bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA08: Functional long noncoding RNAs in lung cancer
Authors: Diederichs Sven 
Published: May 2016

Abstract
The majority of the human genome is transcribed into non-protein-coding RNA. Hence, RNA is also the primary product of the cancer genome. We have defined the ncRNA expression landscape of lung, breast and liver cancer providing a comprehensive expression map of over 17000 long ncRNAs and discovering new lncRNAs associated with cancer whose molecular and cellular functions we are currently elucidating exploiting our custom siRNA library targeting 638 tumor-associated lncRNAs.
The nuclear lncRNA MALAT1 was one of the first lncRNAs associated with cancer: it is associated with metastasis development in lung cancer. However, its high abundance and nuclear localization have hampered its functional analysis. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements site-specifically into the MALAT1 locus. This approach yielded a 1000-fold silencing of MALAT1 providing a unique loss-of-function model.
Proposed mechanisms of MALAT1 action include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but regulates gene expression inducing a signature of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft model. Encouraged by this discovery of the essential function of MALAT1 in lung cancer metastasis, we analyzed whether MALAT1 could serve as therapeutic target for an Antisense oligonucleotide (ASO). Notably, MALAT1-ASO treatment prevented metastasis formation after tumor implantation. Thus, targeting MALAT1 with ASOs provided a therapeutic approach to prevent lung cancer metastasis with MALAT1 serving as both, predictive marker and therapeutic target.
In summary, ten years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unraveled the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis.
Citation Format: Sven Diederichs. Functional long noncoding RNAs in lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr IA08.
Abstract IA12: Mechanisms of tumorigenesis due to somatic mutations in DICER1 and DROSHA in childhood kidney cancers
Authors: Chen Kenneth S. , Rakheja Dinesh , Liu Yangjian , Shukla Abhay A. , Mendell Joshua T. , Amatruda James F. 
Published: May 2016

Abstract
Wilms tumor is the most common pediatric kidney cancer and the fourth most common childhood cancer overall. Wilms tumor is treated with a combination of surgery, chemotherapy, and radiation, and, while most children are cured, patients suffer adverse late effects of therapy and survival remains poor in those with advanced-stage disease. Known driver mutations (in WT1, WTX, and β-catenin) account for only one-third of Wilms tumor cases. To better define the genomic landscape of Wilms tumor, we performed whole-exome sequencing of 44 Wilms tumors to identify somatic mutations. Through this approach, we identified recurrent somatic mutations in MYCN, DROSHA, and DICER1, which were mutually exclusive with known Wilms tumor driver mutations in WT1 and β-catenin. DROSHA and DICER1 somatic hotspot mutations occur at or near critical metal-binding residues in RNase III domains and partially or completely disrupt enzyme activity. Examination of miRNA expression in tumors, in vitro processing assays, and genomic editing in human cells demonstrate that DICER1 and DROSHA mutations influence miRNA processing through distinct mechanisms. While DICER1 RNase IIIB mutations preferentially impair processing of miRNAs that derive from the 5′ arm of pre-miRNA hairpins, DROSHA RNase IIIB mutations globally inhibit miRNA biogenesis through a dominant-negative mechanism. Despite their distinct mechanisms of action, DROSHA and DICER1 mutations result in decreased expression of several common tumor-suppressing miRNAs, including multiple members of the let-7 and miR-15/16 families. We also identified a patient carrying a germline DICER1 loss-of-function allele who subsequently developed multiple malignancies with distinct DICER1 RNase IIIB somatic hotspot mutations, suggesting that DICER1 can act as both a tumor-suppressor and an oncogene depending on the nature of the mutation. These results provide new insights into the mechanisms through which mutations in miRNA biogenesis components reprogram miRNA expression in human cancer and suggest that mutations causing impairment of miRNA processing define a distinct subclass of Wilms tumors.
Citation Format: Kenneth S. Chen, Dinesh Rakheja, Yangjian Liu, Abhay A. Shukla, Joshua T. Mendell, James F. Amatruda. Mechanisms of tumorigenesis due to somatic mutations in DICER1 and DROSHA in childhood kidney cancers. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr IA12.
Abstract IA26: Selective activation of gene expression by targeting long noncoding RNA
Authors: Barsoum Jim 
Published: May 2016

Abstract
Long noncoding RNA (lncRNA) can regulate transcription by recruiting epigenetic regulatory complexes to target genes. Polycomb repressive complex 2 (PRC2), an epigenetic transcriptional repressor, is recruited to its target genes via lncRNA. PRC2 represses transcription through the action of the histone methyltransferase EZH2, which methylates histone H3 at lysine 27 (applying the H3K27me3 repressive mark). Using RIP-Seq, we identified the genome-wide pool of RNA sequences that interact with PRC2. We design short single-strand oligonucleotides that hybridize to an individual lncRNA, and sterically block its binding to PRC2, without degrading the lncRNA. These oligonucleotides selectively block PRC2 binding to a specific lncRNA, thereby de-repressing the expression of an associated target mRNA, resulting in increased amounts of the therapeutic protein. This approach was used to increase SMN2 transcription as a potential treatment for Spinal Muscular Atrophy (SMA). Oligonucleotides that target an antisense lncRNA selectively increase SMN2 mRNA and protein levels in SMA patient cells in vitro and in a mouse SMA model that carries the human SMN2 locus. Data support a mechanism of action whereby the oligonucleotides block recruitment of PRC2 to SMN2 chromatin, decrease the H3K27me3 repressive chromatin mark, increase the presence of activating chromatin marks and increase RNA polymerase II association along the SMN2 gene. This therapeutic approach potentially can be used to elevate the expression of many genes whose gene products are limiting in various human diseases.
Citation Format: Jim Barsoum. Selective activation of gene expression by targeting long noncoding RNA. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr IA26.
Abstract A29: Balanced translocations disrupting SMARCB1 are hallmark recurrent genetic alterations in renal medullary carcinomas
Authors: Calderaro Julien , Masliah-Planchon Julien , Richer Wilfrid , Planque Laetitia , Maille Pascale , Taille Alexandre de la , Boussion Helene , Delattre Olivier , Allory Yves , Bourdeaut Franck 
Published: May 2016

Abstract
Renal medullary carcinoma (RMC) is a rare and highly aggressive neoplasm that most often occurs in young patients or children with sickle cell trait or disease (SCD). Although BAF47 staining is constantly negative in these tumors, the genetic mechanism underlying this phenotype remains unknown, since all cases reported so far show SMARCB1 hemizygous deletion only. By investigating a series of five RMC by gene expression profiling, array-CGH, and RNA and whole-exome sequencing, we demonstrated that SMARCB1 inactivation is related to an original mechanism of inter-chromosomal balanced translocations that disrupt SMARCB1 sequence and thus contribute to its inactivation. RMC were also characterised by a simple genome, with a low mutation rate and a lack of recurrent molecular alterations other than SMARCB1 deficiency, emphasizing its potency as single genetic event to drive oncogenesis. Finally, gene expression profiling revealed that RMC share common oncogenic pathways with pediatric malignant rhabdoid tumors, another lethal tumor subtype characterised by SMARCB1 deficiency
Citation Format: Julien Calderaro, Julien Masliah-Planchon, Wilfrid Richer, Laetitia Planque, Pascale Maille, Alexandre de la Taille, Helene Boussion, Olivier Delattre, Yves Allory, Franck Bourdeaut. Balanced translocations disrupting SMARCB1 are hallmark recurrent genetic alterations in renal medullary carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A29.
Abstract A42: Precision medicine for pediatric, adolescent, and young adult patients with newly diagnosed or refractory/recurrent cancer: Lessons learned from N=1 studies on rare tumors
Authors: McEachron Troy A. , Zabokrtsky Keri B. , Sassoon Aaron , Manoljvic Zarko , Craig David W. , Carpten John D. , Sender Leonard S. 
Published: May 2016

Abstract
Next-generation sequencing has rapidly emerged as the preferred method for unbiased genomic interrogation and is increasingly being integrated into clinical practice. Utilizing this technology, we have developed a precision medicine clinical research protocol focused on pediatric, adolescent, and young adult (AYA) patients with cancer. Our objectives are two-fold: 1) To arrive at genome informed treatment recommendations for individual patients suffering from aggressive and/or worsening disease in a clinically relevant time-frame; 2) To survey the genomic landscape of patients with newly diagnosed and/or recurrent/refractory disease. To accomplish this, we have employed an interdisciplinary workflow including a customized bioinformatic analysis pipeline, contextual biological interpretation of the data, and case reviews during regularly scheduled molecular tumor board meetings. To date we have sequenced over 50 patients. Here, we present the data from those patients diagnosed with rare malignancies. Factors affecting the successful identification of actionable targets and subsequent intervention are varied. Furthermore, we highlight the realistic opportunities, challenges, and insight gained from an ongoing single institution experience.
Citation Format: Troy A. McEachron, Keri B. Zabokrtsky, Aaron Sassoon, Zarko Manoljvic, David W. Craig, John D. Carpten, Leonard S. Sender. Precision medicine for pediatric, adolescent, and young adult patients with newly diagnosed or refractory/recurrent cancer: Lessons learned from N=1 studies on rare tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A42.
Abstract B19: Inactivation of KLF4 in T cell acute lymphoblastic leukemia promotes the expansion of leukemia cells by activating the Map2k7/Jnk pathway.
Authors: Shen Ye , Suppipat Koramit , Park Chun Shik , Mistretta Toni-Ann , Horton Terzah , Rabin Karen , Lacorazza Daniel 
Published: May 2016

Abstract
Acute lymphoblastic leukemia is the most common hematological malignancy in pediatric patients, and disease relapse is the leading cause of cancer-associated death in children. Despite steadily improved outcomes in patients with newly diagnosed disease, little progress has been made to treat relapse leukemia and to reduce the incidence of relapse by increasing the cure rates of frontline therapy. Targeted therapy is currently not available for T-ALL and the development of novel agents requires a better understanding of how leukemia-initiating cells (LIC) are maintained. In contrast to normal blood cells, we found that the transcription factor KLF4 is significantly downregulated in pediatric T-ALL. Next-generation bisulfite sequencing revealed that the KLF4 promoter is hypermethylated in lymphoblasts from T-ALL patients but not in normal bone marrow cells, T cells, and pediatric B-ALL. Deletion of the Klf4-floxed gene with Vav-iCre transgene and transplantation of Klf4Δ/Δ bone marrow cells transduced with the Notch1-L1601P-ΔP mutant resulted in a significant acceleration of T-ALL due to a 9-fold expansion of LIC and increased G1-S transition in leukemic T cells. A combined analysis of global gene expression and genome-wide binding revealed that KLF4 directly represses the dual specificity mitogen-activated protein kinase 7 (Map2k7) and thus Klf4Δ/Δ T-ALL mice exhibit increased Map2k7 expression. Most remarkably, T-ALL cells from both mouse model and pediatric patients showed elevated levels of total and phosphorylated Map2k7 and subsequent activation of downstream targets JNK, c-Jun, and ATF2. Finally, we tested several JNK inhibitors in T-ALL cell lines, primary patient samples, and pre-clinical xenograft models of T-ALL and confirmed that JNK inhibition blocks ATF2 activation and controls expansion of leukemia cells, validating the Map2k7/Jnk pathway as a selective target for T-ALL therapy. Thus, KLF4 emerges as a novel tumor suppressor in T-ALL and Jnk inhibition as a novel therapeutic approach for adjunctive therapy in T-ALL patients with refractory or relapse disease.
Citation Format: Ye Shen, Koramit Suppipat, Chun Shik Park, Toni-Ann Mistretta, Terzah Horton, Karen Rabin, Daniel Lacorazza. Inactivation of KLF4 in T cell acute lymphoblastic leukemia promotes the expansion of leukemia cells by activating the Map2k7/Jnk pathway.. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B19.
Abstract B23: Selective and rapid killing of mixed lineage leukemia and CALM-AF10 leukemia by SM7, a novel small molecule identified by chemical library screening
Authors: Chudakova Daria , Somers Klaartje , Middlemiss Shiloh , Wen Victoria , Kwek Alan , Liu Bing , Clifton Molly , Pan Sukey , Cruikshank Sarah , Scandlyn Marissa , Failes Tim , Hoang Wendy , Kees Ursula , Chernova Olga , Gudkov Andrei V. , Haber Michelle , Norris Murray , Henderson Michelle 
Published: May 2016

Abstract
Translocations involving the Mixed Lineage Leukemia (MLL) gene define the major proportion of infant leukemia, a disease that is characterised by a dismal prognosis due to treatment toxicity and therapy resistance. There is an urgent need for the development of less toxic, more selective and targeted therapies for this disease. In this study, we performed a cell-based chemical library screen on an infant MLL cell line, PER-485, in order to identify selective inhibitors of MLL leukemia. After screening initial hits for viability against a panel of 25 cell lines including MLL rearranged and wild-type MLL leukemia, solid tumors and control cells, SM7 was identified as a compound that significantly and selectively decreased the viability of MLL-rearranged (four out of seven) and related CALM-AF10 (two out of two) leukemia cell lines, without killing cell lines derived from wild-type MLL leukemia, solid tumours or normal cells. In contrast to currently developed MLL-inhibitors, the effect of SM7 in suppressing the characteristic MLL-driven gene expression signature in MLL-rearranged cells, with downregulation of leukemogenic HoxA9 and Meis1 expression, occurred within an hour after treatment. The transcript levels of cMyc and Bcl2, important survival proteins regulated by HoxA9, were also rapidly decreased in response to SM7. SM7 induced a rapid caspase-dependent apoptosis, with mitochondrial depolarization within twenty four hours of treatment. This is distinct from the action of other previously described MLL small molecule inhibitors. The rapid and selective toxicity of SM7 towards MLL-rearranged and CALM-AF10 leukemia cell lines suggests an important new avenue in the development of targeted therapies for this disease.
Citation Format: Daria Chudakova, Klaartje Somers, Shiloh Middlemiss, Victoria Wen, Alan Kwek, Bing Liu, Molly Clifton, Sukey Pan, Sarah Cruikshank, Marissa Scandlyn, Tim Failes, Wendy Hoang, Ursula Kees, Olga Chernova, Andrei V. Gudkov, Michelle Haber, Murray Norris, Michelle Henderson. Selective and rapid killing of mixed lineage leukemia and CALM-AF10 leukemia by SM7, a novel small molecule identified by chemical library screening. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B23.
Abstract B31: Combined siRNA and small molecule screening identifies Aurora B kinase as an effective target in MYCN-driven neuroblastoma
Authors: Bogen Dominik , Wei Jun S. , Azorsa David O. , Ormanoglu Pinar , Buehler Eugen , Guha Rajarshi , Keller Jonathan M. , Griner Lesley A. Mathews , Ferrer Marc , Song Young K. , Liao Hongling , Mendoza Arnulfo , Gryder Berkley E. , Sindri Sivasish , He Jianbin , Wen Xinyu , Wen Xinyu , Zhang Shile , Shern John F. , Yohe Marielle E. , Taschner-Mandl Sabine , Shohet Jason , Thomas Craig J. , Martin Scott E. , Ambros Peter F. , Khan Javed 
Published: May 2016

Abstract
Despite advances in multimodal treatment, neuroblastoma (NB) is often fatal for children with high-risk disease and many survivors need to cope with long-term side effects from high-dose chemotherapy and radiation. To identify new therapeutic targets, we performed a siRNA screen of the druggable genome combined with a small molecule screen of 465 compounds targeting 39 different mechanisms of actions in four NB cell lines. We identified 58 genes as targets, including AURKB, in at least one cell line. In the drug screen, aurora kinase inhibitors (nine molecules) and in particular the AURKB-selective compound, barasertib, were the most discriminatory with regard to sensitivity for MYCN-amplified cell lines. In an expanded panel of NB cell lines, those with MYCN amplification and wild-type TP53 were the most sensitive to low nanomolar concentrations of barasertib. Inhibition of the AURKB kinase activity resulted in decreased phosphorylation of its known target histone H3, and upregulation of p53 pathway in MYCN-amplified NB cells with wild-type TP53. Both wild-type and p53-mutant MYCN-amplified cell lines arrested in G2/M phase upon AURKB inhibition. Additionally, barasertib induced endoreduplication and apoptosis. Treatment of MYCN-amplified/TP53 wild-type neuroblastoma xenografts resulted in profound growth inhibition and tumor regression. Therefore, aurora B kinase inhibition is highly effective in aggressive neuroblastoma and warrants further investigation in clinical trials.
Citation Format: Dominik Bogen, Jun S. Wei, David O. Azorsa, Pinar Ormanoglu, Eugen Buehler, Rajarshi Guha, Jonathan M. Keller, Lesley A. Mathews Griner, Marc Ferrer, Young K. Song, Hongling Liao, Arnulfo Mendoza, Berkley E. Gryder, Sivasish Sindri, Jianbin He, Xinyu Wen, Xinyu Wen, Shile Zhang, John F. Shern, Marielle E. Yohe, Sabine Taschner-Mandl, Jason Shohet, Craig J. Thomas, Scott E. Martin, Peter F. Ambros, Javed Khan. Combined siRNA and small molecule screening identifies Aurora B kinase as an effective target in MYCN-driven neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B31.
Abstract B40: Autocrine and paracrine IL-6 and IL-8 drive osteosarcoma lung tropism and facilitate metastasis
Authors: Roberts Ryan D. , Gross Amy C. , Bid Hemant K. , Phelps Doris , Wedekind Mary F. , Houghton Peter J. 
Published: May 2016

Abstract
Osteosarcoma originates in bone, but metastasizes predictably to the lungs. Patients who develop lung metastases become much more difficult to treat. Metastatic lung disease responds poorly to traditional chemotherapy. We know very little of the mechanisms that mediate this lung tropism, or predilection for spread to lung tissue. A better understanding of this process could facilitate disruption of pathways which drive the metastatic process, potentially preventing or even treating lung metastasis. We thus sought to identify tumor-lung interactions that facilitate extravasation, survival, and growth of tumor cells specifically within the lung environment.
Drawing on published signatures of osteosarcoma metastasis, we curated a list of 59 candidate genes that might facilitate lung metastasis. By comparing expression in metastatic lung lesions relative to paired primary tumors, we found that metastatic tumors reliably express two cytokines, IL-6 and IL-8, at much higher levels than matched primary bone tumors. In a mouse model of osteosarcoma, we found that tumors expressing high levels of autocrine IL-6 and IL-8 established lung metastases much more readily than tumors which expressed low or no IL-6 or IL-8.
Using immunohistochemistry to identify sources of these cytokines within human metastatic lesions, we found higher levels of IL-6 and IL-8 coming from non-malignant cells within the tumor, especially mononuclear infiltrates and peri-bronchiolar cells. Modelling tumor-lung interactions in vitro using a co-culture system, much higher levels of IL-6 and IL-8 were produced when osteosarcoma cells were cultured with bronchial epithelial cells, smooth muscle cells, or macrophages suggesting that paracrine interactions drive production of these cytokines upon interaction of tumor cells with resident lung cells. In murine models of osteosarcoma metastasis, blocking IL-6 and/or IL-8 production within tumor cells using inducible shRNA-expressing lentiviruses dramatically reduced metastatic efficiency.
Our data suggest that IL-6 and IL-8 play a primary role in the development of osteosarcoma lung metastasis. The readily targetable nature of these pathways makes them attractive candidates for therapies designed to prevent and possibly treat osteosarcoma lung metastasis.
Citation Format: Ryan D. Roberts, Amy C. Gross, Hemant K. Bid, Doris Phelps, Mary F. Wedekind, Peter J. Houghton. Autocrine and paracrine IL-6 and IL-8 drive osteosarcoma lung tropism and facilitate metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B40.