bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4693: Mechanism-based combination strategies for BET inhibitors in NUT midline carcinoma
Authors: Wyce Anastasia , Soden Peter , Felitsky Daniel J. , Matteo Jeanne J. , Korenchuk Susan , Thripp Gary , Keenan Kathryn , McHugh Charles F. , Prinjha Rab , Carpenter Christopher , Smithers Nicholas , Barbash Olena 
Published: July 2016

Abstract
NUT midline carcinoma (NMC) is a highly aggressive squamous cell cancer that responds poorly to standard chemotherapuetic approaches. NMC is characterized by translocations involving the NUT (nuclear protein in testes) protein, which in a majority of cases is fused to the BET (bromodomain and extra-terminal) protein family members BRD3 or BRD4. BET proteins (BRD2, BRD3, BRD4, BRDT) are epigenetic readers that modulate expression of genes involved in cell growth and oncogenesis. Selective small molecule inhibitors of BET proteins, such as the GSK I-BETs (I-BET762, I-BET151), abrogate binding of BET proteins to acetylated chromatin and inhibit the expression of BET target genes. Here we describe the activity in I-BET762 and other BET inhibitors in pre-clinical models of NMC. Consistent with previous reports, we observe profound growth inhibition and cytotoxicity in NMC cell lines in vitro, as well as significant tumor growth inhibition or tumor regression in cell line xenografts of NMC. I-BET762 treatment in NMC cell lines results in transcriptional changes affecting MYC and other pathways critical for cancer cell growth. We explore the contribution of these changes to the anti-proliferative effects observed in NMC models, and identify rational combinations to improve upon the efficacy of I-BET762 as a monotherapy. Taken together, our data highlight novel mechanisms through which BET inhibitors impact NMC cell growth and survival, and suggest potential treatment strategies to improve response in this highly aggressive disease. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed by the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed.
Citation Format: Anastasia Wyce, Peter Soden, Daniel J. Felitsky, Jeanne J. Matteo, Susan Korenchuk, Gary Thripp, Kathryn Keenan, Charles F. McHugh, Rab Prinjha, Christopher Carpenter, Nicholas Smithers, Olena Barbash. Mechanism-based combination strategies for BET inhibitors in NUT midline carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4693.
Abstract 4706: ABBV-075 exhibits robust in vitro and in vivo activities against the ABC and GCB subtypes of DLBCL
Authors: Lin Xiaoyu , Huang Xiaoli , Sarthy Aparna , Magoc Terry , Albert Daniel , Lam Lloyd , Uziel Tamar , Lu Xin , Bui Mai-Ha , Faivre Emily , Wilcox Denise , Elmore Steven , McDaniel Keith , Kati Warren , Shen Yu 
Published: July 2016

Abstract
Diffuse Large B-Cell Lymphoma (DLBCL) consists of activated B-cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subtypes. Among these, the ABC subtype of DLBCL often harbors mutations that cause abnormal NF-κB activation, which subsequently activates genes important for cell survival and disease progression in ABC DLBCL. The bromodomain and extraterminal domain (BET) protein BRD4 binds acetylated NF-κB and regulates NF-κB dependent transcription. Accordingly, targeting BET family proteins using small molecule inhibitors such as ABBV-075 might provide therapeutic benefit in ABC DLBCL by blocking the NF-κB pathway. In this study, we examined the activity of ABBV-075 in both the ABC and GCB subtypes of DLBCL. As expected, ABBV-075 diminished NF-κB reporter activity, down-regulated NF-κB target genes, inhibited proliferation and survival of ABC DLBCL cells in vitro, and delayed the growth of ABC DLBCL tumors in vivo. Interestingly, ABBV-075 also exhibited robust anti-proliferative activities in GCB DLBCL cells in vitro and inhibited the growth of GCB DLBCL tumors in vivo. Further characterization of the responses of GCB DLBCL cells to ABBV-075 indicated that ABBV-075 induced strong apoptosis in GCB DLBCL cells that are resistant to the Bcl-2 inhibitor venetoclax (ABT-199), but rarely in venetoclax-sensitive GCB DLBCL cell lines. Our results indicate that ABBV-075 could be active against both the ABC and GCB subtypes of DLBCL. The complementary activity of ABBV-075 and ABT-199 further suggests that ABBV-075 maybe an interesting option for ABT-199 resistant/refractory DLBCL patients.
Citation Format: Xiaoyu Lin, Xiaoli Huang, Aparna Sarthy, Terry Magoc, Daniel Albert, Lloyd Lam, Tamar Uziel, Xin Lu, Mai-Ha Bui, Emily Faivre, Denise Wilcox, Steven Elmore, Keith McDaniel, Warren Kati, Yu Shen. ABBV-075 exhibits robust in vitro and in vivo activities against the ABC and GCB subtypes of DLBCL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4706.
Abstract 4709: Broad activity for the combination of BET and MEK inhibitors across solid and hematologic cancers
Authors: Wyce Anastasia , Felitsky Daniel J. , Zhang Xi-Ping , Matteo Jeanne J. , Korenchuk Susan , Mathew Lijoy K. , Musso Melissa , Khaku Sakina , Ortiz Victoria , Keenan Kathryn , Stern Melissa , Degenhardt Yan , Plant Ramona , McHugh Charles F. , Tummino Peter J. , Carpenter Christopher , Barbash Olena 
Published: July 2016

Abstract
BET (bromodomain and extra-terminal) family proteins are epigenetic readers that modulate expression genes involved in cell growth and oncogenesis. Selective small molecule BET inhibitors, such as the GSK I-BETs (I-BET762, I-BET151), abrogate binding of BET proteins to acetylated chromatin and inhibit transcription of BET target
genes. We and others have previously demonstrated single agent activity for BET inhibitors in a number of pre-clinical solid and hematologic tumor models. Transcriptomics
and mechanistic studies from several of these tumor types indicate that BET inhibitors influence numerous signaling pathways at the transcriptional level, including RAS/RAF/MEK signaling. Here we describe the synergistic effects of combining BET and MEK inhibitors in various solid and hematologic cancer models. We observe synergistic growth inhibition and apoptosis in a subset of cell lines representing multiple tumor types, as well as patient-derived xenograft models treated with the combination ex vivo. Additionally, combination of BET and MEK inhibitors results in improved tumor growth inhibition in cell line xenograft models compared to either single agent therapy. Further exploration of the combination in sensitive tumor types highlights multiple mechanisms potentially driving synergy, and suggests possible markers associated with sensitivity to the combination. Taken together, our data highlight the potential of BET/MEK inhibitor combinations to improve upon the efficacy observed for these agents as monotherapies in a wide variety of preclinical cancer models.
All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed by the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed. Human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents.
Citation Format: Anastasia Wyce, Daniel J. Felitsky, Xi-Ping Zhang, Jeanne J. Matteo, Susan Korenchuk, Lijoy K. Mathew, Melissa Musso, Sakina Khaku, Victoria Ortiz, Kathryn Keenan, Melissa Stern, Yan Degenhardt, Ramona Plant, Charles F. McHugh, Peter J. Tummino, Christopher Carpenter, Olena Barbash. Broad activity for the combination of BET and MEK inhibitors across solid and hematologic cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4709.
Abstract 4711: Broad anti-tumor activity of a novel BET bromodomain inhibitor
Authors: Ma Yan , Powell Ben , Zhang Jiazhong , Zhang Ying , Carias Heidi , Schwertschlag Ullrich , Habets Gaston , Ibrahim Prabha , Spevak Wayne , Zhang Chao , Bollag Gideon 
Published: July 2016

Abstract
Inhibitors against the bromodomain and extra terminal domain (BET) family of proteins have been pursued as promising oncology agents based on growing understanding of epigenetic control of disease processes. Through scaffold-based and crystallography-guided drug design, we discovered PLX51107, a potent and selective small molecule inhibitor of the BET family bromodomains. PLX51107 is structurally unrelated to the benzodiazepines such as JQ1, I-BET762, and OTX015 and other published BET inhibitors. PLX51107 exhibits low nanomolar potency in blocking interactions mediated by the four BET family proteins BRD2, BRD3, BRD4, and BRDT. Pharmacologic inhibition of BET proteins by PLX51107 suppresses the transcription of genes essential for tumor growth and survival and leads to selective killing of cancer cell lines across a broad range of hematologic malignancies (e.g. leukemia, lymphoma and multiple myeloma). A subset of solid tumors (e.g. melanoma and SCLC) is also sensitive to growth inhibition by the BET inhibitor PLX51107. Novel biomarkers in these diseases have been identified. PLX51107 is well tolerated and has sufficient potency and oral bioavailability to demonstrate in vivo efficacy in animal models of a variety of tumor types, representing both hematologic and solid tumors of diverse genetic backgrounds. In combination studies, PLX51107 showed potential to improve the efficacy (response rates and duration of response) of other anticancer treatments without increased toxicity. These results support further development of PLX51107 as an epigenetic-based therapy for a variety of cancer indications.
Citation Format: Yan Ma, Ben Powell, Jiazhong Zhang, Ying Zhang, Heidi Carias, Ullrich Schwertschlag, Gaston Habets, Prabha Ibrahim, Wayne Spevak, Chao Zhang, Gideon Bollag. Broad anti-tumor activity of a novel BET bromodomain inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4711.
Abstract 4728: Histone deacetylase inhibitors induce apoptosis in multiple tumor types through induction of ATF3
Authors: Chueh Anderly C. , Tse Janson , Ioannidis Paul , Tögel Lars , Tan Bee S. , Davlos-Salas Mercedes , Nightingale Rebecca , Thompson Matthew R. , Williams Bryan , Dickinson Michael , Dhillon Amardeep S. , Mariadason John M. 
Published: July 2016

Abstract
Histone deacetylase inhibitors (HDACi) are approved for the treatment of cutaneous T-Cell lymphoma (CTCL) and Multiple Myeloma. In colon cancer cells HDACi-induced apoptosis is linked to induction of a specific transcriptional response involving upregulation of the immediate-early (IE) response genes FOS, JUN, EGR1, EGR3 and ATF3. To determine if this transcriptional response underpins HDACi-induced apoptosis across multiple tumour types, including CTCL and MM, 50 cell lines derived from common solid and haematological cancers were screened for sensitivity to HDACi-induced apoptosis, and response correlated with IE gene induction. HDACi treatment robustly induced IE gene mRNA and protein expression in multiple tumour lines. IE gene induction was sustained over 24 hours and dependent on the Sp1/Sp3 transcription factors and was also observed in vivo in CTCL patients treated with the HDACi panobinostat. The magnitude of induction of FOS, JUN and ATF3 expression correlated significantly with HDACi-induced apoptosis. The induction of ATF3 was critical for HDACi induced apoptosis as ATF3 downregulation markedly attenuated HDACi-induced apoptosis in multiple tumour lines, and ATF3 knockout MEFs were refractory to HDACi-induced apoptosis. To identify downstream targets of ATF3, the magnitude of ATF3 induction following HDACi treatment was correlated with altered expression of pro and anti-apoptotic genes involved in the intrinsic apoptotic pathway. The magnitude of ATF3 induction correlated inversely with repression of the anti-apoptotic gene Bcl-XL, and ATF3 knockdown attenuated HDACi-mediated Bcl-XL repression. Notably, combinatorial treatment of refractory cell lines with an HDACi and a Bcl-XL inhibitor significantly enhanced HDACi-induced apoptosis. This study demonstrates that IE gene induction is a universal feature of HDACi-induced apoptosis, and that ATF3 as a key driver of HDACi-induced apoptosis through repression of Bcl-XL. These findings establish a method for rapid assessment of HDACi response, and identify a combination strategy for enhancing the activity of these compounds.
Citation Format: Anderly C. Chueh, Janson Tse, Paul Ioannidis, Lars Tögel, Bee S. Tan, Mercedes Davlos-Salas, Rebecca Nightingale, Matthew R. Thompson, Bryan Williams, Michael Dickinson, Amardeep S. Dhillon, John M. Mariadason. Histone deacetylase inhibitors induce apoptosis in multiple tumor types through induction of ATF3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4728.
Abstract 4732: A novel analog of Leonurine inhibits melanoma growth and survival through STAT3 signaling pathways
Authors: Pandey Manoj K. , Krzeminski Jacek , Karelia Deepkamal , Sharma Arun K. , Amin Shantu G. 
Published: July 2016

Abstract
Previous studies have shown that a major alkaloid of Leonurus japonicus Houtt, Leonurine, displays a variety of biological effects including inhibition of HMG-CoA reductase, kidney fibrosis, and osteoporosis. However, the full potential of this alkaloid as a cancer therapeutics has not been explored, primarily due to the lack of potency. A limited reports however, do suggest that Leonurine induces apoptosis in lung and liver cancer cells. We hypothesized that this natural product's structure can be optimized to create a more potent and drug-like molecule. A recent structure-activity relationship (SAR) study in our laboratory based on Leonurine structure has led to the identification of three novel analogs which were &gt;100 times potent than Leonurine in killing solid cancer cells. The aim of the current study is to determine whether the novel analogs of Leonurine exhibit anti-proliferative effects against tumor cells through suppression of the signal transducer and activator of transcription 3 (STAT3) activation pathway. We investigated the effects of Leonurine analogs on constitutive STAT3 activation, modulation of tyrosine kinases and phosphatases in STAT3 activation, STAT3-regulated gene products, and growth modulation of tumor cells. We found that these compounds inhibited constitutive STAT3 activation in metastatic melanoma cells. The suppression was mediated through the inhibition of activation of the upstream kinases Janus-like kinase (JAK) 1, and JAK2. Leonurine derivatives down-regulated the expression of STAT3-regulated gene products such as survivin, Bcl-xL, Bcl-2, cyclin D1, and Mcl-1 leading to the suppression of proliferation and induction of apoptosis. Moreover, we found that these Leonurine analogs significantly inhibited the proliferation of variety of cells derived from solid tumors including breast, pancreatic, prostate, and colon cancer. Overall, these results suggest that these new compounds are novel blockers of STAT3 activation and thus may have potential to suppress melanoma cell proliferation and chemoresistance.
Citation Format: Manoj K. Pandey, Jacek Krzeminski, Deepkamal Karelia, Arun K. Sharma, Shantu G. Amin. A novel analog of Leonurine inhibits melanoma growth and survival through STAT3 signaling pathways. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4732.
Abstract 4739: The upregulation of cyclooxygenase-2 protein expression by receptor tyrosine kinase inhibitors in bladder cancer in vitro
Authors: Bourn Jennifer , Cekanova Maria 
Published: July 2016

Abstract
Several types of cancer, including transitional cell carcinoma (TCC) overexpress several receptor tyrosine kinases (RTKs), including the platelet-derived growth factor receptor (PDGFR), c-kit receptor, epidermal growth factor receptor (EGFR), as well as the vascular endothelial growth factor receptor (VEGFR). Receptor tyrosine kinase inhibitors (RTKIs) are used as targeted therapies for patients diagnosed with cancer with high expression of RTKs. Cyclooxygenase-2 (COX-2) is highly expressed in bladder cancer as well other types of cancers and is one of the key proteins during tumorigenesis. In this study, we validated the effects of RTKIs, Masitinib® (AB1010) and Axitinib on cell proliferation of human (UMUC-3 and T24) and canine (K9TCC#1Lillie, K9TCC#2Dakota, and K9TCC#5Lilly) bladder TCC cells. Using WB analysis, tested human and canine TCC cells, except T24 cells, expressed PDGFR and c-kit receptors. There was no detectable EGFR and VEGFR expressions in any of tested cells by WB analysis. The K9TCC#1Lillie and K9TCC#5Lilly cells had a high expression of COX-2, however K9TCC#2Dakota and human T24 had moderate expression of COX-2, and no COX-2 expression was detected in UMUC3 cells by WB analysis. Both RTKIs, Masitinib® and Axitinib inhibited cell proliferation of the tested human and canine bladder TCC cells in a dose-dependent manner by MTS and apoptosis assays. Interestingly, both tested RTKIs, Masitinib® and Axitinib increased COX-2 protein expressions in tested canine TCC cells. Combined treatment of RTKIs with COX-2 inhibitors decreased cell proliferation of tested TCC cells more effectively as either treatments alone. Our results indicate a possible role of COX-2 signaling pathway in developed RTKIs-resistance in bladder cancer cells in vitro. Co-treatment of RTKIs with COX-2 inhibitors might indicate better clinical outcomes in treatments of patients diagnosed with bladder cancer.
Citation Format: Jennifer Bourn, Maria Cekanova. The upregulation of cyclooxygenase-2 protein expression by receptor tyrosine kinase inhibitors in bladder cancer in vitro. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4739.
Abstract 4744: Targeting nitric oxide signaling with nNOS inhibitors as a novel strategy for the therapy and prevention of human melanoma
Authors: YANG SUN , Yang Zhen , Silverman Richard B. , Poulos Thomas , Meyskens Frank L. 
Published: July 2016

Abstract
The incidence of cutaneous melanoma (CM) has increased markedly over the past four decades although there have been some dramatic advances recently in the treatment of advanced melanoma. The development of novel therapeutic interventions blocking melanoma progression would be of high impact. Recently, our group has identified that neuronal NO synthase (nNOS) activated by UV radiation and growth factor plays an important role in melanoma progression, in parallel with generating constitutive NO stress. Knockdown of nNOS significantly reduced tumor growth and lung metastasis in vivo.
The newly developed nNOS inhibitors HHs (HH044 and HH045) exhibited potent anti-melanoma activity both in vitro and in vivo. The IC50s of HH compounds in human melanoma cells are less than 10 μM, which are comparable or even better than that of chemotherapeutic drug cisplatin (4.2μM and 14.3μM in A375 and Sk-Mel28 cells, respectively). Notably, the inhibition by HHs is more predominant in metastatic melanoma A375 cells compared to primary early stage Wm3211 cells, which supports our hypothesis that nNOS/NO signaling is more critical to melanoma progression than in the initiation phase. In a melanoma xenograft tumor model, we further determined the effects of HH044 and HH045 in tumor growth in vivo. Treatments with HH044 and HH045 (50mg/kg i.p for 21 days) significantly reduced the tumor size to 12% and 19% of control respectively with no apparent systematic toxicities observed. The body weight in treated mice was even moderately higher than the control’s. Taken together, these results are consistent with our hypothesis that targeting nNOS is an efficient and practicable approach for human melanoma therapy.
Citation Format: SUN YANG, Zhen Yang, Richard B. Silverman, Thomas Poulos, Frank L. Meyskens. Targeting nitric oxide signaling with nNOS inhibitors as a novel strategy for the therapy and prevention of human melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4744.
Abstract 4749: Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma
Authors: Keller Patricia J. , Conery Andrew R. , Centore Richard C. , Bommi-Reddy Archana , Gascoigne Karen E. , Bryant Barbara M. , Mertz Jennifer A. , Sims Robert J. 
Published: July 2016

Abstract
Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. We demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network.
Citation Format: Patricia J. Keller, Andrew R. Conery, Richard C. Centore, Archana Bommi-Reddy, Karen E. Gascoigne, Barbara M. Bryant, Jennifer A. Mertz, Robert J. Sims. Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4749.