bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A36: Interaction of the MYC oncoprotein with the tumor suppressive SWI/SNF complex member INI1
Authors: Tu William B. , Stojanova Angelina , Ponzielli Romina , Kotlyar Max , Chan Pak-Kei , Boutros Paul C. , Khosravi Fereshteh , Jurisica Igor , Raught Brian , Penn Linda Z. 
Published: October 2015

Abstract
The MYC oncogene is a key driver of cellular transformation that is deregulated in more than half of all human cancers. The transcriptional regulatory function of MYC and the wide spectrum of biological processes it mediates are critically tied to its chromatin interactors and epigenetic context. MYC is linked to chromatin remodeling through its interaction with INI1 (SMARCB1/hSNF5/BAF47), a core member of the SWI/SNF complex and a potent tumour suppressor. Recent sequencing efforts in many cancer types also identified frequent mutations in other members of this complex. However, the mechanistic understanding of the SWI/SNF complex in contributing to oncogenesis and its functional and molecular interaction with MYC remain unclear. Herein, we provide a comprehensive characterization of the MYC-INI1 interaction. We demonstrate their direct interaction and extensively delineate their minimal regions of interaction, corresponding to functionally important regions of MYC (leucine zipper) and INI1 (Repeats I and II). Genome-wide analysis reveals that INI1 and other SWI/SNF complex members share significant portions of MYC DNA-binding regions and target genes. Network analysis demonstrates MYC interaction with the SWI/SNF complex and an extended network of shared interactors belonging to additional chromatin regulatory complexes. Collectively, our findings provide significant insight into the interaction of MYC and INI1 at the level of protein-protein and protein-chromatin interactions.
Citation Format: William B. Tu, Angelina Stojanova, Romina Ponzielli, Max Kotlyar, Pak-Kei Chan, Paul C. Boutros, Fereshteh Khosravi, Igor Jurisica, Brian Raught, Linda Z. Penn. Interaction of the MYC oncoprotein with the tumor suppressive SWI/SNF complex member INI1. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A36.
Abstract A42: In vitro and in vivo studies of c-Myc amplifiers function
Authors: Nie Zuqin , Guo Chunhua , Simons Stoney S. , Levens David L. 
Published: October 2015

Abstract
c-Myc, the product of a proto-oncogene Myc originally was identified as a transcriptional factor, which interacts with MAX protein through the basic helix-loop-helix leucine zipper (bHLHZip) domain and binds to the DNA containing the E-box (CACGTG) to regulate global gene expression. Recently, we and others found that c-Myc is a genome-wide non-linear amplifier of all expressed genes. The purpose of this study is to confirm previous results that c-Myc targets active promoters and enhancers to amplify the gene expression and to define the contributions of different Myc boxes (Mbs) in the regulation of gene expression and to identify the protein partners of Mbs.
A Gibson Assembly system was used to create the A to N mutations of conserved amino acids in different Mbs. The wild type (WT) and mutated Myc –Pd4-EGFP fusion genes were transiently co-transfected to U2OS cells with Tk-, GRE-TK-, PR-TK-Luc vectors and analyze the reporter activities with a Dual-Luciferase Reporter Assay System, respectively. Our preliminary data demonstrated that WT-c-Myc does amplify reporter gene activity non-linearly. However, constructs with mutatied MbI and MbII were handicapped for amplification. Interestingly, mutated MbIII-b dramatically enhanced reporter gene amplification especially at higher Myc concentrations. Using reporter constructs with and without E-boxes, we found that this element is not necessary to enable c-Myc 's amplification function. To understand c-Myc's function in vivo, we established several Tet-inducible WT and mutated c-Myc stable cell lines with lenti-virus transduced system. The gene expression profiles of these cell lines are being compared. The screening of the partners of different Mb domains is on the way.
Citation Format: Zuqin Nie, Chunhua Guo, Stoney S. Simons, David L. Levens. In vitro and in vivo studies of c-Myc amplifiers function. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A42.
Abstract B16: A novel long non-coding RNA connects c-Myc to tumor metabolism
Authors: Wang Ling-Yu , Hung Chiu-Lien , Yu Yen-Ling , Chen Hongwu , Srivastava Shiv , Petrovics Gyorgy , Kung Hsing-Jien 
Published: October 2015

Abstract
Long non-coding RNAs have been implicated in a variety of physiological and pathological processes including cancer. In prostate cancer, PCGEM1 (prostate cancer gene expression marker 1) is an androgen-induced prostate specific lncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenic potential was recently shown to be in part due to its ability to activate androgen receptor (AR). Here we report a novel function of PCGEM1 that provides growth advantages for cancer cell by regulating tumor metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates metabolism at the transcriptional level that affects multiple metabolic pathways including glucose and glutamine metabolism, pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and TCA cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified c-Myc binding domain on PCGEM1 that contributes to the PCGEM1 dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cell. By being a coactivator for both c-Myc and AR, PCGEM1 reprograms the androgen network and the central metabolism in a tumor specific way, making it a promising target for therapeutic intervention.
Citation Format: Ling-Yu Wang, Chiu-Lien Hung, Yen-Ling Yu, Hongwu Chen, Shiv Srivastava, Gyorgy Petrovics, Hsing-Jien Kung. A novel long non-coding RNA connects c-Myc to tumor metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B16.
Abstract B20: EnCore-LNP mediated tumor delivery of MYC and CTNNB1 Dicer Substrate RNAs (DsiRNAs)
Authors: Abrams Marc , Ganesh Shanthi , Ying Bo , Chopda Girish , Saxena Utsav , Shah Anee , Koser Martin , Arvan Rokhand , Chen Dongyu , Shui Serena , Diwanji Rohan , Zhou Wei , Holmes Benjamin , Kim Boyoung , Yang Hailin , Patel Mihir , Cyr Wendy , Cyr Wendy , Pursell Natalie , Avitahl-Curtis Nicole , Dudek Hank , Lai Cheng , Wang Weimin , Brown Bob D. 
Published: October 2015

Abstract
MYC and CTNNB1 are well-characterized drivers of numerous tumor types. Human and preclinical genetic evidence suggest that pharmacological intervention to reduce transactivation of MYC and CTNNB1-regulated genes would yield therapeutic benefit to many cancer patients. Since the proteins encoded by these genes are challenging to target via conventional modalities, progress in new therapeutic agents has been slow despite decades of research. RNA interference technology has enabled the inhibition of previously-undruggable genetic targets at the mRNA level, and has advanced to clinical development for several indications. DCR-MYC is a Phase I-stage lipid nanoparticle (LNP)-formulated Dicer substrate siRNA (DsiRNA), representing a potent class of RNAi triggers being developed by Dicerna Pharmaceuticals. Here we describe new preclinical data that increase our understanding of the parameters that impact tumor delivery and activity of DsiRNA. We demonstrate that the cationic lipid and PEG-lipid components of Dicerna's unique EnCore LNP platform can be modulated to improve delivery of DsiRNA to both orthotopic and spontaneous liver tumors, as well as xenograft tumors of diverse non-hepatic tissue origin. Characterization of LNP formulations with respect to plasma PK, tissue exposure and target mRNA knockdown was employed towards understanding the pharmacology of LNP-mediated tumor delivery.
Citation Format: Marc Abrams, Shanthi Ganesh, Bo Ying, Girish Chopda, Utsav Saxena, Anee Shah, Martin Koser, Rokhand Arvan, Dongyu Chen, Serena Shui, Rohan Diwanji, Wei Zhou, Benjamin Holmes, Boyoung Kim, Hailin Yang, Mihir Patel, Wendy Cyr, Wendy Cyr, Natalie Pursell, Nicole Avitahl-Curtis, Hank Dudek, Cheng Lai, Weimin Wang, Bob D. Brown. EnCore-LNP mediated tumor delivery of MYC and CTNNB1 Dicer Substrate RNAs (DsiRNAs). [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B20.
Abstract B23: Pushing Myc inhibition towards the clinic by direct delivery of cell-penetrating peptides
Authors: Beaulieu Marie-Eve , Jauset Toni , Massó-Valles Daniel , Whitfield Jonathan R. , Pozo Erika Serrano del , Tremblay Cynthia , Maltais Loïka , Montagne Martin , Lavigne Pierre , Soucek Laura 
Published: October 2015

Abstract
Inhibiting Myc has long been regarded as a promising cancer treatment. However, clinical Myc inhibition was considered unfeasible due to its central role in normal proliferation and the difficulties of targeting a nuclear transcription factor. The expression of Omomyc (a Myc inhibitor derived from the dimerization and DNA-binding domain of Myc) in the KRasG12D non-small cell lung cancer (NSCLC) mouse model challenged these assumptions, as it resulted in dramatic tumor clearance with only limited and well tolerated side effects in normal tissues (Soucek et al., 2008 and 2013). Omomyc expression proved equally potent in several other mouse models of cancer, revealing the huge potential of this inhibitory approach against multiple cancer types including papilloma, pancreas and glioma (Soucek et al., 2004; Sodir et al., 2011; Annibali et al., 2014). Recently, Max*, a b-HLH-LZ peptide derived from Myc's obligate protein partner Max, was shown to spontaneously enter cells (Montagne et al., 2012). As Omomyc and Max* display high structural homology, we hypothesized that Omomyc could also behave as a cell-penetrating peptide and thus recapitulate the effects of its transgenic counterpart. Our preliminary results show that the Omomyc peptide is well folded in solution; it transduces into cancer cells and effectively stops their proliferation in a dose-dependent manner.In vivo, nasal instillation of fluorescently-labeled Omomyc peptide leads to its rapid distribution to lungs and brain, as well as to other organs (G.I. tract, liver), as observed by IVIS® imaging and immunohistochemistry. Finally, a short treatment with the Omomyc peptide reduces the tumor size and number of Ki67 positive cells in the KRasG12D-induced NSCLC mouse model. In summary, the Omomyc cell penetrating peptide represents a new opportunity to pharmacologically inhibit Myc in a variety of malignant diseases.
Citation Format: Marie-Eve Beaulieu, Toni Jauset, Daniel Massó-Valles, Jonathan R. Whitfield, Erika Serrano del Pozo, Cynthia Tremblay, Loïka Maltais, Martin Montagne, Pierre Lavigne, Laura Soucek. Pushing Myc inhibition towards the clinic by direct delivery of cell-penetrating peptides. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B23.
Abstract B26: BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma
Authors: Bhadury Joydeep , Nilsson Lisa M. , Somsundar Muralidharan Veppil , Green Lydia C. , Keller Ulrich B. , McLure Kevin G. , Nilsson Jonas A. 
Published: October 2015

Abstract
Bromodomain and extraterminal (BET) proteins bind acetylated proteins, including histones, and regulate transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anti-cancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BETi RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice, in vitro and in vivo. We find that BET inhibition exhibited broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have been largely ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. To date many of the effects of BETi have been attributed to transcriptional suppression of genes like the MYC oncogene. Moreover, global profiling of the expression of miRNAs demonstrated that HDACi and BETi exhibited a very similar miRNA transcriptome. We also show one of the possible mechanism which might leads to the similarity of induced genes by BETi and HDACi using ChIP-sequencing experiments. Finally, we unravel a genetic and functional link between BET proteins and histone deacetylases (HDAC) that opens up avenues for combination therapies against a variety of cancer.
Citation Format: Joydeep Bhadury, Lisa M. Nilsson, Muralidharan Veppil Somsundar, Lydia C. Green, Ulrich B. Keller, Kevin G. McLure, Jonas A. Nilsson. BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B26.
Abstract B48: Identification of novel drug interactions with MYC via a quantitative chemical-genetic interaction map
Authors: Zhou Alicia Y. , Martins Maria M. , Corella Alexandra , Horiuchi Dai , Yau Christina , Rakshandehroo Taha , Gordan John D. , Levin Rebecca S. , Johnson Jeff , Jascur John , Shales Mike , Sorrentino Antonio , Cheah Jaime , Clemons Paul A. , Shamji Alykhan , Schreiber Stuart L. , Krogan Nevan J. , Shokat Kevan M. , McCormick Frank , Goga Andrei , Bandyopadhyay Sourav 
Published: October 2015

Abstract
There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or emergent dependencies that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated an unbiased and quantitative chemical-genetic interaction map that measures the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model more complex cellular contexts. Applied to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene including resistance to AKT/PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic-lethal manner, providing new drug and biomarker pairs for clinical investigation. This scalable approach enables the prediction of drug responses from patient data and can be used to accelerate the development of new genotype-directed therapies.
Citation Format: Alicia Y. Zhou, Maria M. Martins, Alexandra Corella, Dai Horiuchi, Christina Yau, Taha Rakshandehroo, John D. Gordan, Rebecca S. Levin, Jeff Johnson, John Jascur, Mike Shales, Antonio Sorrentino, Jaime Cheah, Paul A. Clemons, Alykhan Shamji, Stuart L. Schreiber, Nevan J. Krogan, Kevan M. Shokat, Frank McCormick, Andrei Goga, Sourav Bandyopadhyay. Identification of novel drug interactions with MYC via a quantitative chemical-genetic interaction map. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B48.
Abstract IA12: Mechanisms of MYC addiction
Authors: Felsher Dean 
Published: October 2015

Abstract
Many human cancers are caused by the activation of the MYC oncogene. We have developed experimental transgenic mouse models to model and predict the therapeutic efficacy of targeted therapy of oncogenes. Using the Tet system, we can conditionally regulate oncogene expression in vivo in a temporally controlled and tissue specific manner. We have shown that many oncogenes (MYC, RAS, BCR-ABL) induce tumorigenesis that is completely reversible upon their inactivation. We have described this phenomenon as oncogene addiction. Oncogene addiction is associated with proliferative arrest, apoptosis, differentiation, cellular senescence and the shutdown of angiogenesis.
The specific consequences of MYC oncogene inactivation depend both on the genetic and cellular context. In some cases, even brief inactivation of an oncogene can result in sustained tumor regression. In other cases, oncogene inactivation is associated with tumor dormancy. Tumor cell intrinsic and host-dependent cell autonomous mechanisms are involved. Tumor cell intrinsic mechanisms appear to involve mechanisms that are dependent upon DNA repair processes, the regulation of protein synthesis and of cellular metabolism. Host-dependent mechanisms include the regulation of angiogenesis and immune cell elimination. In addition, tumor cells secrete autocrine factors critical to oncogene addiction.
We have uncovered that oncogene addiction is both dependent upon cell autonomous and host cell dependent mechanisms. Thus, MYC via miR17-92 regulates chromatin regulatory gene products required to in a cell autonomous manner regulate cellular proliferation, survival and self-renewal programs. However, MYC through regulation of host immune mechanisms and the recruitement of CD4+ T-cells, in a host cell dependent manner, regulates the tumor microenvironment.
Our experimental model systems have been employed to generate nanotechnologies and molecular imaging approaches as well as innovative therapies to respectively predict and to elicit MYC addiction.
Citation Format: Dean Felsher. Mechanisms of MYC addiction. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA12.
Abstract IA20: Reduced expression of MYC increases longevity and enhances healthspan
Authors: Sedivy John M. 
Published: October 2015

Abstract
MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. We find that Myc haploinsufficient (Myc+/–) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR and S6K activities. In contrast to observations in other longevity models, Myc+/– mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.
Citation Format: John M. Sedivy. Reduced expression of MYC increases longevity and enhances healthspan. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA20.
Abstract IA27: Inhibition of MYC transcriptional signaling
Authors: Bradner James E. 
Published: October 2015

Abstract
MYC is a master regulator of stem cell state, embryogenesis, tissue homeostasis, and aging. As in health, in disease MYC figures prominently. Decades of biological research have identified a central role for MYC in the pathophysiology of cancer, inflammation and heart disease. The centrality of MYC to such a vast breadth of disease biology has attracted significant attention to the historic challenge of developing inhibitors of MYC. This presentation will discuss therapeutic strategies towards the development of inhibitors of MYC-dependent transcriptional signaling and the elusive goal of developing potent, direct-acting inhibitors of MYC.
Citation Format: James E. Bradner. Inhibition of MYC transcriptional signaling. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA27.
Abstract PR13: miR-17-92 mediates MYC oncogene addiction
Authors: Li Yulin , Choi Peter S. , Casey Stephanie C. , Dill David L. , Felsher Dean W. 
Published: October 2015

Abstract
The MYC oncogene is frequently overexpressed in human cancers. MYC can transcriptionally and translationally regulate the expression of thousands of genes. However, it was unclear which specific genes are responsible for MYC to maintain a neoplastic state. The microRNA cluster miR-17-92 is a major MYC target gene known to regulate proliferation, survival, and angiogenesis, which are several of the key phenotypes associated with MYC oncogene addiction. The resemblance of biological functions between MYC and miR-17-92 thus evoked the hypothesis that miR-17-92 is causally responsible for at least part of the mechanism by which MYC maintains a neoplastic state. We have found that miR-17-92 regulates multiple histone modifiers, such as Sin3b, Hbp1, Suv420h1, and Btg1, as well as the apoptosis regulator Bim, to maintain autonomous proliferation, survival, and self-renewal of MYC-driven tumors. Conversely, MYC inactivation downregulates the expression of miR-17-92 and results in the loss of neoplastic features as a consequence of restoration of senescence, apoptosis, and differentiation. Thus, the expression of miR-17-92 can dictate the cellular fates of MYC-driven tumors between survival versus apoptosis and proliferation versus senescence. Our findings provide a mechanistic insight into why tumors are dependent on or addicted to MYC.
Citation Format: Yulin Li, Peter S. Choi, Stephanie C. Casey, David L. Dill, Dean W. Felsher. miR-17-92 mediates MYC oncogene addiction. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR13.