bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2498: Over-expression of dual-specificity phosphatase 4 (DUSP4) in multiple myeloma
Authors: Xia Tian , Lau Kin-Mang , Cheng Chi Keung , Chan Nelson CN , Ng Margaret H. L. 
Published: August 2018

Abstract
Super-enhancers are unique genomic domains with dense binding of transcription factors (TFs)/cofactors that drive expression of genes defining cell identity. They also contribute to over-expression of oncogenes. The abundance of multiple TFs and coactivators at the super-enhancers favors their cooperative binding and synergistic gene activation. Thus, super-enhancers are more sensitive to perturbation of TF levels than typical enhancers, providing a therapeutic window for preferential targeting oncogenic expression in cancer cells. Recently, a list of super-enhancer associated genes (SEAG) was identified in a multiple myeloma (MM) cell line MM1S and inhibition of transcriptional coactivator BRD4 by JQ1 selectively repressed MYC oncogene expression through reduction of BRD4 binding at the associated super-enhancer. Significances of SEAG other than MYC in myeloma cells remains unclear. By unsupervised hierarchical clustering analysis of expression of 682 identified SEAG in 74 MM, 28 relapsed MM and 15 normal plasma cells (NPC) (GSE6477), distinct expression pattern of SEAG was associated with MM as compared to NPC, indicating their importance in MM. Among the upregulated genes, DUSP4 (Dual Specificity Phosphatase 4), an inducible phosphatase of MAPK (Mitogen-Activated Protein Kinases), was significantly overexpressed in MM and further upregulated in the relapsed MM. High expression was associated with inferior patient outcomes. The overexpression was confirmed in our patient cohort which includes CD138-immunosorted myeloma cells from 30 untreated and 3 relapsed MM patients, 6 smoldering MM patients and 5 MGUS patients, 5 sorted normal plasma cells (NPC) and 7 MM cell lines. Using the cutoff for over-expression as higher than the mean level of NPC plus 2X Standard Deviation, 10 out of 30 MM and all the 3 relapsed samples showed significant DUSP4 over-expression. Functional significance of DUSP4 in MM was explored by siRNA knockdown and the knockdown inhibited myeloma cell growth, implying an oncogenic role of DUSP4 in MM. To study the significances of super-enhancer in regulation of DUSP4 expression, JQ1 was used and inhibition of BRD4 by JQ1 in MM1S, L363 and OPM2 repressed both DUSP4 expression and MM cell growth. By ChIP-PCR, we demonstrated BRD4 specifically bound onto the proximal region of DUSP4 promoter and the binding was blocked by JQ1. Taken together, the oncogenic role of DUSP4 as SEAG in MM was revealed and the preferential targeting SEAG by BRD4 inhibitor could provide insights into further developments of effective therapeutic approaches for MM patients.
Citation Format: Tian Xia, Kin-Mang Lau, Chi Keung Cheng, Nelson CN Chan, Margaret H. L. Ng. Over-expression of dual-specificity phosphatase 4 (DUSP4) in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2498.
Abstract 2523: Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma cells
Authors: Jiang Chen Chen , Wang Yu Fang , Sherwin Simonne , Farrelly Margaret , Liu Fen , Yan Xu Guang , Croft Amanda , Liu Tao , Jin Lei , Zhang Xu Dong 
Published: August 2018

Abstract
While the expression of programmed death-ligand 1 (PD-L1) is an important mechanism by which cancer cells evade the immune system, PD-L1 expression in cancer cells are commonly associated with patients' responses to treatment with anti-PD-1/PD-L1 antibodies. However, how PD-L1 expression is regulated in melanoma cells remains to be fully elucidated. Here we report that the class I histone deacetylase (HDAC) HDAC8 controls transcriptional activation of PD-L1 by a transcription complex consisting of transcription factors homeobox A5 (HOXA5) and signal transducer and activator of transcription 3 (STAT3). Inhibition of HDAC8 upregulated PD-L1 in melanoma cells. This was due to an increase in the activity of a fragment of the PD-L1 gene promoter that is enriched with binding sites for both HOXA5 and STAT3. Indeed, knockdown of HOXA5 or STAT3 abolished upregulation of PD-L1 by HDAC8 inhibition. Moreover, HOXA5 and STAT3
were physically associated and appeared interdependent in activating PD-L1 transcription. Functional studies showed that HDAC8-mediated regulation of PD-L1 expression participated in modulating anti-melanoma T cell responses. Collectively, these results identify HDAC8 as an important epigenetic regulator of PD-L1 expression, with implications for better understanding of the interaction between melanoma cells and the immune system.
Citation Format: Chen Chen Jiang, Yu Fang Wang, Simonne Sherwin, Margaret Farrelly, Fen Liu, Xu Guang Yan, Amanda Croft, Tao Liu, Lei Jin, Xu Dong Zhang. Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2523.
Abstract 260: Apigenin nanoparticle suppresses sphere formation in CD133+/ALDH1high prostate cancer stem cells through downregulation of stem cell markers
Authors: Kanwal Rajnee , Shukla Sanjeev , Exner Agata A. , Tzakos Andreas G. , Gupta Sanjay 
Published: August 2018

Abstract
The recurrence of prostate cancer after definitive treatment(s) is thought to be due to the potential of rare cancer stem cells (CSCs) to withstand therapy and initiate tumor formation. CSCs are a subpopulation of cancer cells capable of self-renewal and plastic adaptation mediating tumorigenesis, metastasis, and therapy resistance. CSCs are associated with cancer progression and clinical outcome in cancer patients. In the present study, we isolated CSCs from various human prostate cancer 22Rv1, DU145 and PC-3 cells by applying selection of cluster of differentiation 133 cell surface marker and high ALDH1 activity (CD133+/ALDH1high). Next we aimed to identify CD133+/ALDH1high CSCs isolated from human prostate cancer cells and compare their profiles with non-CSCs as bulk counterparts of the population. Subsequently, the CSC population continued to grow in the three-dimensional multicellular spheroids. Differentiation investigated with stem cell-related genomic characteristics exhibited significant increase in genes viz. CD44, Nanog, β-catenin, c-Myc, SOX2 and Oct4 in CSCs at the message level. In further studies we determine the effect of natural plant flavone apigenin on CSC population. Apigenin is abundantly present in common fruits and vegetables and possess remarkable anticancer, anti-angiogenic and anti-metastatic properties. Apigenin loaded polyethylene glycol nanoparticles (Ap-NP) was characterized for particle size, morphology, zeta potential, drug release and encapsulation. Cellular entry and intracellular localization of Ap-NP were assessed by transmission electron microscopy. Treatment of CD133+/ALDH1high CSCs with Ap-NP inhibited cell viability and sphere formation at higher extent in time dependent manner, compared to the non-CSCs counterparts. Furthermore, Ap-NP exposure resulted in the downregulation of Nanog, β-catenin, c-Myc, SOX2 and Oct4 in the CSCs. Taken together, our study demonstrate overexpression of potential CSC markers and the ability to target these CSCs by the use of non-toxic agent apigenin killing this rare population that may lead to the total abolition of tumor recurrence and/or metastasis.
Citation Format: Rajnee Kanwal, Sanjeev Shukla, Agata A. Exner, Andreas G. Tzakos, Sanjay Gupta. Apigenin nanoparticle suppresses sphere formation in CD133+/ALDH1high prostate cancer stem cells through downregulation of stem cell markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 260.
Abstract 2698: Phosphoproteomics-guided anticancer drug combination design with a novel small-molecule PP2A activator
Authors: Wiredja Danica D. , Liao Peter , Sangodkar Jaya , Schlatzer Daniela , Chance Mark R. , Narla Goutham 
Published: August 2018

Abstract
Significance: Phosphatases are cellular antagonists of kinase signaling and have a diverse range of substrates, many of which are ideal targets for small molecule-based anticancer treatment. Our lab and collaborators have generated a novel series of compounds that bind to and activate the serine/threonine protein phosphatase 2A (PP2A), and these small-molecule activators of PP2A (SMAPs) induce apoptosis and inhibit tumor growth in numerous cancer models. Based on these findings, this project aimed to identify drug combinations with our SMAP that could drive optimal anticancer activity.
Methods: We first turned to global shotgun phosphoproteomics to compare the signaling response signatures of our SMAP against a combination of a MEK inhibitor (MEKi) and an AKT inhibitor (AKTi). We then applied Kinase-Substrate Enrichment Analysis (KSEA) to extract key diverging biologic patterns between these two arms, with the goal of identifying distinct pathways that are inhibited in each condition. These results, in turn, could provide insight to differences between phosphatase activation versus kinase inhibition.
Results: KSEA profiling revealed distinct signaling responses between the two arms. Notably, the kinase inhibitors caused robust downregulation of the MAPK signaling pathway, whereas SMAP treatment showed limited involvement of that cascade. Thus, we hypothesized that a combination of SMAP + MEKi would yield enhanced anticancer response compared to either single agent. Subsequent murine xenograft testing demonstrated superior tumor response with SMAP + MEKi versus either compound alone.
Conclusion: This project offers a phosphoproteomics-level glimpse to the signaling effects between phosphatase activation compared to kinase inhibition. The data, in turn, could be used for rational drug combination design to improve antitumor therapy.
Citation Format: Danica D. Wiredja, Peter Liao, Jaya Sangodkar, Daniela Schlatzer, Mark R. Chance, Goutham Narla. Phosphoproteomics-guided anticancer drug combination design with a novel small-molecule PP2A activator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2698.
Abstract 2735: Cancer immunotherapy with agonistic anti-4-1BB scFv producing and secreting Bifidobacterium in syngeneic mouse model
Authors: Matsumura Tomio , Shioya Koichiro , Kanari Yasuyoshi , Shimatani Yuko , Kataoka Shiro , Taniguchi Shun'ichiro , Nakamura Takaaki 
Published: August 2018

Abstract
Agonistic antibodies against immune checkpoint molecules, such as 4-1BB, reportedly demonstrate antitumor effects at the early clinical phase, whereas immune-related adverse events hamper further development. A single chain variable fragment (scFv), which is expected to have better penetration into tissues, is clinically being investigated, however, poor distribution into tumor tissues due to rapid clearance is a serious issue.
In order to improve drug delivery and decrease adverse events, we have developed in situ Delivery and Production System (i-DPS) by genetically engineering a non-pathogenic anaerobic Bifidobacterium. We previously reported that the modified Bifidobacteria localized and proliferated only in the hypoxic area of the tumor engrafted in the mouse post i.v. injection, thus producing anti-tumor molecules persistently and selectively at the tumor site (AACR2010).
Here we present i-DPS with agonistic anti-murine 4-1BB scFv. We created a recombinant Bifidobacterium producing and secreting anti-murine 4-1BB scFv. The anti-murine 4-1BB scFv increased IFN-γ production by 171% over the control group (PBS(-)) in the mouse splenocytes activated by ant-CD3 antibody in vitro. Anti-tumor effects of Bifidobacteria producing the anti-murine 4-1BB scFv were demonstrated in the syngeneic model of CT-26 in Balb/c mouse (61.7% tumor growth inhibition (TGI) at 1×109 cfu/mouse, i.v. on day 14). We further evaluated the anti-tumor effects of i-DPS for anti-murine 4-1BB scFv (1×109 cfu/mouse, i.v.) in combination with PD-1 antibody (i.p.), and confirmed that the combination therapy significantly suppressed the tumor growth on day 21 (TGI: combination, 60.7%; anti-murine 4-1BB scFv, 38.8%; anti-mPD-1 mAb, 8.9%). In conclusion, i-DPS for anti-4-1BB scFv will provide a new promising modality for the immune-therapy targeting hypoxic solid tumors.
Citation Format: Tomio Matsumura, Koichiro Shioya, Yasuyoshi Kanari, Yuko Shimatani, Shiro Kataoka, Shun'ichiro Taniguchi, Takaaki Nakamura. Cancer immunotherapy with agonistic anti-4-1BB scFv producing and secreting Bifidobacterium in syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2735.
Abstract 2895: Verteporfin targets p62 in prostate cancer therapeutics
Authors: Wang Lei , Kim Donghern , Wise James , Shi Xianglin , Zhang Zhuo , DiPaola Robert S. 
Published: August 2018

Abstract
To test the hypothesis that p62 is an optimal target for autophagy inhibition and Verteporfin, a clinically available drug approved by FDA to treat macular degeneration that inhibits autophagy by targeting p62 protein, can be developed clinically to improve therapy for advanced prostate cancer. Results showed that Verteporfin inhibited cell growth and colony formation in PC-3 cells. Verteporfin generated crosslinked p62 oligomers, resulting in inhibition of autophagy and constitutive activation of Nrf2 as well as its target proteins, Bcl-2 and TNF-α. In normal prostate epithelial cells, forced expression of p62 caused constitutive Nrf2 activation and development of apoptosis resistance and Verteporfin treatment exhibited inhibitory effects. Verteporfin treatments also inhibited starvation-induced autophagic influx of these cells. Verteporfin inhibited tumorigenesis of both normal prostate epithelial cells with p62 expression and prostate cancer cells and decreased p62, constitutive Nrf2, and Bcl-xL in xenograft tumor tissues, indicating that p62 can be developed as a drug target against prostate cancer. So p62 has a high potential to be developed as a therapeutic target. Verteporfin represents a prototypical agent with therapeutic potential against prostate cancer through inhibition of autophagy by a novel mechanism of p62 inhibition.
Citation Format: Lei Wang, Donghern Kim, James Wise, Xianglin Shi, Zhuo Zhang, Robert S. DiPaola. Verteporfin targets p62 in prostate cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2895.
Abstract 3061: The clinicopathologic roles of SOX2 and Oct4 expressions in stage 1 and 2 oral squamous cell carcinoma
Authors: Tamatani Tetsuya , Takamaru Natsumi , Ohe Go , Nakagawa Takayuki , Kurio Naito , Kudou Keiko , Yamamura Yoshiko , Mano Takamitsu , Miyamoto Youji 
Published: August 2018

Abstract
[Background] Cancer stem cells (CSCs) exhibit self-replication, self-differentiation, drug resistance, and immune evasion activities. Recently, CSC has become increasingly important in the treatment of malignant tumors. Cancer stem cells express specific molecules termed CSC marker, including sex determining region Y-box2 (SOX2), and octamer-binding transcription factor 4 (Oct4), and their expression has been reported to be the potential prognostic values. However, the prognostic values of SOX2 and Oct4 expression in patients with stage I and II oral cancer are less understood.
[Purpose] The aims of present study were to evaluate the expression of SOX2 and Oct4 in stage I and II oral squamous cell carcinoma (OSCC) and to elucidate the relationships among the CSC marker expression, clinical stages, histological differentiation, classification of invasion mode, cerebral lymph node metastasis, distant metastasis, and disease-free survival rate.
[Materials and Methods] Tissue specimens were obtains from 83 patients with OSCC after surgery or biopsy. Immunohistochemistry was used to assess SOX2 and Oct4 protein using at least 10% staining-positive cells as the definition of positive staining. [Results] Immunohistochemical analysis of 83 cases showed that 31 cases (37%) expressed SOX2. There was no significant association between SOX2 expression and tumor size, invasion mode or histological differentiation. However, there was significant association between SOX2 expression and distant metastasis or disease-free survival rate at stage 1 and 2 patients. Otherwise, fifty three cases (64%) of 83 OSCC patients expressed Oct4. There was significant association between Oct4 expression and histological differentiation. There was no significant association between Oct4 expression and tumor size, invasion mode, metastasis, or disease-free survival rate.
[Conclusions] These findings suggested that the expression of SOX2 may be good marker indicating survival in patients with stage 1 and 2 OSCC.
Citation Format: Tetsuya Tamatani, Natsumi Takamaru, Go Ohe, Takayuki Nakagawa, Naito Kurio, Keiko Kudou, Yoshiko Yamamura, Takamitsu Mano, Youji Miyamoto. The clinicopathologic roles of SOX2 and Oct4 expressions in stage 1 and 2 oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3061.
Abstract 3157: p53 inactivation and STAT2 cooperate to enhance migration and metastasis of colon tumor cells
Authors: Gamero Ana M. , Kotredes Kevin , Abezis Aliza , Gohimukkula Sruthi R. , Afanassiev Alexandra , Cremers Tess , Swain John J. 
Published: August 2018

Abstract
STAT2 is a pivotal signaling component in the antiviral and antiproliferative effects of type I and type III interferon (IFN), but its role in cancer remains understudied. To date, only IFNs are known to activate STAT2. Work by us and others has demonstrated that STAT2 deficiency impairs the antitumor effects of type I IFN, supporting its role in suppressing tumor growth. With the availability of Stat2-/- mice, we interrogated the tumor-suppressive role of STAT2 by employing the AOM/DSS model of colitis-associated cancer and the spontaneous ApcMin/+ model of colorectal cancer (CRC). In both cancer models, loss of STAT2 reduced the number of adenomas, showing that under specific conditions STAT2 can be tumorigenic. Next, immunohistochemical staining of human normal colon and CRC tumors revealed elevated STAT2 protein in both adenomas and adenocarcinomas, suggesting that STAT2 is implicated in human CRC. Conversion of adenomas to adenocarcinomas is linked to loss of p53 function, which occurs in &gt;50% of colorectal cancers. Therefore, we evaluated whether STAT2 altered the aggressive phenotype of p53-deficient colon carcinoma cells. We silenced STAT2 in isogenic p53 null and p53 wild-type tumor cells. STAT2 knockdown in p53 null colon carcinoma cells reduced migration of 3D tumor spheroids and tumor colony formation while no effect was seen in p53 wild-type tumor cells. We also observed that STAT2 knockdown in p53 null tumor cells increased protein levels of the marker of epithelial-mesenchymal transition, E-cadherin. Conversely, overexpression of STAT2 in p53 null cells reduced E-cadherin protein. In vivo, STAT2 knockdown delayed subcutaneous tumor growth of p53 null tumor cells. Furthermore, using an experimental liver metastasis tumor model, STAT2 knockdown abrogated the formation of tumor nodules in the liver. RNA-seq profiling of subcutaneous p53 null tumors revealed a subset of genes that were differentially expressed in a STAT2-dependent manner. Clinically, analysis of the TCGA database showed a STAT2 transcriptional signature in colorectal tumors that we are presently correlating with p53 alterations. Overall, we conclude that STAT2 enhances tumor growth and can contribute to disease progression by promoting migration and invasion when normal p53 function is lost.
Citation Format: Ana M. Gamero, Kevin Kotredes, Aliza Abezis, Sruthi R. Gohimukkula, Alexandra Afanassiev, Tess Cremers, John J. Swain. p53 inactivation and STAT2 cooperate to enhance migration and metastasis of colon tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3157.
Abstract 328: Targeting Mcl-1 enhances DNA replication stress sensitivity for cancer therapy
Authors: Chen Guo , Magis Andrew , Xu Ke , Park Dongkyoo , Yu David , Owonikoko Taofeek , Sica Gabriel , Satola Sarah , Ramalingam Suresh , Curran Walter , Doetsch Paul , Deng Xingming 
Published: August 2018

Abstract
DNA double-strand breaks (DSBs) are mainly repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways. Here we report that Mcl-1 acts as a functional switch in pathway choice between HR and NHEJ. Mcl-1 was cell cycle-regulated, with expression peaking in S/G2 phase when HR occurred. Endogenous Mcl-1 depletion reduced HR and enhanced NHEJ. Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with Ku via its BH1 and BH3 domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ and promote Mre11 complex-mediated DNA resection and HR-dependent DSB repair. Using the Mcl-1 BH1 domain (aa256-265) as docking site, we identified a novel small molecule, MI-223, that directly bound to BH1 and blocked Mcl-1-stimulated HR DNA repair leading to a significant sensitization of cancer cells to hydroxyurea- or olaparib-induced DNA replication stress. Combined treatment with MI-223 and hydroxyurea or olaparib exhibited a strong synergy against lung cancer in vivo. This mechanism-driven combination of agents provides a highly attractive therapeutic strategy to improve lung cancer outcome.
Citation Format: Guo Chen, Andrew Magis, Ke Xu, Dongkyoo Park, David Yu, Taofeek Owonikoko, Gabriel Sica, Sarah Satola, Suresh Ramalingam, Walter Curran, Paul Doetsch, Xingming Deng. Targeting Mcl-1 enhances DNA replication stress sensitivity for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 328.