bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-190: CDC25A suppression of apoptosis in cutaneous squamous cell carcinoma depends on 14-3-3ϵ
Authors: Holmes Thomas R. , Al-Matouq Jenan , Hammiller Brianna , Nicholson Yawah T. , Holmes Matti J. , Hansen Laura A. 
Published: August 2018

Abstract
Cytoplasmic relocalization of the dual-specificity phosphatase, CDC25A, occurs during nonmelanoma skin cancer development and progression, leading to suppression of cell death. Cytoplasmic CDC25A is phosphorylated at Ser178, which allows for its association with 14-3-3ϵ. 14-3-3ϵ is a member of the 14-3-3 family of proteins that bind phosphoserine/threonine-containing proteins and are involved in various processes including scaffolding, nuclear transport, protein degradation, cell cycle regulation, apoptosis and cell signaling. We hypothesized that CDC25A's antiapoptotic function depends upon 14-3-3ϵ binding to trigger activation of prosurvival signaling pathways in SCC cells. Co-immunoprecipitation of CDC25A from the SCC cell line SCC12B.2 followed by immunoblotting for 14-3-3ϵ confirmed an association between CDC25A and14-3-3ϵ. CDC25A over-expression in SCC12B.2 cells reduced apoptosis by approximately 50%, as assessed by a caspase 3/7 glo assay. However, inhibition of 14-3-3ϵ with the peptide R18, or silencing of 14-3-3ϵ, blocked the anti-apoptotic effect of CDC25A in SCC cells. Treatment with serial dilutions of R18 increased cell death with an IC50 of 8.9 μM in SCC12B.2 cells. Interestingly, over-expression of CDC25A significantly increased P-Akt (p=0.011), P-BAD (p=0.034) and Survivin (p=0.036) when compared to control. Consistent with our hypothesis that 14-3-3ϵ facilitates CDC25A's antiapoptotic activity, silencing of 14-3-3ϵ decreased P-Akt (p=0.044), P-BAD (p=0.034) and Survivin (p=0.008). Taken together, these results indicate that cytoplasmic CDC25A and 14-3-3ϵ interact in skin carcinomas to suppress apoptosis through a mechanism involving activation of Akt/BAD/Survivin signaling, rendering SCC cells sensitive to 14-3-3ϵ or CDC25A inhibition, a mechanism that requires further study.
Citation Format: Thomas R. Holmes, Jenan Al-Matouq, Brianna Hammiller, Yawah T. Nicholson, Matti J. Holmes, Laura A. Hansen. CDC25A suppression of apoptosis in cutaneous squamous cell carcinoma depends on 14-3-3ϵ [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 LB-190.
Abstract LB-192: 2,2'-Methylenebis (6-tert-butyl 4-methylphenol) enhances the antitumor efficacy of belotecan, a derivative of camptothecin, by inducing autophagy
Authors: Park Junsoo , Lee Eun-Ju 
Published: August 2018

Abstract
Autophagy regulation is important for tumor cell survival. Activation and inhibition of autophagy can sensitize tumor cells to anticancer drugs. However, few autophagy-regulating small molecules are available to increase the efficacy of anticancer drugs. Here, we report that 2,2'-methylenebis (6-tert-butyl 4-methylphenol), hereafter referred to as methylenebis, is a novel autophagy-regulating small molecule that sensitizes tumor cells to belotecan, which is a derivative of camptothecin, a topoisomerase I inhibitor. Methylenebis activates autophagic flux by increasing the level of LC3-II and forming autolysosome puncta. Moreover, methylenebis enhances the antitumor efficacy of belotecan by activating both autophagy and apoptosis. Interestingly, methylenebis increased the level of LC3-II and belotecan independently decreased the level of p62, suggesting that methylenebis and belotecan target different steps of autophagy. Finally, we searched for compounds that are structurally similar to methylenebis. Our results imply that the specific structure of methylenebis contributes to its ability to activate autophagy.
Citation Format: Junsoo Park, Eun-Ju Lee. 2,2'-Methylenebis (6-tert-butyl 4-methylphenol) enhances the antitumor efficacy of belotecan, a derivative of camptothecin, by inducing autophagy [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 LB-192.
Abstract LB-216: Protein pathway activation analysis of a panel of patient-derived epithelial tumor models identifies signatures of response to ErbB1-3 co-targeting
Authors: Calvert Valerie S. , Fröhlich Camilla , Poulsen Thomas T. , Pedersen Mikkel W. , Kragh Michael , Horak Ivan D. , Petricoin Emanuel F. 
Published: August 2018

Abstract
Plasticity of the ErbB family of receptors and ligands is a hallmark of many human tumors and drives resistance to EGFR and HER2 targeting agents such as cetuximab or trastuzumab. Pan-HER is a unique antibody mixture designed to counter ErbB family plasticity by simultaneously targeting EGFR, HER2 and HER3. Pan-HER contains pairs of antibodies against each of the receptors, six antibodies in total, and induces efficient internalization and degradation of all three receptors. Here, the anti-tumor activity of Pan-HER was investigated in a panel of 57 patient-derived epithelial tumor models (PDXs) of various origin including pancreatic (18), colorectal (11), triple negative breast (11), lung (6), squamous head and neck (6), ovarian (3), and gastric (2) cancer, and the level of activity was correlated to baseline protein and phosphoprotein status using laser capture microdissection (LCM) and Reverse Phase Protein Arrays (RPPA). This panel has been preselected to represent hard-to-treat cancers and that are not overtly HER family positive. Pan-HER demonstrated anti-tumor activity across all indications except the gastric models and induced tumor regression in 26 of the 57 PDX models tested. The LCM-RPPA analysis of over 150 proteins and phosphoproteins that are known to be central for receptor tyrosine kinase signaling, survival, apoptosis, growth, inflammation, motility and autophagy identified both broad and indication specific signatures of response to Pan-HER and points to a key role for the KRAS/BRAF/ERK and PIK3CA/AKT pathway activation that associate with therapeutic sensitivity. In conclusion, our results demonstrate that Pan-HER has broad anti-tumor activity across indications and identify phosphoprotein pathway activation signatures predicting for sensitivity or resistance that should be explored clinically.
Citation Format: Valerie S. Calvert, Camilla Fröhlich, Thomas T. Poulsen, Mikkel W. Pedersen, Michael Kragh, Ivan D. Horak, Emanuel F. Petricoin. Protein pathway activation analysis of a panel of patient-derived epithelial tumor models identifies signatures of response to ErbB1-3 co-targeting [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 LB-216.
Abstract LB-229: Mesothelin expression is a predict factor for peritoneal recurrence in gastric cancer
Authors: Shin Su-Jin , Kim Hyunki , Choi Yoon Young , Park Sejung , Nam Chung Mo , Chung Hyun Cheol 
Published: August 2018

Abstract
Background: Mesothelin is overexpressed in many solid tumors. Recent studies showed that mesothelin expression is associated with poor outcome in several malignant tumors and it may play a role of cancer cell proliferation, local invasion and metastasis. Clinical trials of mesothelin-targeted immunotherapies are currently in progress. However, the correlation between mesothelin expression and prognosis of gastric cancer is still conflicting.
Patients and Methods: Mesothelin expression in tumour cells were immunohistochemically evaluated in 964 advanced gastric cancer patients, and their associations with clinical outcome were analysed. The prediction model for recurrence was developed by cox proportional hazard models.
Results: High mesothelin expression was observed in 49.6% and significantly associated with a high stage (P = 0.022) and the presence of recurrence with peritoneal carcinomatosis (P = 0.002). In univariate survival analysis, high mesothelin expression was significantly associated with shorter recurrent-free survival (RFS) (P=0.003) and overall survival (OS) (P=0.006). Multivariate survival analysis revealed that high mesothelin expression was independently associated with poor RFS and OS (P=0.001; P=0.002, respectively) in addition to stage, lymphovascular invasion and Lauren classification (all, P&lt;0.001). In multivariate analysis for recurrence with peritoneal carcinomatosis, high mesothelin expression was also independent prognostic factors in all advanced gastric cancer patients (P&lt;0.001) and in intestinal (P=0.017) and diffuse/mixed type (P=0.005) subgroups. The overall discrimination ability of prediction model for recurrence, the model with mesothelin was better than model without mesothelin.
Conclusions: High mesothelin expression was correlated with poor outcome. And, mesothelin expression, along with Lauren classification was meaningful predict factor for peritoneal recurrence.
Citation Format: Su-Jin Shin, Hyunki Kim, Yoon Young Choi, Sejung Park, Chung Mo Nam, Hyun Cheol Chung. Mesothelin expression is a predict factor for peritoneal recurrence in gastric cancer [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 LB-229.
Abstract LB-241: Genomic characterization of breast cancer cells resistant to the histone deacetylase inhibitor romidepsin
Authors: Ali-Rahmani Fatima G. , Robey Robert , Lack Justin , Tebase Bethelihem , Bates Susan , Gottesman Michael 
Published: August 2018

Abstract
Overexpression of histone deacetylases (HDACs) has been reported in many cancers. As such, histone deacetylase inhibitors (HDIs) have emerged as potent antitumor agents that prevent HDACs from removing acetyl groups from both histone and non-histone proteins, thereby maintaining transcriptionally active DNA. Romidepsin (Rd) is an HDI that targets primarily class I HDACs and has shown efficacy in T-cell lymphomas. However, many solid tumors have been found to be intrinsically resistant to Rd. To investigate potential mechanisms of resistance, we performed a stepwise selection of MCF7 breast cancer cells in romidepsin in the presence of 2.5 μg/ml verapamil to prevent the emergence of P-glycoprotein, an ATP-binding cassette transporter, as a mechanism of resistance. Resistant cells were stable in 300 ng/ml romidepsin. Romidepsin-resistant (RdVp) cells were more than 100-fold resistant to Rd relative to untreated control cells. In addition, measurement of cell viability with CellTiterGlow showed that RdVp cells exhibited cross-resistance to other HDIs such as panobinostat, belinostat, and vorinostat. We performed RNA-Seq to identify genes responsible for the observed resistance to Rd. Downstream data analysis was performed using Partek Genomics Suite, followed by network analysis using Ingenuity Pathway Analysis (IPA) software. Only expression changes with p&lt; 0.01 were considered significant for pathway analysis. Out of 47788 total transcripts identified, only 1910 transcripts were significantly altered in RdVp cells relative to untreated controls. Transcription of several genes involved in the cholesterol and lipid biosynthesis pathway was increased in RdVp cells, indicating increased cholesterol synthesis to support increased cell growth. Several members of the sonic hedgehog pathway were elevated in cells resistant to Rd. The GLI1 gene that encodes a zinc finger protein was upregulated in RdVp cells by 14-fold. Treatment with a GLI1 inhibitor resulted in decreased survival of cells resistant to Rd. The sequencing data were analyzed to identify single nucleotide variations and short insertions/deletions, and only those present in coding sequences of RdVp cells were further confirmed with Sanger sequencing. We identified novel mutations in MCCC2, HIPK3, ABR, SIRT6, TRAK2, and ZNF100 in RdVp cells. Our results suggest potential targets for combination therapy to sensitize cancer cells resistant to romidepsin and enhance its antitumor efficacy in the clinic.
Citation Format: Fatima G. Ali-Rahmani, Robert Robey, Justin Lack, Bethelihem Tebase, Susan Bates, Michael Gottesman. Genomic characterization of breast cancer cells resistant to the histone deacetylase inhibitor romidepsin [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 LB-241.
Abstract LB-253: Suppression of clear cell ovarian carcinoma growth by glutaminase-1 inhibitor as single agent and in combination with PARP-1 inhibitor
Authors: Yi Tianjin , Christodoulou Danos , Okazaki Arimichi , Birrer Michael , Iliopoulos Othon 
Published: August 2018

Abstract
Tumor hypoxia and cancer-associated mutations reprogram central carbon metabolism and enhance the dependence of cancer cells on glutamine for growth. Clear cell ovarian cancer (CCOC) is a unique epithelial ovarian cancer histotype that is less responsive to chemotherapy and has poorer prognosis than serous histotype. Whole genomic analysis identified major pathways activated in clear cell involving in hypoxic cell growth and carbohydrate metabolism, which were driven by hypoxia-inducible factors HIF1a and/or 2a. We demonstrated before that treatment of HIF-expressing cancer cells with glutaminase 1 (GLS1) inhibitor CB-839, restricts nucleotide synthesis and causes DNA replication stress, which sensitizes cells to the PARP-1 inhibitor. Herein, we observed a range of sensitivities to CB-839 treatment in vitro in CCOC cell lines, from which we selected 4 most sensitive cell lines (ES2, SMOV2, TOV21G and RMG1) and 4 most resistant cell lines (OVSAYO, KK, HAC2 and OVISE) for further study. The synergistic effect of combination treatment of CB-839 and olaparib was achieved in all eight cell lines in vitro. To identify more molecular and metabolic biomarkers of CCOC sensitivity to GLS1 inhibitors, we are currently profiling the gene expression signatures of the most sensitive and resistant CCOC cell lines by RNAseq as well as and the metabolic profile of the CCOC lines. To test the sensitivity of the ES2 cells in vivo to a GLS1 as a single agent or in combination with PARP-1 inhibitors we injected them orthotopically in nude mice. Thirty mice bearing growing ES2 derived tumors were randomly assigned into four groups: vehicle control (n=8), treatment with CB-839 (200mg/kg, gavage, twice daily, n=7), olaparib (75mg/kg, gavage, once daily, n=7) or their combination (n=8). We monitored tumor growth by serial bioluminescence imaging, animal body weight as well as animal survival. To date, after 15-day treatment, we detected a synergistic effect between the 2 agents CB-839 and olaparib in controlling ovarian tumor growth in vivo. Our work discovered a range of sensitivities of CCOC cell lines to GLS1 inhibitor and supports the therapeutic strategies of combining GLS1 inhibitor and PARP inhibitor for targeting HIF-driven CCOC.
Citation Format: Tianjin Yi, Danos Christodoulou, Arimichi Okazaki, Michael Birrer, Othon Iliopoulos. Suppression of clear cell ovarian carcinoma growth by glutaminase-1 inhibitor as single agent and in combination with PARP-1 inhibitor [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 LB-253.
Abstract LB-260: Development and validation of propeptide therapeutics for treating bone metastatic prostate cancer
Authors: Salameh Janelle W. , Umbaugh Charles S. , Figueiredo Marxa L. 
Published: August 2018

Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the United States. Most prostate cancer related fatalities are not due to tumors at origination sites, but rather due to prostate cancer metastasis throughout the body. Although the relative 5-year survival rate for localized prostate cancer nears 100%, unfortunately, upon metastasis the 5-year survival rate drops to 29.8%. Bone metastases disrupt tissue homeostasis and weaken the skeleton, resulting in an increased risk of severe bone pain and fracture. This is due to increased formation of immature unmineralized bone by osteoblasts, and increased osteolysis by osteoclasts, which induce high levels of bone resorption. Thus, a primary therapeutic objective for malignant bone disease is to eliminate tumors while promoting bone homeostasis. Current therapies are very limited and include palliative radiotherapy, and biphosphate or anti-RANK treatments, which target osteoclasts and decrease the rate of bone resorption. However, these treatments only delay, but do not prevent, skeletal related injuries. Our laboratory has recently developed a strategy aimed at disrupting malignant cytokines signals using inhibitory peptides targeting IL-6 receptors. I here present a novel strategy to express these peptides in vivo following gene delivery as targeted and multifunctional “propeptides.” These propeptides target bone metastases via EGFR antagonist (tumor-homing peptide) and contain dual therapeutic domains consistent of IL-6Ra antagonistic peptides and a pro-osteogenesis peptide, osteostatin. The propeptides are activated by metalloproteases (MMP2/9), which are overexpressed in metastatic prostate tumors and associated bone lesions. We can detect expression of the propeptides following C2C12 muscle cell transfection via real time quantitative PCR and are currently optimizing biochemical strategies for detecting propeptide products via western blot. We hypothesize that optimized secretion and targeting of the therapeutic propeptides will be effective in eliminating prostate tumor metastases, and restoring bone homeostasis. Future studies will examine the expression of propeptide in vivo following gene delivery to muscle and efficacy of propeptides in treating bone metastatic prostate tumors in a TRAMP-C2Ras tibial implantation model.
Citation Format: Janelle W. Salameh, Charles S. Umbaugh, Marxa L. Figueiredo. Development and validation of propeptide therapeutics for treating bone metastatic prostate cancer [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 LB-260.
Abstract LB-274: Overcoming colorectal cancer resistance to death receptor agonists: Design and delivery of treatment combinations
Authors: Manzari Mandana T. , Li Xinghai , Anderson Grace , Wood Kris , Chilkoti Ashutosh 
Published: August 2018

Abstract
Death Receptor 5 (DR5) is a key upregulated marker in colorectal cancer (CRC), overexpressed in over 90% of patients. There is a dire clinical need for drugs that can deliver targeted cell killing via this receptor. Over the past decade, various DR5 agonists have shown poor clinical efficacy, including both engineered antibodies and TRAIL, the natural ligand for this receptor. Comprehensive studies suggest that there are three major obstacles to success of these agents: 1) potency, 2) delivery, and 3) resistance. If these issues are addressed, DR5 will be an excellent therapeutic target for a variety of cancers, and provide a novel means for substantially advancing the clinical treatment of CRC. To improve delivery and overcome drug resistance, we have developed a platform that harnesses the power of genetic screening and protein engineering to design and deliver efficacious protein drug combinations. To pinpoint the genetic drivers of CRC resistance to a multivalent DR5 agonist (DRA), we used a CRISPR/Cas9 knockout screen. The screen identified genes that confer sensitivity to the DRA in resistant CRC cell lines. Over twenty small molecule drugs targeting pathways and proteins identified from the screens were then tested in combination with the DRA to identify highly synergistic combinations using cytotoxicity assays. Clonogenic, time-to-progression, and cell viability assays showed that pharmacological blockade of XIAP, Bcl-XL, and CDK4/6 strongly enhances antitumor activity of DRA in established human CRC cell lines and patient-derived CRC cells. To address the need for sustained delivery of therapeutic proteins, we developed injectable depots of anti-cancer proteins recombinantly fused to thermally responsive elastin-like polypeptide (ELP) biopolymers. The bioactive DRA-ELP fusions undergo temperature-driven phase transition upon subcutaneous injection in vivo, resulting in the formation of a gel-like depot suitable for sustained drug delivery. A single 30 mg/kg injection of the gel-like DRA-ELP depot induced significant tumor regression in Colo205 mouse xenografts. By addressing both delivery and resistance issues with our protein engineering and genomics platform, we have overcome key obstacles to clinical translation of a pro-apoptotic DRA.
Citation Format: Mandana T. Manzari, Xinghai Li, Grace Anderson, Kris Wood, Ashutosh Chilkoti. Overcoming colorectal cancer resistance to death receptor agonists: Design and delivery of treatment combinations [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 LB-274.
Abstract LB-289: Polarization of adipose-derived mesenchymal stem cells by toll-like receptors stimulation
Authors: Rivera-Cruz Cosette M. , Huff Krista , Figueiredo Marxa L. 
Published: August 2018

Abstract
Mesenchymal stem cells (MSCs) are a potential tool for cell therapy because of their ability to home to injury sites, modulate immune responses, promote tissue repair, among other features. MSCs can also home to tumors, similarly to how they home to injury sites, and exert modulatory functions in the tumor microenvironment. However, the mechanisms by which MSCs affect tumor cells is not well understood, and apparent contradictory effects of MSC-tumor interactions can be found in the literature, claiming that MSCs either promote or repress tumor growth and cell migration. In recent years, it was shown that MSCs derived from bone marrow (BM-MSCs) can be polarized by Toll-like receptor (TLR) signaling into two phenotypes with opposite effects on tumor development. TLR4 signaling induces an immune activating MSC1 population shown to inhibit tumor growth and migration, whereas TLR3 signaling induces an immune suppressive MSC2 population that promotes tumor progression. Adipose-derived mesenchymal stem cells (ASCs) are important constituents of tumor microenvironments. Their ability to migrate into tumors make these cells a potential candidate for delivering immunotherapy against tumor progression. Although the MSC1 and MSC2 duality has not been reported for ASCs, we hypothesized that due to their similarity to bone marrow MSCs, that ASC share the polarization phenotype. To test our hypothesis, we stimulated, or primed, hASCs with TLR3 and TLR4 agonists and evaluated gene expression changes expected to occur, in accordance to the previously described MSC1 and MSC2 phenotypes. Upregulation of IL-8 was observed for hASCs primed towards the MSC1 phenotype. CCL5 and IP10 were upregulated in cells primed towards the MSC2 phenotype. These results suggest that a polarization of hASCs may occur in a similar way as previously shown for BM-MSCs. On the other hand, no changes were observed in the expression of TGFβ, IL-6 and other associated genes, hinting to cell lineage phenotypical differences upon TLR stimulation. In addition, some phenotypical differences have been observed across different donor cells and priming conditions, which could contribute to the immunomodulatory inconsistencies reported in the literature.
Citation Format: Cosette M. Rivera-Cruz, Krista Huff, Marxa L. Figueiredo. Polarization of adipose-derived mesenchymal stem cells by toll-like receptors stimulation [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 LB-289.