80%. Similarly, expression of Qa-1, the mouse homologue of HLA-E, on tumor cells also increased after therapeutic vaccination. As a proof of concept that the NKG2A - Qa-1 axis limits the efficacy of immunotherapy, NKG2A blocking antibodies were applied in the TC-1 model together with therapeutic peptide vaccination. Combination treatment with vaccine and NKG2A blockade significantly improved the therapeutic efficacy compared to the vaccine alone, both in terms of survival (P&lt;0.05, median survival 44 vs 31 days) as well as overall response rate, defined as decreased tumor size of more than 30% (93.8% vs 43.8%, respectively). Similar results were obtained in Qa-1-deficient mice, suggesting that Qa-1 on tumor cells is of importance. In conclusion, inhibitory receptor NKG2A is enriched on CD8+ TIL and functions as an immune checkpoint that restrains therapeutic efficacy of a cancer vaccine.
Citation Format: Thorbald van Hall, Nadine van Montfoort, Sytse Piersma, Marjolein Sluijter, Marij J. Welters, Pascale André, Nicolai Wagtmann, Sjoerd H. van der Burg. NKG2A checkpoint receptor expression on tumor-infiltrating CD8+ T cells restrains efficacy of immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2999. doi:10.1158/1538-7445.AM2017-2999
Abstract 3: Targeting epigenetic modifiers in diffuse large B-cell lymphoma
Authors: Goverdhan Aarthi , Lee Heng-Huan , Hung Mien-Chie 
Published: July 2017

Abstract
Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma, accounting for approximately 40% of all cases worldwide. In the last five years, researchers uncovered that DLBCL is characterized by widespread epigenetic deregulation. Lymphoma cells harbor loss-of-function mutations in transcriptional activators (KMT2D, EP300, CREBBP) and gain-of-function mutations in transcriptional repressors (EZH2). In our study, we aim to identify epigenetic vulnerabilities in lymphoma cells that can be targeted to deliver cytotoxic responses. We screened the therapeutic efficacy of a panel of lysine and arginine methyltransferase inhibitors in multiple lymphoma cell lines. Through these screens, we identified the Type I Protein Arginine Methyltransferase (PRMT) family as an attractive therapeutic target that induced cytotoxicity. Mechanistic dissection revealed that Type I PRMT inhibition caused apoptosis through deregulation of transcription factors and pro-survival genes. In addition, we uncovered novel crosstalk between PRMTs and other epigenetic modifiers that influenced cell fate in lymphoma. Our study demonstrates a critical role for Type I PRMTs in DLBCL, and adds a lucrative target to the growing list of promising epigenetics-based therapies.
Citation Format: Aarthi Goverdhan, Heng-Huan Lee, Mien-Chie Hung. Targeting epigenetic modifiers in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3. doi:10.1158/1538-7445.AM2017-3
Abstract 300: Taeumjowi-tang (TJ001) induces G2/M cell cycle arrest but not apoptosis in p53-mutant prostate cancer via up-regulation of p21WAF/CIP1
Authors: Kang Soo-Yeon , Kim Hyo In , Hong Se Hyang , Ku Jin Mo , Lee Kangwook , Kim Myeong-Sun , Choi Yu-jeong , Cheon Chunhoo , Ko Youme , Huang Ching Wen , Sasaki Yui , Kang Sohyeon , Seo Hye-Sook , Kim Tai Young , Kim Ji Hye , Shin Yong Cheol , Ko Seong-Gyu 
Published: July 2017

Abstract
Taeumjowi-tang (TJ001) is a traditional Korean medicine that usually prescribed for Tae-um person to regulate stomach-related symptoms including headache, indigestion, and jaundice. Other studies on anti-obesity effect of TJ001 have also been researched, but have never been reported as a cure for cancer. In the present study, we investigated the molecular mechanism that TJ001 induces G2/M cell cycle arrest in DU145 (p53-mutant) prostate cancer cells. The missense mutation in human p53 gene (TP53) confers oncological effect to tumor suppressor p53-mutant protein. In prostate cancer, this gain-of-function of p53-mutant is associated with androgen-independence, increased angiogenesis, and metastasis. Our in vitro studies showed that a water extract of TJ001 induced G2/M cell cycle arrest via p53-mutant status and p21WAF/CIP1 up-regulation. Conventinally, p21WAF/CIP1 is induced by mediating p53 regulation, but, in experiments, handling the p53-dependent and -independent pathway. Although serine15-phosphorylated p53 and p53 proteins remained unchanged, p21WAF/CIP1 expression is induced and cyclin B1/Cdc2 complex is inactivated by a decrease of cyclin B1. In addition, in p53-independent pathway, the level of Cdc25C expression decreased and Serine-216 phosphorylated Cdc25C increased. Generally, concomitant with G2/M cell cycle arrest come the apoptosis cell death, but in the study, prolonged G2/M cell cycle arrest developed not apoptosis but cell senescence. Therefore, our data suggest that TJ001 is helpful for p53-mutant prostate cancer treatment.
Citation Format: Soo-Yeon Kang, Hyo In Kim, Se Hyang Hong, Jin Mo Ku, Kangwook Lee, Myeong-Sun Kim, Yu-jeong Choi, Chunhoo Cheon, Youme Ko, Ching Wen Huang, Yui Sasaki, Sohyeon Kang, Hye-Sook Seo, Tai Young Kim, Ji Hye Kim, Yong Cheol Shin, Seong-Gyu Ko. Taeumjowi-tang (TJ001) induces G2/M cell cycle arrest but not apoptosis in p53-mutant prostate cancer via up-regulation of p21WAF/CIP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 300. doi:10.1158/1538-7445.AM2017-300
Abstract 3002: Therapeutic targeting of PGBD5-induced DNA repair dependence in pediatric solid tumors
Authors: Henssen Anton , Reed Casie , Jiang Eileen , Wai Wong , Stanchina Elisa de , Kuwahara Yasumichi , Hosoi Hajime , Schulte Johannes H. , Ganem Neil , Petrini John , Kentsis Alex 
Published: July 2017

Abstract
Despite intense efforts, the cure rates of childhood solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined, particularly for tumors caused by aberrant developmental and epigenetic factors. We have now found that the majority of childhood solid tumors, rhabdoid tumors, neuroblastoma, medulloblastoma and Ewing sarcoma, express an active DNA transposase PGBD5. Using functional genetic approaches, we observed that mouse and human cells deficient in non-homologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA repair inhibitors, we identified the ATR/ATM inhibitor AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. Ectopic expression of PGBD5 was sufficient to induce hypersensitivity to AZD6738, and endogenous PGBD5 was necessary for its anti-tumor effects. We found that PGBD5-expressing tumor cells accumulate unrepaired DNA damage in response to AZD6738 treatment, and undergo apoptosis in both dividing and G1 phase cells in the absence of measureable DNA replication stress. Accordingly, AZD6738 exhibits nanomolar potency against the majority of neuroblastoma, medulloblastoma, Ewing sarcoma and rhabdoid tumor cells tested, while sparing non-transformed human and mouse embryonic fibroblasts in vitro. Finally, AZD6738 exhibits excellent single-agent activity against high-risk neuroblastoma and medulloblastoma xenografts, with induction of apoptosis and tumor regression in vivo. These findings delineate a therapeutically actionable synthetic lethality for the majority of childhood solid tumors.
Citation Format: Anton Henssen, Casie Reed, Eileen Jiang, Wong Wai, Elisa de Stanchina, Yasumichi Kuwahara, Hajime Hosoi, Johannes H. Schulte, Neil Ganem, John Petrini, Alex Kentsis. Therapeutic targeting of PGBD5-induced DNA repair dependence in pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3002. doi:10.1158/1538-7445.AM2017-3002