bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A17: Metronomic topotecan causes MYCN inactivation and impedes tumor growth selectively in MYCN-amplified neuroblastoma cells in vitro and in vivo by therapy-induced senescence
Authors: Taschner-Mandl Sabine , Gerber Teresa , Schwarz Magdalena , Blaha Johanna , Kauer Maximilian , Kromp Florian , Frank Nelli , Rifatbegovic Fikret , Weiss Tamara , Ladenstein Ruth , Hohenegger Martin , Ambros Inge M. , Ambros Peter F. 
Published: February 2019

Abstract
Background: Poor prognosis and frequent relapses are major challenges for patients with high-risk neuroblastoma (NB), especially when tumors show MYCN amplification. High-dose chemotherapy triggers apoptosis, necrosis, and senescence, a cellular stress response leading to permanent proliferative arrest and a typical senescence-associated secretome (SASP). SASP components reinforce growth arrest and act in an immune-stimulatory fashion, while others are tumor promoting. Studies on low-dose long-term, i.e., metronomic, treatment schedules have demonstrated effects on the tumor microenvironment, but have not comprehensively analyzed cellular responses in tumor cells.
Methods and Results: We evaluated efficacy and mode of action of low-dose metronomic treatment schedules in in vitro and in vivo NB models. Importantly, by using the secretome as a discriminator for beneficial versus adverse effects of senescence, drugs with a tumor-inhibiting SASP were identified. Our preclinical work has demonstrated that low-dose long-term topotecan (TPT) treatment (0.1 mg/kg/d, i.p., daily over 15 weeks) improves survival in mouse NB xenografts and leads to long-term cure in 40% of mice. TPT induces a tumor-inhibiting type of senescence, accompanied by changes in the tumor transcriptome and secretome, specifically in MYCN-amplified NB cells. As senescent NB cells showed a reduced MYCN copy number and strongly downregulated MYCN expression, we investigated the mechanism of MYCN inactivation. This showed that upon senescence MYCN is epigenetically silenced and gene copies are recruited to the nuclear periphery where changes in the nuclear lamina composition take place.
Conclusion: This new mode of action of metronomic TPT treatment, i.e., promoting a tumor-inhibiting type of senescence selectively in MYCN-amplified neuroblastoma, is clinically relevant as metronomic regimens are increasingly implemented in therapy protocols of various cancer entities and are considered as a feasible maintenance treatment option with moderate adverse event profiles.
Citation Format: Sabine Taschner-Mandl, Teresa Gerber, Magdalena Schwarz, Johanna Blaha, Maximilian Kauer, Florian Kromp, Nelli Frank, Fikret Rifatbegovic, Tamara Weiss, Ruth Ladenstein, Martin Hohenegger, Inge M. Ambros, Peter F. Ambros. Metronomic topotecan causes MYCN inactivation and impedes tumor growth selectively in MYCN-amplified neuroblastoma cells in vitro and in vivo by therapy-induced senescence [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A17.
Abstract B32: A novel role for the EWS portion of EWS/FLI in binding GGAA-microsatellites required for oncogenic transformation in Ewing sarcoma
Authors: Johnson K. M. , Lessnick S. L. 
Published: February 2019

Abstract
Objective: Ewing sarcoma is a pediatric bone malignancy initiated by a t(11;22) chromosomal translocation that produces the EWS/FLI oncoprotein. EWS/FLI transcriptionally activates and represses its target genes to mediate oncogenic reprogramming. Expression of its upregulated targets correlates with EWS/FLI binding to associated GGAA-microsatellites, which show length polymorphisms. These microsatellite polymorphisms may critically affect EWS/FLI-responsiveness of key gene targets. For example, NR0B1 is necessary for EWS/FLI mediated oncogenic transformation, and we found a “sweet spot” of 18-26 repeat length as optimal for EWS/FLI mediated transcriptional activity at NR0B1 through clinical observations and in vitro studies. The mechanism underlying this optimal length is unknown.
Methods: We explored the stoichiometry and binding affinity of EWS/FLI for different GGAA-repeat lengths through biochemical studies, including fluorescence polarization, ChIP-seq, and RNA-seq, combined with bioinformatics analysis. Additionally, use of mutant constructs of EWS/FLI has been critical for elucidating particular binding behavior of EWS/FLI at different microsatellite repeat lengths.
Results: Our biochemical studies, using recombinant Δ22 (a version of EWS/FLI containing only the FLI portion) demonstrate a stoichiometry of one Δ22-monomer binding to every two consecutive GGAA-repeats on shorter microsatellite sequences. Surprisingly, the affinity for Δ22 binding to GGAA-microsatellites significantly decreased, and ultimately became unmeasurable, when the size of the microsatellite was increased to the “sweet spot” length. In contrast, a fully functional EWS/FLI mutant (Mut9, which retains approximately half of the EWS portion of the fusion) showed low affinity for smaller GGAA-microsatellites, but instead significantly increased its affinity at “sweet spot” microsatellite lengths. Single-gene ChIP and genome-wide ChIP-seq and RNA-seq studies extended these findings to the in vivo setting.
Conclusion: Together, these data reveal an unexpected novel role for the EWS portion of the EWS/FLI fusion in DNA binding. Additionally, our data suggest a length-dependent biochemical mechanism for EWS/FLI binding and transcriptional regulation at GGAA-microsatellites.
Citation Format: K. M. Johnson, S. L. Lessnick. A novel role for the EWS portion of EWS/FLI in binding GGAA-microsatellites required for oncogenic transformation in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B32.
Abstract IA03: Subgroup-specific enhancer hijacking in medulloblastoma
Authors: Northcott Paul A. 
Published: February 2019

Abstract
In recent years, next-generation sequencing has uncovered the spectrum of driver genes and molecular processes contributing to most cancer entities, including pediatric cancer. This holds true for medulloblastoma (MB), the most common malignant childhood brain tumor. A multitude of genomic studies conducted on large patient cohorts have culminated in the recognition of at least four molecular and clinically distinct MB subgroups: WNT, SHH, Group 3, and Group 4. Moreover, comprehensive sequencing efforts have reported the prevalence and subgroup distribution of somatically altered genes in MB, informing tumor biology and suggesting rational candidates for molecularly targeted therapy. In contrast to WNT and SHH subgroup MB, which are typically characterized by mutations/copy-number alterations leading to aberrant signaling of the WNT and SHH pathways, respectively, Groups 3 and 4 harbor a paucity of recurrently mutated genes and exhibit remarkable heterogeneity in their molecular landscapes. Looking beyond somatic gene-level mutations and focusing our analyses on recurrent structural variants (SVs) in Group 3 and Group 4, we recently discovered a series of atypical SVs converging on chr9q34 that coincided with aberrant induction of GFI1B expression, a transcription factor normally active in the hematopoietic system. Meticulous mapping of SV breakpoints and subsequent integration with DNA methylation and histone ChIP-seq datasets implicated misappropriation of highly active enhancers secondary to the observed SV, a mechanism we termed “enhancer hijacking.” In light of this surprising discovery, we have now extended our analyses, including the development of new computational pipelines, to systematically explore the extent of enhancer hijacking in MB and other pediatric brain tumors. Emerging results from these efforts will be presented, including strategies being employed to validate aberrant enhancer-promoter interactions in MBs with presumed enhancer hijacking, as well as functional approaches we are using to engineer these alterations in relevant cellular systems.
Citation Format: Paul A. Northcott. Subgroup-specific enhancer hijacking in medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA03.
Abstract IA08: Epigenetic mechanisms of resistance to targeted therapy
Authors: George Rani E. 
Published: February 2019

Abstract
Targeted cancer therapies, such as inhibitors of the ALK receptor tyrosine kinase, have yielded promising outcomes in patients whose tumors aberrantly express ALK, yet the development of resistance invariably limits their efficacy. To address this issue, we have investigated potential mechanisms of resistance to ALK inhibitors in neuroblastoma cells expressing ALK point mutations. In tumor cells expressing the ALKF1174L mutant kinase in the absence of MYCN amplification, we observed that resistance to ALK inhibitors develops through activation of MAPK signaling and induction of epithelial-to-mesenchymal transition. By contrast, in tumor cells expressing the same mutation but with concomitant MYCN overexpression due to genomic amplification, resistance arises through a different mechanism, characterized by extensive chromatin remodeling and conversion to a stem cell-like state. I will describe our latest insights into the molecular details underlying this latter mechanism with emphasis on transcriptional regulators.
Citation Format: Rani E. George. Epigenetic mechanisms of resistance to targeted therapy [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA08.
Abstract IA15: SWI/SNF (BAF) chromatin remodeling complexes are frequently mutated in cancer: Mechanisms and vulnerabilities
Authors: Roberts Charles W. M. 
Published: February 2019

Abstract
Data emerging over the last several years implicate SWI/SNF (BAF) chromatin remodeling complexes as a major tumor suppressor as frequent inactivating mutations in at least nine different SWI/SNF subunits, collectively identified in 20% of all cancers. These include recurrent mutations of ARID1A (BAF250a) in ovarian, endometrioid, bladder, stomach, colorectal, and pancreatic cancers and neuroblastoma; of the BRG1 (SMARCA4) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; and of the BRD7 subunit in breast cancers. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when SNF5 (SMARCB1/INI1/BAF47) became the first SWI/SNF subunit linked to tumor suppression over fifteen years ago when it was found to be biallelically inactivated in nearly all cases of a highly aggressive type of pediatric cancer called malignant rhabdoid tumor (MRT). Despite the extremely aggressive and lethal nature of MRT, we have shown that these cancers are diploid and have remarkably simple genomes. We now study the complex using mouse models, cell lines, and primary human tumor samples. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented, including our recent efforts that identify a central role for SWI/SNF complexes in enhancer regulation.
Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) chromatin remodeling complexes are frequently mutated in cancer: Mechanisms and vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA15.
Abstract A023: Regulation of ERG function in prostate cells by phosphorylation and interaction with Ewing’s sarcoma breakpoint protein EWS
Authors: Kedage Vivekananda , Nicholas Taylor R. , Strittmatter Brady G. , Selvaraj Nagarathinam , Budka Justin A. , Jerde Travis J. , Hollenhorst Peter C. 
Published: February 2019

Abstract
More than one-half of prostate tumors have a chromosomal rearrangement that results in the overexpression of an oncogenic ETS family transcription factor. The most common fusion, TMPRSS2/ERG, results in expression of ERG, a protein that is not normally expressed in prostate epithelia. When ERG is expressed in prostate cells it is thought to bind to enhancer elements and regulate gene expression by recruiting transcriptional coactivators and/or corepressors. We have recently shown that the EWS protein acts as a coactivator for ERG in prostate cells and this interaction is required for ERG-mediated xenograft tumor growth. Interestingly, the EWS interaction may be the key requirement that separates oncogenic from nononcogenic ETS factors, as EWS only interacts with four ETS family members involved in prostate cancer gene rearrangements (ERG, ETV1, ETV4, and ETV5), but not with other ETS family members. This ETS/EWS interaction also indicates a common molecular mechanism involved in prostate cancer and Ewing’s sarcoma, a cancer caused by gene fusions that express chimeric EWS/ETS proteins. ERG also interacts with corepressors such as EZH2, a subunit of PRC2. We have recently found that the interaction between ERG and EZH2/PRC2 is regulated by a series of phosphorylation events on ERG. The MAP kinase ERK can bind a high-affinity docking sequence in ERG, resulting in phosphorylation of a nearby serine, S215. This phosphorylation event leads to a conformational change in ERG that allows ERK to phosphorylate a second serine, S96. S96 phosphorylation then disrupts the interaction between ERG and EZH2/PRC2, allowing ERG to activate gene expression. Together, the interaction of ERG with EWS and the regulation of ERG function by ERK-mediated phosphorylation, represent molecular mechanisms that could serve as targets for therapeutic intervention in ERG-positive prostate cancer.
Citation Format: Vivekananda Kedage, Taylor R. Nicholas, Brady G. Strittmatter, Nagarathinam Selvaraj, Justin A. Budka, Travis J. Jerde, Peter C. Hollenhorst. Regulation of ERG function in prostate cells by phosphorylation and interaction with Ewing’s sarcoma breakpoint protein EWS [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A023.
Abstract A029: Targeting neural transcription factor BRN2 in neuroendocrine prostate tumors
Authors: Munuganti Ravi Shashi Nayana , Thaper Daksh , Zoubeidi Amina 
Published: February 2019

Abstract
Introduction: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as enzalutamide (ENZ), rapidly emerges and patients generally die within two years. In particular, a subset of patients who relapse following ARPI therapy exhibit lineage switching whereby tumors shed their dependence on AR signaling and emerge with neuroendocrine features. These tumors, termed treatment-induced neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and to date treatment remains decades-old cytotoxic chemotherapy, which carries a short-lived response at the cost of significant toxicity. Thus, the need to develop targeted treatments for this devastating disease is of paramount importance. Recently our group identified the neural transcription factor BRN2 as a major clinically relevant driver of NEPC and aggressive tumor growth, both in vitro and in vivo, suggesting that targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC.
Methods: Using the integrated power of computational drug discovery platform and biologic testing we identified first-in-field inhibitors for BRN2.
Results: One of the most potent inhibitors identified, Cpd 18, binds to BRN2 using a Drug Affinity Responsive Target Stability (DARTS) assay, decreases the expression of the neuroendocrine genes SOX2, NCAM1, CGA, NSE, PEG10, and N-Myc in BRN2Hi NCI-H660 cells with similar effect in 42DENZR cells. Moreover, Cpd18 displays pronounced antiproliferative activity in NCI-H660 and 42DENZR without any effect on BRN2 low/neg 16DCRPC and LNCaP cells. Combination treatment of Cpd 18 with ENZ prevents the trans-differentiation of 16DCRPC cells into NEPC-like morphology and downregulates the expression of NEPC markers. These outcomes confirmed that the BRN2 is a novel drug target that can help address the problem of ENZ-resistant form of NEPC.
Conclusion: No therapies exist for highly lethal NEPC. Hence, the described work will identify first-in-field inhibitors for BRN2, a central driver of NEPC, and lay the preclinical foundation for the integration of such drugs into the treatment landscape to improve survival and quality of life for patients suffering from deadly form of prostate cancer.
Citation Format: Ravi Shashi Nayana Munuganti, Daksh Thaper, Amina Zoubeidi. Targeting neural transcription factor BRN2 in neuroendocrine prostate tumors [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A029.
Abstract A094: The study of single-nucleotide polymorphisms (SNPs) of tumor suppressor gene in prostate cancer patient of Bangladeshi population
Authors: Imtiaz Hasnain , Afroz Sharmin , Hossain Md. Amir , Bellah Sm Faysal , Rahman Md. Mustafizur 
Published: February 2019

Abstract
Background: Prostate cancer (PCa) is the second leading cause of death among males in present world. The polymorphisms of invasion suppressor gene CDH1 and DNA mismatch repair gene Exo1 have been reported to play a critical role in the tumorigenesis, development, and prognosis of several kinds of cancers, including prostate cancer in some countries. The present study was designed to analyze the contribution of single-nucleotide polymorphisms (SNP) of the CDH1 (-160C/A) and Exo1 (K589E) to prostate cancer susceptibility in Bangladeshi population.
Methods: The study included 100 prostate cancer cases and age-matched 100 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to determine the genetic polymorphisms.
Results: A significant association was found between CDH1 -160 C/A (rs16260) and Exo1 (K589E) polymorphisms and prostate cancer risk. In case of CDH1 -160C/A (rs16260) polymorphism, the frequencies of the three genotypes C/C, C/A, and A/A were 45, 48, and 7% in cases vs. 63, 32, and 5% in controls, respectively. The frequency of C/A heterozygote and combined C/A+A/A genotypes was found to be significantly associated (OR=2.1000, 95% CI= 1.2956. to 4.0905 p=0.013; OR=2.0811, 95% CI= 1.1820-3.6641, p= 0.011, respectively) with increased susceptibility to prostate cancer. The variant A allele also increased the risk of prostate cancer (OR=1.6901, 95% CI= 1.0740 to 2.6597, p= 0.0233). In case of Exo1 (K589E) polymorphism, G/A heterozygote, A/A homozygote, and combined G/A+A/A genotypes were found to be strongly associated (OR= 2.3021, 95% CI=2956. to 4.0905, p=0.0031; OR= 4.8462, 95% CI=1.0198 to 23.0284, p=0.0291; OR= 3.0362, 95% CI=1.7054 to 5.4053, p=0.0001, respectively) with prostate cancer risk. The “A” allele frequency was also found to be significantly associated with increased susceptibility to prostate cancer (OR=2.2955, 95% CI= 1.4529-3.6270, p= 0.0004).
Conclusions: Results of our present study suggest that CDH1 -160 C/A and Exo1 K589E polymorphisms are associated with increased susceptibility to prostate cancer in Bangladeshi population.
Citation Format: Hasnain Imtiaz, Sharmin Afroz, Md. Amir Hossain, Sm Faysal Bellah, Md. Mustafizur Rahman. The study of single-nucleotide polymorphisms (SNPs) of tumor suppressor gene in prostate cancer patient of Bangladeshi population [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A094.
Abstract A097: Regulation of immunophenotype modulation of monocytes-macrophages from M1 to M2 by prostate cancer cell culture supernatant via the transcription factor STAT3
Authors: Solis Raul , Bravo Alejandro , Hernandez Georgina , Bravo Alejandro 
Published: February 2019

Abstract
Background: The transcription factor STAT3 has a prominent innate immunity effect on cancer progression. We determined the regulation of STAT3 in the immunophenotype modulation of macrophages from M1 to M2 induced by the cell culture supernatant of the prostate cancer line PC3.
Methods: Monocyte-macrophages from healthy donors were cultured in the supernatant of PC3 cells, membrane proteins and intracytoplasmic and phosphorylated STAT3 were measured using flow cytometry, and cytokines and growth factors were studied using luminescence. Cytotoxicity and nitric oxide were evaluated via colorimetric assays.
Results: The supernatant of prostate tumor PC3 cells effectively induced macrophages toward an M2 profile, and the expression of phosphorylated STAT3 in the monocytes-macrophages notably increased. In the group of monocytes-macrophages treated with an STAT3 inhibitor, the macrophages were induced towards an M1 phenotype.
Conclusions: In this study, we show that the secretion profile of PC3 prostate cancer cells induces a change in macrophage phenotype from M1 to M2, and this phenomenon is related to phosphorylation of the transcription factor STAT3.
Citation Format: Raul Solis, Alejandro Bravo, Jr., Georgina Hernandez, Alejandro Bravo. Regulation of immunophenotype modulation of monocytes-macrophages from M1 to M2 by prostate cancer cell culture supernatant via the transcription factor STAT3 [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A097.