bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B11: Expression and functional analysis of aurora kinase A/B in double hit and triple hit B-cell lymphomas
Authors: Cinar Munevver , Peker Deniz , Akyurek Nalan , Huang Qin , Lopategui Jean , Cinar Bekir , Alkan Serhan 
Published: October 2015

Abstract
Background: Double-hit lymphoma (DHL) or triple-hit lymphoma (THL) is associated with translocations of MYC along with the genomic rearrangements of BCL-2 and BCL-6. MYC is demonstrated to upregulate Aurora kinase (AURK) A and B expression, which is implicated in MYC-driven lymphomagenesis. Although a novel AURK inhibitor MLN8237 showed promising treatment outcomes in a phase II clinical trial in patients with various lymphomas including B-cell lineage, expression patterns and functional inhibition of AURK A and B in DHL and THL remains to be determined.
Methods: Expression patterns of AURK A and B proteins in DHL (15 BCL2+; 4 BCL6+ cases), THL (1 case) and reactive lymphoid hyperplasia were analyzed by IHC in formalin-fixed, paraffin-embedded tissues utilizing AURK A and B specific antibodies. Cases with strong nuclear staining in more than 30% of lymphoma cells were scored positive. Cell viability by MTS assays and apoptosis by flow cytometry were assessed in DoGKiT DHL cell line and CS-THL1 THL cell line at 72h post treatment with AURK inhibitor MLN8237 single or combination with DNA methyltransferase inhibitor, Decitabine (DAC), proteasome inhibitor, Bortezomib (BTZ) or classical chemotherapeutic agent, Doxorubicin (DOX).
Results: All cases of DHL (19/19) showed nuclear positivity for AURK A and B; THL was AURK A reactive but AURK B noted only in 5% of the cells. AURK A expression in reactive hyperplasia was diffuse in germinal center cells (GCC) and AURK B had prominence in the dark zone of the GCC, but no significant expression seen in mantle or marginal zone cells. Combine exposure of MLN8237 with DAC, Bortezomib or DOX synergistically attenuated growth of DoGKiT and CS-THL1cells compare to single agent in vitro.
Conclusion: AURK A and B expression is common in DHL and THL. AURK inhibitor exposure attenuated growth and induced apoptosis particularly in combination with DAC, BTZ and DOX. Thus, targeted therapy against AURK A and B should be considered in future clinical trials for the development of effective treatment modalities for DHL or THL.
Note: This abstract was not presented at the conference.
Citation Format: Munevver Cinar, Deniz Peker, Nalan Akyurek, Qin Huang, Jean Lopategui, Bekir Cinar, Serhan Alkan. Expression and functional analysis of aurora kinase A/B in double hit and triple hit B-cell lymphomas. [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 B11.
Abstract B12: Co-targeting of MYC and BCL2 signaling is a promising treatment strategy for double hit and triple hit B-cell lymphomas
Authors: Cinar Munevver , Rosenfelt Fred , Rokshar Sepehr , Pillai Raju , Lopategui Jean , Cervania Melissa , Cinar Bekir , Alkan Serhan 
Published: October 2015

Abstract
Background: Overexpression of MYC and BCL2 or/and BCL6 due to genomic rearrangements is the key molecular feature of double hit lymphoma (DHL) or triple hit lymphoma (THL). Patients with DHL and THL show very aggressive disease course and poor survival because there is no effective treatment modality. The objective of this study is to assess the impact of MYC and BCL2 inhibition on established DHL and patient derived THL cells in vitro.
Methods: Primary THL cell line named as CS-THL1 was established from an 85 year-old lymphoma patient. Immunohistochemistry (IHC) was conducted to determine the levels of MYC, BCL2, BCL6, or Ki-67 expression in formalin-fixed, paraffin-embedded tissues. MTS assays were employed to evaluate the anti-growth efficacy of MYC inhibitor 10058-F4 or JQ-1, and BCL-2 inhibitor ABT-199, a BH3 mimetic, in CS-THL1 and DoGKiT cells alone or together and with or without vincristine or doxorubicin. Apoptosis, cytochrome c release and intracellular expression of BCL2, BCL-xL, BIM, and MCL-1 protein in response to drugs were analyzed by flow cytometry.
Results: Expression of MYC, BCL2, BCL6 and proliferation factor Ki-67 protein was increased in THL, as shown by IHC. Analysis of cell viability demonstrated that inhibition of MYC by 10058-F4 or JQ-1 or BCL2 by ABT-199 as a single agent significantly attenuated the growth of CS-THL1 and DoGKiT cells in dose- and time-dependent manners. Combination of 10058-F4 or JQ-1 and ABT-199 or together with vincristine or doxorubicin synergistically suppressed CS-THL1 and DoGKiT cell growth compared with single agent treatment. As demonstrated by multiple approaches, apoptosis due to inhibition of BCL2 by ABT-199 or inhibition of MYC with 10058-F4 or JQ-1 exposure was the underlying cause of the observed growth retardation in CS-THL1 and DoGKiT cells.
Conclusion: These observations suggest that concurrent inhibition of MYC and BCL2 pathway signaling is a potential treatment modality for patients with aggressive DH and TH B-cell lymphomas.
Citation Format: Munevver Cinar, Fred Rosenfelt, Sepehr Rokshar, Raju Pillai, Jean Lopategui, Melissa Cervania, Bekir Cinar, Serhan Alkan. Co-targeting of MYC and BCL2 signaling is a promising treatment strategy for double hit and triple hit B-cell lymphomas. [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 B12.
Abstract B19: MYC induces PLD6 to suppress YAP/TAZ-dependent self-renewal of mammary stem cells
Authors: Eyss Bjoern von , Jaenicke Laura Annika , Wiese Katrin , Rosenwald Andreas , Eilers Martin 
Published: October 2015

Abstract
For the maintenance of a given tissue it is absolutely critical to balance proliferation and differentiation of stem cells, progenitor cells and terminally differentiated cells. Perturbations of these finely tuned processes can lead to various diseases such as cancer.
One factor that has been implicated in the transition from a stem cell to a progenitor/ transit-amplifying cell is the oncogenic transcription factor MYC. Paradoxically, despite its strong pro-tumorigenic capabilities it has been shown to promote differentiation in several tissues such as the skin or the hematopoietic system.
To identify critical pathways that might explain MYC's effect on the differentiation of epithelial stem cells we expressed MYC in mammary stem cells. Here, MYC induction led to a drastic reduction in sphere formation indicative of a decreased stem cell potential. Further RNA-Seq and bioinformatical analysis revealed that one of MYC's main functions in mammary stem cells is the repression of YAP/TAZ target genes.
YAP and its orthologue TAZ act as nuclear co-activators and are the downstream effectors of the Hippo pathway, a recently discovered pathway with key functions in adult stem cell maintenance and growth control.
Using a targeted siRNA screen for MYC target genes we were able to identify a single target gene that is absolutely essential for MYC's ability to repress YAP/TAZ, namely PLD6.
PLD6 is a mitochondrial protein that promotes mitochondrial fusion, so that this MYC target gene couples a mitochondrial checkpoint to repression of YAP/TAZ.
We were also able to demonstrate the relevance of this pathway in vivo using a mouse that expresses MYC in the mammary stem cell compartment. Interestingly, this pathway is also operational in human breast cancer since a high MYC signature correlates with a low YAP/TAZ signatue in breast cancer patients ultimately leading to a bad prognosis for the respective patient.
In summary, we were able to identify a new pathway that couples MYC to mitochondrial biogenesis and the repression of an adult stem cell program.
Citation Format: Bjoern von Eyss, Laura Annika Jaenicke, Katrin Wiese, Andreas Rosenwald, Martin Eilers. MYC induces PLD6 to suppress YAP/TAZ-dependent self-renewal of mammary stem 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 B19.
Abstract B24: Targeting ERK-MYC axis in pancreatic cancer
Authors: Beglyarova Natalia , Banina Eugenia , Skobeleva Natalya , Khazak Vladimir , Astsaturov Igor 
Published: October 2015

Abstract
Pancreatic cancer (PCa) is a devastating malignancy with almost 90% lethality of all stages. In PCa, constitutively activated mutated KRAS induces persistent ERK signaling which stabilizes the oncogenic MYC protein. With very limited efficacy of chemotherapy, novel treatment options are urgently need for PCa.
Here, we used patient-derived PCa cells and matched PCa tissue explants (PDX) to search for cytotoxic anti-PCa activity among the existing 867 drugs. Only a minority of tested agents were confirmed as active in vivo on patient-matched PDX models. From a short list of the agents with activity in vivo, we focused on triptolide (TLD), an irreversible inhibitor of ERCC3. In pilot testing of triptolide efficacy in a “xenopatient” trial of 8 PCa PDX models, we found that TLD was highly effective against a minority of tumors which achieved complete regression lasting for 3-6 weeks, while other models only showed growth delay. Genomic profiling of highly sensitive PDX models unfirmly demonstrated MYC-amplification.
We tested TLD activity in vitro using PDX-matched patient-derived PCa cell lines. Nanomolar TLD elicited rapid (1-4 hours) and profound depletion of MYC oncoprotein in MYC-amplified PCa cell lines, but in PCa cells with normal MYC gene copy number. Furthermore, TLD-resistant PCa cells and PDX tumors exhibited rapid increase of phosphorylated ERK and its downstream targets including stable phospho-MYC protein. This activity of TLD against non-phosphorylated forms of MYC protein suggests interdependence of ERCC3 and MYC in cancer. Expression of ERCC3 was MYC-dependent in a Tet-OFF MYC cell line model. Conversely, silencing of ERCC3 suppressed MYC level.
The KRAS-&gt;ERK pathway is critical for initiation and progression of PCa. Attempts to disrupt this signaling axis by blocking MEK activity produces only transient cytostatic effect followed by rapid reactivation of the pathway mediated by MYC. Our results further confirm this dependency of PCa on the integrity of the activated KRAS-&gt;ERK-&gt;MYC signaling axis, and that pharmacological blockade of ERCC3 can be a highly effective strategy against PCa, and in other recalcitrant carcinomas with MYC-amplification. We thus provide a useful biomarker for future clinical development of TLD analogs such as Minnelide which is currently being tested in a Phase I clinical trial.
Citation Format: Natalia Beglyarova, Eugenia Banina, Natalya Skobeleva, Vladimir Khazak, Igor Astsaturov. Targeting ERK-MYC axis in 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 B24.
Abstract B27: CDK inhibition impairs homologous recombination and induces PARP inhibitor sensitivity via loss of c-myc expression in TNBC
Authors: Carey Jason Patrick , Keyomarsi Khandan 
Published: October 2015

Abstract
The c-myc oncogene is a “master regulator” amplified in several types of cancer including ovarian, breast, colorectal and pancreatic cancers. C-myc controls several cellular processes during tumor maintenance including the cell cycle, metabolism, and DNA damage repair while also playing an essential role in transforming normal cells during tumorigensis. C-myc amplification correlates with poor survival and a higher frequency of relapse in triple negative breast cancer (TNBC) patients. C-myc amplification promotes deregulation of the cell cycle, via transcriptional activation of G1-S-phase cell cycle and DNA replication genes. CDK inhibition has been shown to down regulate c-myc expression in cancer cells, in vitro. Therefore, we hypothesize that transient CDK inhibition downregulates c-myc expression and increases susceptibility to DNA damaging agents in TNBC cells. We observed the long-term response of several c-myc overexpressing TNBC cells to Dinaciclib, a potent CDK inhibitor (CDK 1, 2, 5, 9) in vitro. High Throughput Survival Assay (HTSA) analysis revealed that c-myc expressing TNBC cells have a potent response to CDK inhibition via Dinaciclib (IC50 10-20nM). Dinaciclib induces an S-phase arrest and downregulation of the c-myc/E2F1 pathway in both normal (MCF10A) and TNBC (MB231, SUM149, HCC1937) breast cancer cells. Loss of c-myc expression correlates with increased apoptosis in TNBC cells but not HMECs. C-myc downregulation also correlates with increased γH2AX DNA damage and downregulation of BRCA1 foci formation. The resultant impaired homologous recombination (HR) pathway in TNBC cells treated with Dinaciclib proposed an increased susceptibility to PARP inhibitor induced DNA damage. Combination Dinaciclib + PARP inhibition exhibited a Dinaciclib dose dependent synergistic growth inhibition of BRCA1 wild-type and mutant TNBC cells to PARP inhibitors. Dinaciclib also increased susceptibility of PARP inhibition in resistant BRCA1 mutant cell lines (HCC1937, SUM149). Dinaciclib + PARP Inhibitor combination therapy induced increased apoptosis, γH2AX DNA damage and decreased BRCA1, RAD51 foci formation. These results demonstrate that Dinaciclib + PARP inhibition induces growth arrest and induction of apoptosis in c-myc overexpressing cancer cells. C-myc is frequently amplified in TNBC tumors and may serve as a biomarker for CDK + PARP inhibitor combination therapy.
Citation Format: Jason Patrick Carey, Khandan Keyomarsi. CDK inhibition impairs homologous recombination and induces PARP inhibitor sensitivity via loss of c-myc expression in TNBC. [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 B27.
Abstract B32: Pro-apoptotic functions of AMPK revealed by Myc
Authors: Haikala Heidi M. , Marques Elsa , Eskelinen Vilja , Viheriäranta-Nieminen Anni , Saarikoski Sirkku , Nevalaita Liina , Kovanen Panu , Heikkilä Päivi , Leidenius Marjut , Laajala Daniel , Aittokallio Tero , Munne Pauliina , Klefström Juha 
Published: October 2015

Abstract
Oncogenic transcription factor Myc deregulates the cell cycle and simultaneously reprograms cellular metabolism to meet the biosynthetic and bioenergetic needs of proliferation. Myc also sensitizes cells to mitochondria-dependent apoptosis. Although metabolic reprogramming has been circumstantially connected to vulnerability to apoptosis, the connecting molecular pathways have remained poorly defined. Our recent studies revealed that Myc-dependent ATP depletion activates the energy sensor AMP-activated protein kinase (AMPK), which induces stabilizing phosphorylation of p53 at Ser15. AMPK-stabilized tumor suppressor protein p53 then accumulates in the mitochondria and interacts with the protein complex comprised of Bak and Bcl-xL, to sensitize cells to apoptosis. These results reveal an unexpected pro-apoptotic function of AMPK in context of Myc transformed cells.
We have explored possibilities to therapeutically exploit the Myc-AMPK facilitated apoptosis pathway. We show that a BH3-mimetic small molecule ABT-737, which neutralizes Bcl-2 and Bcl-xL, sensitizes to Myc-dependent apoptosis ex vivo and in vivo WAP-Myc tumours. ABT-737 also reduced WAP-Myc driven primary tumor growth and lung metastases in transgenic and syngrafted mice. Nevertheless, ABT-737 only delayed but did not prevent the formation of Wap-Myc tumors.
In a drug combination screen designed to identify small molecules that potentiate the efficacy of ABT-737, we found several compounds influencing the status of AMPK activity. The synergistic apoptotic action between ABT-737 and AMPK modulating agents has been validated in explant 3D cultures from patient derived Myc positive breast cancers. The mechanisms behind the proapoptotic AMPK function will be discussed. Our results provide evidence that AMPK has a context-dependent pro-apoptotic function that can be therapeutically exploited as a tumour cell-specific vulnerability.
Citation Format: Heidi M. Haikala, Elsa Marques, Vilja Eskelinen, Anni Viheriäranta-Nieminen, Sirkku Saarikoski, Liina Nevalaita, Panu Kovanen, Päivi Heikkilä, Marjut Leidenius, Daniel Laajala, Tero Aittokallio, Pauliina Munne, Juha Klefström. Pro-apoptotic functions of AMPK revealed by 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 B32.
Abstract B43: Reversible linkage of two distinct small molecule inhibitors of MYC generates a more potent and selective dimeric inhibitor that is active in cancer cell lines over-expressing MYC
Authors: Wanner Jutta , Romashko Darlene , Werner Douglas S. , May Earl W. , Peng Yue , Schulz Ryan , Foreman Kenneth W. , Russo Suzanne , Arnold Lee D. , Pingle Maneesh , Bergstrom Donald E. , Barany Francis , Thomson Stuart 
Published: October 2015

Abstract
Up to 70% of all human cancers have deregulated or elevated levels of MYC, making MYC a high profile cancer drug target. The disordered structure of the MYC protein has made identifying small molecule inhibitors of this target very challenging, however recent reports have identified molecules that bind to MYC and block its function. Here we describe the successful application of a novel approach for generating selective dimeric MYC inhibitors by modifying and reversibly linking two previously described small molecule inhibitors of MYC (10058-F4 and 10074-G5) that bind to distinct sites in the bHLHZip domain of the protein. We synthesized two directed libraries of monomers based on each of these molecules to identify the optimal dimer configuration required to inhibit MYC activity. Each monomer contains one of the respective ligands, a connector of varying length, and a bioorthogonal linker element that allows reversible dimerization. We identified specific combinations of monomers (termed active dimers), which displayed synergistic inhibition of MYC in biochemical and cellular assays. Through SPR, ELISA and EMSA we demonstrate that these dimers directly bind to MYC, block its interaction with Max and thus its binding to DNA, respectively. These dimeric inhibitors have superior anti-proliferative activity in MYC over-expressing cell lines compared to their monomeric components, and this activity is correlated with a decrease in MYC protein levels and an inhibition of MYC-dependent gene expression. Control combinations that lack a linker element, and thus are unable to form a dimer, do not show any synergistic effects in these assay systems. Collectively, these data validate our new approach to generate selective inhibitors of MYC assembled from smaller, lower affinity components. This approach provides an opportunity for developing novel therapeutics against MYC and other challenging intracellular drug target classes.
Citation Format: Jutta Wanner, Darlene Romashko, Douglas S. Werner, Earl W. May, Yue Peng, Ryan Schulz, Kenneth W. Foreman, Suzanne Russo, Lee D. Arnold, Maneesh Pingle, Donald E. Bergstrom, Francis Barany, Stuart Thomson. Reversible linkage of two distinct small molecule inhibitors of MYC generates a more potent and selective dimeric inhibitor that is active in cancer cell lines over-expressing 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 B43.
Abstract B44: Effects of BET bromodomain inhibitors on replication and cell cycle progression
Authors: Muralidharan Somsundar Veppil , Bhadury Joydeep , Green Lydia , Nilsson Lisa M. , McLure Kevin G. , Nilsson Jonas A. 
Published: October 2015

Abstract
Myc family of transcription factors are deregulated in most cancers and their expression projects a poor prognosis. Genetic and pharmacological inhibition of Myc and several Myc targets leads to tumor regression and apoptosis. Recently, inhibitors of BET Bromodomain proteins (BETi) were shown to have anti-tumor properties and this has been attributed to Myc down-regulation. Here we show that two structurally distinct BETi affects replication and cell cycle progression at low concentrations where the transcriptome remains largely unaltered. Thymidine incorporation and flow cytometry analyses demonstrates that S-phase progression is hindered at these concentrations. However, in a cell-free system replication is not impaired suggesting that BETi-mediated block of replication is linked to effects on chromatin. Furthermore, at higher concentration of BETi, S-phase entry of cells is completely abrogated. Ectopic expression of Myc fails to rescue these phenotypes, suggesting a novel function of BET bromodomain proteins in replication and cell cycle regulation. Our pharmacogenetic screen in the presence of sub-lethal doses of BETi has identified several small molecule inhibitors to synergize with BETi to enhance apoptosis of Myc driven tumors.
Citation Format: Somsundar Veppil Muralidharan, Joydeep Bhadury, Lydia Green, Lisa M. Nilsson, Kevin G. McLure, Jonas A. Nilsson. Effects of BET bromodomain inhibitors on replication and cell cycle progression. [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 B44.
Abstract IA01: Myc functions within a transcriptional regulatory network
Authors: Eisenman Robert 
Published: October 2015

Abstract
In this talk I will explore the idea that Myc proteins do not act independently, but rather function in the context of a larger network of transcription factors. This network can be considered as having two interconnected branches, each requiring heterodimerization with either Max or the Max-like protein, Mlx. Max forms heterodimers with Myc and Mxd family proteins (including Mnt and Mga), while Mlx heterodimerizes with the large BHLHZ proteins MondoA and ChREBP. A subset of Mxd proteins also heterodimerize with Mlx. Based on our current knowledge of the organization and the functions of its different components, it is possible to view the network as a transcriptional module that responds to and integrates extracellular and intracellular stimuli in order to modulate gene expression programs that ultimately act to affect cellular behavior. We can consider the three sub-families within the network, Myc, Mxd, and MondoA/ChREBP, as being responsive to mitogenic signaling, growth arrest/differentiation signals, and nutrient availability, respectively. The transcriptional response mediated by these factors is further modified by their ability to interact with other transcriptional regulators (e.g. Miz1) and to recruit chromatin modifying factors.
Importantly, the notion of an extended Max/Mlx network is likely to go beyond the simple wiring diagram described above. For example functional interactions have been described among network members such as the antagonism at molecular and biological levels between Myc and Mxd proteins. Recently we have shown that the metabolic reprograming induced by deregulated Myc proteins in several distinct tumor types is cooperatively regulated by, and dependent on, MondoA-Mlx. The transcriptional changes mediated by Myc-Max and MondoA-Mlx are critical for tumor cell survival. Analysis of Myc's activities within the context of the extended network, as well as the dynamics of the network as a whole, may provide insights into the molecular basis and the consequences of Myc deregulation in the etiology of cancer and new approaches to inhibit Myc.
Citation Format: Robert Eisenman. Myc functions within a transcriptional regulatory network. [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 IA01.