bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A20: A leukemic model of acquired resistance to BET inhibition reveals a role for CBP/EP300 bromodomains in the regulation of c-MYC expression
Authors: Conery Andrew R. , Centore Richard C. , Hatton Charlie , Neiss Adrianne , Huang Hon-Ren , Keller Patricia J. , Taylor Alexander M. , Cote Alexandre , Hewitt Michael C. , Nasveschuk Christopher G. , Leblanc Yves , Yao Shihua , Pardo Eneida , Zawadzke Laura , Poy Florence , Jayaram Hari , Joshi Shivangi , Sandy Peter , Romero Anthony , Crawford Terry , Pastor Richard , Lai Tommy , Chen Kevin , Wang Jian , Magnuson Steven , Albrecht Brian K. , Bellon Steve , Bryant Barbara M. , Sims Robert J. 
Published: October 2015

Abstract
Pharmacological modulation of c-MYC expression has recently become possible through small molecule engagement of the BET bromodomain proteins. As multiple BET inhibitors (BETi) progress through clinical trials, understanding possible mechanisms of acquired resistance becomes imperative to maximize therapeutic efficacy, assess possible drug combination strategies, and identify characteristics of next generation BET inhibitors. In the present study, we describe a cellular model of BETi resistance, which demonstrates a significantly blunted phenotypic and molecular response to BETi. The expression of c-MYC mRNA, highly susceptible to BETi in the parental cells, is restored in resistant cells through transcriptional bypass of BET-mediated co-activation. Through the use of a novel CBP/EP300 bromodomain inhibitor (CBP/EP300i), we show that c-MYC expression in BETi-resistant cells is dependent on CBP/EP300 bromodomain function, and that co-treatment with CBP/EP300i restores phenotypic sensitivity. CBP/EP300i was additionally found to transcriptionally silence MYC expression in numerous myeloma and leukemia derived cell lines in a manner comparable to BETi, identifying a novel modality to pharmacologically target the MYC oncogenic axis. While both BET and CBP/EP300 bromodomains regulate the expression of MYC, their transcriptional and phenotypic effects are otherwise distinct, suggesting that CBP/EP300 bromodomain inhibition may represent an alternative or complementary therapeutic option to BET bromodomain inhibition.
Citation Format: Andrew R. Conery, Richard C. Centore, Charlie Hatton, Adrianne Neiss, Hon-Ren Huang, Patricia J. Keller, Alexander M. Taylor, Alexandre Cote, Michael C. Hewitt, Christopher G. Nasveschuk, Yves Leblanc, Shihua Yao, Eneida Pardo, Laura Zawadzke, Florence Poy, Hari Jayaram, Shivangi Joshi, Peter Sandy, Anthony Romero, Terry Crawford, Richard Pastor, Tommy Lai, Kevin Chen, Jian Wang, Steven Magnuson, Brian K. Albrecht, Steve Bellon, Barbara M. Bryant, Robert J. Sims, III. A leukemic model of acquired resistance to BET inhibition reveals a role for CBP/EP300 bromodomains in the regulation of c-MYC expression. [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 A20.
Abstract A43: Sequence specificity incompletely defines the genome-wide occupancy of Myc
Authors: Guo Jiannan , Li Tiandao , Schipper Joshua , Nilson Kyle A. , Fordjour Francis K. , Cooper Jeffrey J. , Gordan Raluca , Price David H. 
Published: October 2015

Abstract
Background: The Myc-Max heterodimer is a transcription factor that regulates expression of a large number of genes. Genome occupancy of Myc-Max is thought to be driven by Enhancer box (E-box) DNA elements (CACGTG or variants) to which the heterodimer binds in vitro in the context of accessible chromatin.
Results: By analyzing ChIP-Seq datasets, we demonstrated that the positions occupied by Myc-Max across the human genome correlate with the RNA polymerase II (Pol II) transcription machinery better than with E-boxes. Metagene analyses showed that in promoter regions, Myc was uniformly positioned about 100 bp upstream of essentially all promoter proximal paused polymerases with Max about 15 bp upstream of Myc. We re-evaluated the DNA binding properties of full length Myc-Max proteins using electrophoretic mobility shift assays (EMSA) and universal protein-binding microarrays (PBM). EMSA results demonstrated Myc-Max heterodimers display significant sequence preference, but have high affinity for any DNA. Quantification of the relative affinities of Myc-Max for all possible 8-mers using PBM assays showed that sequences surrounding core 6-mers significantly affect binding. Compared to the in vitro sequence preferences, Myc-Max genomic occupancy measured by ChIP-Seq was largely, although not completely, independent of sequence specificity.
Conclusions: Our results indicate that the genomic occupancy of Myc cannot be explained solely by its intrinsic DNA specificity and suggest that the transcription machinery and associated promoter accessibility play a predominant role in Myc recruitment.
Citation Format: Jiannan Guo, Tiandao Li, Joshua Schipper, Kyle A. Nilson, Francis K. Fordjour, Jeffrey J. Cooper, Raluca Gordan, David H. Price. Sequence specificity incompletely defines the genome-wide occupancy of Myc. [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 A43.
Abstract B07: Expression of MYCS62A in thymocytes is anti-proliferative, but promotes the later emergence of tumorigenic cells
Authors: Daniel Colin J. , Link Jason Michael , Byers Sarah , Sears Rosalie C. 
Published: October 2015

Abstract
Oncogenic alterations that promote stability of MYC proteins are common in several human tumor types, and expression of stabilized MYC in mice promotes tumorigenesis from breast, pancreas, and thymus. Mutations that inhibit phosphorylation of T58 in MYC limit proteasomal degradation and enhance S62 phosphorylation and protein stability. Physiologically low expression of MycT58A from the ROSA26 locus (ROSA-MYCT58A) causes robust tumorigenesis, whereas tumor development in ROSA-MYCWT expressing cells is rare. Mice with T cell-specific expression of MYCT58A (LckCre ROSA-MYCT58A) typically succumb to thymomas within six months, whereas survival of LckCre ROSA-MYCWT mice is unaltered from control. In contrast to T58A mutation, S62A mutation stabilizes MYC but decreases cell production in breast tissue. Unexpectedly, LckCre ROSA-MYCS62A mice develop tumors and have significantly shorter lifespans than LckCre ROSA-MYCWT mice. However, unlike LckCre ROSA-MYCT58A mice, tumors in LckCre ROSA-MYCS62A mice are not exclusively thymomas and tumorigenesis takes significantly longer. Analysis of tumors from LckCre ROSA-MYCS62A mice revealed abundant S62-phosphorylated MYC indicating elevated expression and activation of endogenous MYC, despite suppression of endogenous Myc transcription in thymocytes and splenic T cells from young LckCre ROSA-MYCS62A mice. In order to test possible tumorigenic effects of S62A mutation apart from the effects of endogenous MYC, we developed mice that would simultaneously delete endogenous Myc and express ectopic ROSA-Myc in developing T cells. CRE-mediated deletion of endogenous Myc decreased the median survival of LckCre ROSA-MYCS62A mice and caused very early onset thymomas in a subset of young mice. Although LckCre ROSA-MYCT58A mice provide another classic example connecting increased MYC expression to tumor development, LckCre ROSA-MYCS62A mice demonstrate that limitations on MYC function can also promote tumorigenesis; likely by selecting for mutant cells that have escaped deletion or suppression of endogenous Myc. Strong, constitutive, mitogenic signals in developing thymocytes may increase the chance that MYC-suppression-escapees will be tumorigenic.
Citation Format: Colin J. Daniel, Jason Michael Link, Sarah Byers, Rosalie C. Sears. Expression of MYCS62A in thymocytes is anti-proliferative, but promotes the later emergence of tumorigenic cells. [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 B07.
Abstract B42: Therapeutic effects of an anti-myc drug on mouse pancreatic cancer
Authors: Stellas Dimitris , Szabolcs Matthias , Koul Sanjay , Li Zhe , Polyzos Alexander , Anagnostopoulos Constantinos , Cournia Zoe , Tamvakopoulos Constantin , Klinakis Apostolos , Efstratiadis Argiris 
Published: October 2015

Abstract
Background: Pancreatic ductal adenocarcinoma (PDA) is frequently driven by oncogenic KRAS(KRAS*) mutations. We developed a mouse model of KRAS*-induced PDA and, based on genetic results demonstrating that KRAS* tumorigenicity depends on Myc activity, we evaluated the therapeutic potential of an orally administered anti-Myc drug.
Methods: We tested the efficacy of Mycro3, a small-molecule inhibitor of Myc-Max dimerization, in the treatment of mouse PDA (n = 9) and also of xenografts of human pancreatic cancer cell lines (NOD/SCID mice, n = 3–12). Tumor responses to the drug were evaluated by PET/CT imaging, and histological, immunohistochemical, molecular and microarray analyses. The Student's t test was used for differences between groups. All statistical tests were two-sided.
Results: Transgenic overexpression of KRAS* in the pancreas resulted in pancreatic intraepithelial neoplasia in two-week old mice, which developed invasive PDA a week later and became moribund at one month. However, this aggressive form of pancreatic tumorigenesis was effectively prevented by genetic ablation of Myc specifically in the pancreas. We then treated moribund, PDA-bearing mice daily with the Mycro3 Myc-inhibitor. The mice survived until killed at two months. PET/CT image analysis (n = 5) demonstrated marked shrinkage of PDA, while immunohistochemical analyses showed an increase in cancer cell apoptosis and reduction in cell proliferation (treated/untreated proliferation index ratio: 0.29, P &lt; .001, n = 3, each group). Tumor growth was also drastically attenuated in Mycro3-treated NOD/SCID mice (n = 12) carrying orthotopic or heterotopic xenografts of human pancreatic cancer cells (eg, mean tumor weight ± SD of treated heterotopic xenografts vs vehicle-treated controls: 15.2 ± 5.8 mg vs 230.2 ± 43.9 mg, P &lt; .001).
Conclusion: These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA.
Citation Format: Dimitris Stellas, Matthias Szabolcs, Sanjay Koul, Zhe Li, Alexander Polyzos, Constantinos Anagnostopoulos, Zoe Cournia, Constantin Tamvakopoulos, Apostolos Klinakis, Argiris Efstratiadis. Therapeutic effects of an anti-myc drug on mouse pancreatic cancer. [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 B42.
Abstract B47: Incomplete RFA-generated heat shock response provokes colorectal cancer liver metastases (CRLMs) recurrence by inducing cancer cell stemness and invasion
Authors: Zhang Zhan-Guo , Zhang Wan-Guang , Wu Yan-Hui , Liang Hui-Fang , Zhang Bi-Xiang , Chen. Xiao-Ping 
Published: October 2015

Abstract
Even now, radiofrequency ablation (RFA) is accepted as a curative therapy for colorectal cancer liver metastasis (CRLMs). Accumulating data have shown that incomplete radiofrequency ablation (ICR) associates with increase of tumor recurrence and more aggressive malignant phenotype. We determined the mechanisms of this progression, including effectively predict biologic behaviors.We established a mouse model highly mimicking the process of RFA treatment. Functional studies were performed in vitro and in vivo. Our xenograft model unveiled ICR increases the risk in CRLMs recurrence. Here we focused on the heat shock (HS)-induced CRC malignance. Sublethal HS in CRC cell lines provoked cell growth, invasion, and tumor initiation in vitro. Consistently, the xenograft mouse model also confirmed the effects of HS in promoting tumor growth. With Western blot analysis, we found that Fra-1, which is a typical down-stream of the transcription factor ERK1/2, was significantly increased by heat shock stimuli compared with the untreated CRC cells. Furthermore, we demonstrated that silence of Fra-1 in HS treated cells could abolish the effects of HS in promoting malignant phenotype. Significantly, proliferation markers (Ki67, c-Myc, CyclinD1, CDK2), stem cell markers (Sox-2, Sox-9, Oct3/4, Lgr5) and invasion related MMP1 were up-regulated in the HS treated cells and in xenograft model. Taken together, this study established a novel mouse model to study the effect of ICR in CRLM. HS induces CRC proliferation and metastasis by targeting Fra-1, which is a potential prognostic marker and a promising therapeutic strategy for CRC recurrence after RFA treatment.
Citation Format: Zhan-Guo Zhang, Wan-Guang Zhang, Yan-Hui Wu, Hui-Fang Liang, Bi-Xiang Zhang, Xiao-Ping Chen. Incomplete RFA-generated heat shock response provokes colorectal cancer liver metastases (CRLMs) recurrence by inducing cancer cell stemness and invasion. [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 B47.
Abstract B49: Using small molecule activators of PP2A to negatively regulate c-myc in small cell lung cancer
Authors: Wolpaw Benjamin Jonathan , Narla Goutham , Cheemalavagu Shashank 
Published: October 2015

Abstract
Treatment for small cell lung cancer (SCLC) is based on combination chemotherapy with a five-year survival of just 10-13% for patients with limited disease. A common molecular alteration in SCLC is the overexpression of MYC family oncogenes, occurring in 18-31% of SCLCs, and more commonly in chemo-refractory disease. Several FDA approved tricyclic antidepressants were recently shown to have efficacy in SCLC cell lines based on G-protein coupled receptor (GPCR) mediated effects, and a phase IIa trial is testing one of these compounds. A reverse chemical engineering approach was employed to remove GPCR pharmacology from the tricyclic family of compounds, generating a novel class known as SMAPs, small molecule activators of protein phosphatase 2A (PP2A). PP2A is a tumor suppressor with an established negative regulatory action on c-myc. Thus, it was hypothesized that SMAPs could represent a novel treatment approach in SCLC via activation of PP2A with downstream effects on targets including c-myc. A genetic signature score for SMAP efficacy predicted broad activity of these compounds in SCLC and identified myc family pathways as strongly correlated to IC50 in a panel of tumor cell lines. Incubation with the SMAP TRC-794 was shown to induce apoptosis in the SCLC cell lines H82 and H69 as seen by induction of annexin V as well as parp and caspace-3 cleavage. Loss of c-myc in the c-myc amplified cell line H82 was observed in a dose dependent manner at 24hrs. Loss of c-myc was observed by 6 hours of drug treatment in H82 and H2081 cells. Supporting a PP2A dependent mechanism, molecular effects on c-myc in H82 were partially reversed with the phosphatase inhibitor okadaic acid. IC50s for these cell lines were similar to those for a lung adenocarcinoma line with established in vivo sensitivity to TRC-794. TRC-1154, a more potent SMAP, was shown to produce statistically significant tumor growth inhibition compared to vehicle control in a xenograft model when orally dosed at 100mg/kg daily. In summary, SMAPs may represent a viable treatment approach in SCLC, possibly via a PP2A mediated negative regulation of c-myc.
Citation Format: Benjamin Jonathan Wolpaw, Goutham Narla, Shashank Cheemalavagu. Using small molecule activators of PP2A to negatively regulate c-myc in small cell lung cancer. [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 B49.
Abstract IA08: MYC and mitochondrial metabolism in childhood neuroblastoma
Authors: Arsenian-Henriksson Marie 
Published: October 2015

Abstract
Neuroblastoma, which arises from the sympathetic nervous system is one of the most aggressive solid tumors of early childhood. Amplification of the MYCN oncogene has been found in around 30% of neuroblastoma patients and it is associated with rapid tumor progression and poor prognosis. New treatment options are urgently needed for this group of patients. As metabolic adaptations are crucial for cancer cell survival during tumor progression, identifying metabolic discrepancies of aggressive tumors may be central in order to find new treatment strategies. We have recently highlighted the importance MYC driven mitochondrial metabolism in neuroblastoma pathogenesis. Our findings suggest that a small chemical molecule, 10058-F4, previously identified as a c-MYC inhibitor also targets the MYCN/MAX complex resulting in apoptosis and neuronal differentiation in MYCN-amplified neuroblastoma cells. Importantly, we found that inhibition of MYCN results in changes in neuroblastoma cell metabolism including mitochondrial dysfunction leading to accumulation of intracellular lipid droplets. Taken together, our results highlight that MYCN regulates important metabolic pathways in MYCN-amplified neuroblastoma, which may be the basis for development future therapies for this patient group.
Citation Format: Marie Arsenian-Henriksson. MYC and mitochondrial metabolism in childhood neuroblastoma. [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 IA08.
Abstract PR07: Myc-dependent translation makes an impact: Tailor-made protein expression for cancer development
Authors: Stumpf Craig , Cunningham Tom , Ruggero Davide 
Published: October 2015

Abstract
Our research delineates how the “cancer translatome” can reprogram gene expression at the post-transcriptional level, by controlling the translation of specific subsets of mRNAs during distinct steps of cancer progression. Here, we have genetically engineered a novel mouse model in which two of the most commonly perturbed oncogenes, MYC and KRAS, are stochastically activated in a small number of hepatocytes resulting in a dramatic increase in metastatic tumors, recapitulating the process of liver tumor development in human cancers. Therefore, we have used this model to detail the evolution of gene expression from primary tumor initiation to metastasis at both the transcriptional and translational levels. We used a genome-wide ribosome profiling approach to assess changes in gene expression at the earliest possible time point after oncogenic activation to metastasis formation in order to develop the first functional comprehensive network of widespread changes in translational regulation that occur during the course of tumor development. We characterized networks of translational regulation unique to each individual oncogene, as well as networks that are synergistically regulated upon activation of both oncogenes. For example, we have identified common networks that are translationally induced upon activation of either MYC or KRAS (e.g. protein synthesis, energy metabolism). We discovered that each oncogene also regulates the translation of unique mRNA networks. MYC induces the translation of genes involved in cell proliferation, mRNA splicing, and lipid metabolism, while KRAS specifically induces the translation of stress response genes, especially the pathway that responds to hypoxia. In addition to the additive effects of regulating their cognate mRNA networks, the combination of MYC and KRAS activation in the same cells can also induce a synergistic effect on the translation of new networks including genes involved in integrin signaling, which may partially explain the increased metastasis observed in this mouse model. Additionally, we uncovered independent regulatory mechanisms that may allow for temporal regulation of discrete oncogenic processes, either at the level of transcription or translation, required at different times during the course of tumor development. Understanding the mechanisms and specific targets of translational regulation downstream of MYC and KRAS activation will provide a novel platform from which to develop therapeutic strategies targeting cancers possessing two of the most common and currently “undruggable” oncogenic lesions.
Citation Format: Craig Stumpf, Tom Cunningham, Davide Ruggero. Myc-dependent translation makes an impact: Tailor-made protein expression for cancer development. [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 PR07.
Abstract PR12: Selective targeting of MYC mRNA by chemically stabilized antisense oligonucleotides
Authors: Ott Christopher J. , Bandaru Raj , Gill Taylor , Tao Junyan , Chen Xin , Zhang Yixian , Bradner James E. 
Published: October 2015

Abstract
Despite its well-characterized properties as a proto-oncogene in numerous cancers, direct potent and selective inhibition of MYC or its protein product c-Myc with cell-permeable synthetic agents remains a significant challenge. Systemic inhibition of c-Myc activity in mice by expression of dominant negative MYC transgenes has been shown to dramatically decrease tumor burden with apparently tolerable side effects (Soucek et al, Nature 2008). In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC at the transcriptional, translational, and post-translational level. Here we describe the application of synthetic antisense oligonucleotides designed to target specific sequences of the MYC mRNA (MYCASOs). We have incorporated several chemical features into MYCASOs, including the addition of locked nucleic acid (LNA) bases at the 5' and 3' ends, phosphorothioate linkers, and internal DNA bases in order to increase mRNA target affinity and cleavage, cellular permeability, stability, and systemic distribution in vivo. Treatment of MYC¬-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and c-Myc protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5' rapid amplification of cDNA ends (RACE) assay. MYCASO-treatment of cancer cell lines leads to significant inhibition of cellular proliferation and induces apoptosis in c-Myc-dependent myeloma and leukemia cell lines while decreasing c-Myc-mediated gene expression. In vivo administration of MYCASOs simply dissolved in saline was performed in mice by tail vein injection. MYCASOs are well tolerated up to 25 mg per kg on a twice-weekly dosing regimen. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment leads to detectable cleavage of the MYC transcript, decreases c-Myc levels within tumors, and significantly decreases tumor burden. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of c-Myc activity, and promising therapeutic agents for MYC-driven tumors.
Citation Format: Christopher J. Ott, Raj Bandaru, Taylor Gill, Junyan Tao, Xin Chen, Yixian Zhang, James E. Bradner. Selective targeting of MYC mRNA by chemically stabilized antisense oligonucleotides. [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 PR12.