bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1100: Synergistic interaction between gemcitabine and PD-0325901 in C-33A cervical carcinoma cell line
Authors: Irigoyen Macarena , Castillo Gonzalo 
Published: July 2017

Abstract
Cervical cancer affects over half a million women worldwide, and is one of the most common causes of death in women. Treatment of cervical cancers consists of surgery, radiation, chemotherapy, or combination of therapies. However, about half of patients with advance cancer will show recurrent tumors. Signaling cascades are often dysregulated in human cancer cells making them attractive targets for combination drug therapies. PD-0325901, an inhibitor of the mitogen-activated protein kinase, is a promising target for metastatic cancer. Another drug used to treat cervical carcinoma is gemcitabine, a nucleoside analog inhibitor of the ribonucleotide reductase and DNA damage inducible protein 45a (Gadd45a). This drug is generally used in combination with other drugs, after reoccurrence of the disease state. We decided to evaluate the efficacy of gemcitabine in combination with PD-0325901 in C-33A, a metastatic cervical cancer-derived cell line. We evaluated the potency of gemcitabine and PD-0325901 alone and in combination. Cell viability after incubation with the drugs was determined at 72 hours and at 7 days by measuring ATP content. Synergy was determined assessed utilizing BIOENSIS’s suite of drug combination analysis tools including: isobologram, combination index (CI) and Bliss analysis. Isobologram analysis at 72 hours of incubation revealed that the mean values of the observed data were significantly smaller than those of the predicted maximum additive values, indicating synergy. Bliss and combination index analysis confirmed the observation, showing a synergistic effect at concentrations between 2 - 200 nM PD-0325901 and 0.3 - 3 nM gemcitabine. Similar patterns of synergy were observed with 7 day incubations of C-33A with gemcitabine and PD-0325901. These results indicate that gemcitabine and PD-0325901 showed significantly more growth inhibition than either drug alone in the C-33A tumor cell line, suggesting that the combination of gemcitabine - PD-0325901 could be used in cervical cancer therapy.
Citation Format: Macarena Irigoyen, Gonzalo Castillo. Synergistic interaction between gemcitabine and PD-0325901 in C-33A cervical carcinoma cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1100. doi:10.1158/1538-7445.AM2017-1100
Abstract 1122: ATR inhibitors synergize with PARP inhibitors in killing glioblastoma stem cells and treating glioblastoma
Authors: Ning Jianfang , Wakimoto Hiroaki , Martuza Robert L. , Rabkin Samuel D. 
Published: July 2017

Abstract
PARP inhibitors (PARPi) have been used alone or in combination with other agents for the treatment of tumors with homologous repair (HR) deficiencies. However, challenges remain for the treatment of tumors that are PARPi-resistant or HR-proficient. Glioblastoma (GBM) is an invariably lethal tumor that is not associated with HR deficiencies. GBM stem cells (GSCs), thought to be critical for tumor growth and resistance to therapy, can be isolated from GBM specimens and are representative of the patient's tumors. GSCs exhibit variable PARPi sensitivity, with at least half being resistant. In order to enhance the antitumor efficacy of PARPi for GBM, we examined the combination of PARPi with inhibitors of oncogenic or DNA damage pathways, including inhibitors of PTEN, PI3K, ATM, ATR, and temozolomide, some of which have been reported to sensitize cancer cells to PARPi. Only inhibitors of ATR (VE821, VE822, AZ20) synergized with PARPi in killing GSCs in vitro. VE822 inhibited ATR activity both in vitro and in vivo, and modestly, but significantly, extended survival in mice bearing GSC-derived tumors. However, ATR inhibitor (ATRi) in combination with PARPi further prolonged survival, compared to each drug alone, even in mice bearing PARPi-resistant GSC-derived tumors. This is the first report that ATRi alone or in combination with PARPi is effective in treating GBM and provides a rationale for clinical trials for GBM.
Citation Format: Jianfang Ning, Hiroaki Wakimoto, Robert L. Martuza, Samuel D. Rabkin. ATR inhibitors synergize with PARP inhibitors in killing glioblastoma stem cells and treating glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1122. doi:10.1158/1538-7445.AM2017-1122
Abstract 1132: Lactate dehydrogenase expression in African American women with triple-negative breast cancer
Authors: Torres-Luquis Odalys J. , Mohammed Sulma 
Published: July 2017

Abstract
The incidence of breast cancer in African American women (AAW) is much lower than those of their Caucasian counterparts. However, the age adjusted mortality rates are much greater for AAW compared to Caucasian American women (CAW). These differences in survival between AAW and CAW were attributed to socioeconomic factors and access to health care. Yet, after adjusting these differences, AAW still had lower survival rates than CAW. Genetic and immunohistochemical studies have revealed that biological variations may account for this disparity. These studies have suggested as a causative: a higher prevalence of basal-like tumors in premenopausal AAW and low prevalence of luminal tumor. These are characterized by being high-grade aggressive tumors that are estrogen receptor negative (ER-), progesterone receptor negative (PR-), human epidermal growth factor receptor-2 (HER-2) +/-; with high rate of lymph node involvement. Despite this understanding, there is little evidence to indicate which genetic or non-genetic factors contribute to causing aggressive breast cancer thereby limiting the development of prevention and treatment option. We proposed that the phenotypic diversity of breast cancer might be accompanied by a corresponding diversity in protein expression patterns that can be reveal using proteomic technologies. We hypothesized that in addition to ER- and PR-, and the absence in expression of HER-2, the protein composition of triple-negative tumors varies among African-American and Caucasian. Two-dimensional gel electrophoresis, mass spectrophotometry and data analysis of protein from breast cancer tissues were used to identify differentially expressed proteins from African American and Caucasian women. Western blot of luminal and TNBC cell lines were used to confirm the expression of identified proteins. We have found that many proteins were differentially expressed in AAW breast cancer tissues compared to CAW. One of these is lactate dehydrogenase which was found to be overexpressed in tissues from AAW. Western blot analysis confirmed expression.
Citation Format: Odalys J. Torres-Luquis, Sulma Mohammed. Lactate dehydrogenase expression in African American women with triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1132. doi:10.1158/1538-7445.AM2017-1132
Abstract 1134: Tissue transglutaminase is a new therapeutic target to overcome steroid resistance in T cell acute lymphoblastic leukemia
Authors: Jung Hyun Joo 
Published: July 2017

Abstract
Background: The treatment response to steroid is the most important predictive factor for treatment outcome of T-cell acute lymphoblastic leukemia (T-ALL). To improve survival for steroid-resistant T-ALL patients, it is necessary to develop innovative therapeutic strategies to overcome steroid resistance. This study attempts to determine new therapeutic strategies to overcome steroid resistance for patients with T-ALL. Tissue transglutaminase (TG2) is a intracellular calcium-dependent protein cross-linking enzyme reported to be highly expressed in various metastatic or drug-resistant cancer cells, and chronic expression of TG2 constitutively activates nuclear factor kappa B (NF-kappaB).
Methods: We used biochemical and molecular methodologies to demonstrate that TG2 modulation leaded to overcome the steroid resistance in T-ALL.
Results: We generated the steroid-adapted subclones of T-ALL cell lines that were extremely less sensitive to steroid than their parent T-ALL cells. We found that steroid-resistant subclones of T-ALL cells expressed much higher levels of TG2 than their parent cells and the modulation of TG2 activities altered NF-kappaB expression in this steroid-resistant cells. Inhibition of TG2 suppressed steroid resistance and improved the cytotoxicity of leukemia cells in steroid-adapted subclones of T-ALL.
Conclusion: This study shows that TG2 expression is elevated with steroid resistance in T-ALL and the modulation of TG2 induces the cytotoxicity of steroid-adapted T-ALL. TG2 could be a new therapeutic target to overcome steroid resistance in T-ALL. Furthermore, change of TG2 expression could serve as markers of induced steroid resistance in T-ALL.
Citation Format: Hyun Joo Jung. Tissue transglutaminase is a new therapeutic target to overcome steroid resistance in T cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1134. doi:10.1158/1538-7445.AM2017-1134
Abstract 114: TG02 induces cell cycle arrest in glioblastoma
Authors: Su Yu-Ting , Chen Robert , Lappin Hallie , Wang Herui , Maric Dragan , Celiku Orieta , Li Aiguo , Gilbert Mark R. , Wu Jing 
Published: July 2017

Abstract
Dysregulated cell cycle contributes to the limitless replicative potential of cancer cells. The cyclin-dependent kinases (CDKs) and cyclins, the CDK-regulatory proteins are the key cell cycle machinery and can be targets for cancer therapy. TG02, a pyrimidine-based multi-kinase inhibitor has an anti-glioma effect which was demonstrated by our previous studies. An in vitro kinase spectrum assay of TG02 demonstrated inhibitory effects in several CDKs at the nanomolar level. To further investigate the molecular mechanisms of TG02-induced cell cycle regulation in glioma, a cell cycle analysis was performed by flow cytometry using the Click-It Edu Flow Cytometric Assay Kit in GSC923 and U251 cell lines, a human stem-like cell and patient derived cell line, respectively. Protein expression of CDKs and cyclins was tested by Western blotting. RNAseq analysis using Next Generation Sequencing was performed (only GSC923) and followed by a supervised hierarchical clustering analysis of cell cycle pathways that were derived from Qiangen’s Ingenuity Pathway Analysis (IPA). Our results showed that TG02 treatment results in G2/M-phase arrest in glioma cell lines. The protein expression of CDK1, CDK2, cyclin A2 and cyclinB1 are downregulated in both TG02 treated cell lines. Additionally, RNAseq analysis revealed downregulation of cyclins A2, B1 and B2 and significant irregulation in mRNA expression of G2/M checkpoint and spindle formation proteins, indicating G2 checkpoint and mitosis progression are also affected by TG02. Taken together, we demonstrated that TG02 induced cell cycle G2/M arrest through downregulating CDK and cyclin expression signaling in the preclinical models of glioblastoma. These findings strongly support the further investigation of TG02 as a potential therapy for malignant gliomas. &lt;!–EndFragment–&gt;
Citation Format: Yu-Ting Su, Robert Chen, Hallie Lappin, Herui Wang, Dragan Maric, Orieta Celiku, Aiguo Li, Mark R. Gilbert, Jing Wu. TG02 induces cell cycle arrest in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 114. doi:10.1158/1538-7445.AM2017-114
Abstract 1144: Dual inhibition of MEK1/2 and PLK1 specifically targets aggressive breast cancer cell population with CEP55 elevated expression
Authors: Sinha Debottam , Kalimutho Murugan , Lopez J. Alejandro , Khanna Kum Kum 
Published: July 2017

Abstract
Triple negative breast cancers (TNBCs), lacking the expression of ER, PR and HER2 amplification, are the most aggressive form of breast cancer (BC). Due to their heterogeneity influenced by high level of genomic instability and aneuploidy, treatment of TNBC patients is one of the biggest challenges faced in the clinics. CEP55, discovered first by our laboratory, is a key regulator of cytokinesis malfunction of which has been shown to cause multinucleation. Furthermore, ERK2/PLK1 critically regulates the functional role of CEP55 via phosphorylation of CEP55 at particular stages of mitosis, allowing it to localize to the midbody for accurate cytokinesis. Research has demonstrated association of CEP55 with various cancers especially BC as over-expression of CEP55 mRNA is associated with worse BC prognosis and poor survival. We hypothesized that, CEP55 regulates the fate of aneuploid cell population, which are highly dependent on mitotic genes for tumor progression among aggressive BC, thus can be targeted for therapy development. We have performed a series of in vitro studies demonstrating that depletion of CEP55 sensitizes cells to anti-mitotic drugs like PLK1 inhibitor (BI2536) and leads to unscheduled CDK1/Cyclin B activation and favor CDK1-Caspase 3-dependent mitotic catastrophe. We also demonstrate that ERK1/2 transcriptionally controls CEP55 mRNA and due to lack of a specific small molecule inhibitor against CEP55, inhibition of MEK1/2 using the small molecule inhibitor Selumetinib, can mimic depletion of CEP55 in vivo. Thus, we rationalized the usage of a MEK1/2 inhibitor in combination with a PLK1 inhibitor across a series of BC cell lines. We observed synthetic lethality among the aggressive hormone receptor negative cell lines, which expressed higher expression of CEP55 compared to normal like and hormone receptor positive BC cell lines with lower CEP55 level. The combination synergistically increased apoptosis of aneuploid population via premature entry of these cells into mitosis in the presence of antimitotic drugs due to exhaustion of CEP55. We have also validated this synergistic effect of MEK1/2 and PLK1 inhibition using xenograft models, results of which imitated the in vitro findings. Therefore, we propose a novel treatment strategy of MEK1/2-PLK1 dual combination for selectively targeting CEP55 over-expressing BC in the clinics.
Citation Format: Debottam Sinha, Murugan Kalimutho, J. Alejandro Lopez, Kum Kum Khanna. Dual inhibition of MEK1/2 and PLK1 specifically targets aggressive breast cancer cell population with CEP55 elevated expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1144. doi:10.1158/1538-7445.AM2017-1144
Abstract 1146: Biomarker-driven targeted oral treatment strategy for bladder cancer
Authors: Morera Daley S. , Jordan Andre , Lokeshwar Vinata B. 
Published: July 2017

Abstract
INTRODUCTION AND OBJECTIVE: Hyaluronic acid (HA) family of molecules, HA-synthases (HAS-1,2,3), HA-receptors (CD44, RHAMM) and hyaluronidase (HYAL-1) are markers for bladder cancer (BCa) diagnosis and predicting prognosis. HA-family promotes tumor growth and metastasis by inducing epithelial mesenchymal transition (EMT). 4-Methylumbelliferone (4-MU) is an orally bioavailable dietary supplement that inhibits HA synthesis. We evaluated the expression of HA family and EMT markers in bladder tissues as well as the antitumor effects of 4-MU as a potential targeted therapeutic agent in preclinical models of BCa.
METHODS: Quantitative PCR was used to measure mRNA expression of HA-family and EMT genes (β-catenin, Twist, and Snail) in 72 bladder tissue specimens (28 normal; 44 tumor); follow-up: 20.3±2.5 months; median 17 months. The effect of 4-MU (0-0.6 mM) on cell proliferation, apoptosis, intracellular signaling, and the expression of HA receptors, and EMT genes were examined in BCa cell lines by Q-PCR, immunoblotting, proximal ligation and PI-3K activity assays. Mechanism of action was analyzed by HA addition and mAkt overexpression. Effect of oral administration of 4-MU (100, 200-mg/kg) on tumor growth was analyzed in subcutaneous xenografts.
RESULTS: HAS-1, -2 -3, HYAL-1 and Snail levels were 10-20-fold elevated in BCa tissues as compared to normal bladder (P&lt;0.001). In univariate analysis, HAS-1, -2, HYAL-1 and Twist levels correlated with metastasis (P&lt;0.001); HYAL-1 was an independent predictor of metastasis. 4-MU inhibited cell proliferation, chemotactic motility and invasion in a dose-dependent manner; 50-70% inhibition at IC50 (0.4 mM) for HA-synthesis inhibition. 4-MU induced apoptosis (&gt;3-fold) via the death receptor pathway. 4-MU downregulated HA-signaling, specifically transcript and/or protein levels of CD44, RHAMM, p-Akt, β-catenin, pβ-catenin(S552). Snail and twist were downregulated by 2-5-fold, but pβcatenin((T41/S45), pGSK-3α/β and E-cadherin levels were increased. 4-MU also inhibited CD44/PI-3K complex formation and PI-3K activity. HA addition or myristoylated Akt expression attenuated 4-MU effects. In xenograft studies, 4-MU oral treatment abrogated tumor growth of established tumors (vehicle, day 50: 766±221 mm3; 4-MU: 128±61, day 50) by abrogating HA-synthesis. No weight loss or serum or organ toxicity was observed in treated mice.
CONCULUSION: This study demonstrates that HA-family signaling is upregulated in BCa and can be specifically targeted for treatment by a non-toxic dietary supplement. Support: 7R01 CA072821-16; 7R01CA176691-03
Citation Format: Daley S. Morera, Andre Jordan, Vinata B. Lokeshwar. Biomarker-driven targeted oral treatment strategy for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1146. doi:10.1158/1538-7445.AM2017-1146
Abstract 1152: Lipid elongation: an unexplored therapeutic target in prostate cancer
Authors: Nassar Zeyad D. , Centenera Margaret M. , Machiels Jelle , Polacek Samuel J. , Bloch Katarzyna , Tilley Wayne D. , Selth Luke A. , Swinnen Johannes V. , Butler Lisa 
Published: July 2017

Abstract
Dysregulated lipid metabolism is one of the hallmarks of cancer, particularly for prostate cancer (PCa). PCa cells exhibit distinctive metabolic features such as upregulation of enzymes involved in de novo synthesis, uptake and beta-oxidation of lipids, which promote prostate cancer growth, metastasis, and drug resistance. Androgen signalling is a major driver of both PCa growth and lipid metabolism in PCa cells, however the precise effects of androgens on cellular lipid composition and the molecular pathways by which androgens regulate lipid metabolism in PCa cells are yet to be elucidated. In this study we investigated the effect of androgens on the lipid composition of PCa cell membranes and the enzymes involved in lipid metabolism, and explored the influence of these enzymes on tumour cell behaviour such as cell migration, proliferation and attachment. PCa cell lines (AR positive and negative) were cultured in the absence or presence of androgens or the anti-androgen enzalutamide, and changes in intact phospholipid species were assessed by ESI-MS/MS-based lipidomics. This analysis revealed a complexity of changes in phospholipid profiles in response to androgen treatment. Strikingly, elongation of the fatty acyl chains was consistently observed for multiple phospholipid classes in response to the androgens mibolerone or 5α-dihydotestosterone, whereas inhibition of elongation was observed in the presence of enzalutamide. Transcriptional analysis of critical lipid metabolism pathways revealed that the enzymes that catalyse lipid elongation (ELOVLs) were markedly induced by androgens in multiple PCa cell lines, and siRNA depletion of these enzymes, either alone or in combination, reversed the androgen-induced fatty acyl elongation phenotype. The androgenic regulation of ELOVL enzymes was confirmed in clinical PCa cohorts and in primary tumours cultured as explants. Targeting ELOVL gene expression also significantly attenuated the tumorigenic properties of PCa cells. ELOVL downregulation decreased LNCaP cell migration, and adhesion to fibronectin. Furthermore, ELOVL knock down significantly decreased three-dimensional spheroid growth of LNCaP cells using a hang drop assay. The impact of these enzymes on the lipid profile of PCa cell membrane and cell viability, adhesion and migration suggests that they may represent promising and previously unexplored therapeutic targets.
Citation Format: Zeyad D. Nassar, Margaret M. Centenera, Jelle Machiels, Samuel J. Polacek, Katarzyna Bloch, Wayne D. Tilley, Luke A. Selth, Johannes V. Swinnen, Lisa Butler. Lipid elongation: an unexplored therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1152. doi:10.1158/1538-7445.AM2017-1152
Abstract 1153: Heparan sulfate proteoglycans as novel target in cancer precise therapy
Authors: Falciani Chiara , Brunetti Jlenia , Depau Lorenzo , Pini Alessandro , Riolo Giulia , Mandarini Elisabetta , Bracci Luisa 
Published: July 2017

Abstract
Heparan sulfate proteoglycans (HSPGs) have crucial regulatory roles in tumor onset and progression. HSPGs
are composed of a core protein and glycan chains characterized by repeated disaccharide units which can
be sulfated at different amount and position. HSPG have enormous structural diversity due to the different
possible modifications of the single saccharide units within the polysaccharide, such as position, sulphation
and acetylation. As a result HSPG can bind and modulate their binding to signaling molecules such as
growth factors, morphogens and chemokines1 .
HSPG proved to be important in mediating cancer development and progression by enhancing the binding
of growth factors, morphogens and cytokines to their cognate receptors, thus activating signaling pathways
that give rise to angiogensis, cell growth and proliferation, together with invasion and metastasis 2-3.
NT4 is a branched peptides that targets HSPGs. NT4 specifically binds to sulfated glycosaminoglycans on
cancer cells and tissues. NT4 can be conjugated to many different cytotoxic units and tracers. NT4
conjugated to paclitaxel produced tumor regression in a breast cancer orthotopic mouse model 4. NT4
conjugated to tracers can discriminate between tumor and healthy tissue in different human cancer
specimen5.
We will show the ability of NT4 to drive tracers onto tumor lesions by means of Qdots and in vivo imaging,
proving their promising features as theranostics. We will also show NT4 ability to interfere with HSPG-
modulated activities such as: tumor cell proliferation, migration and invasion of matrix; as well as
endothelial cells proliferation, migration and tube formation. NT4-HSPG interactions and consequent
modulation of signaling pathways will prove the importance of this versatile tool, NT4, in addressing tumor
cells and interfering in their cell-cell and cell-matrix communications.
Bibliography
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3. Lee JH et al. J Biol Chem. 2009; 284:27167-75.
4. Brunetti, J. et al. Scientific Reports. DOI:10.1038/srep17736
5. Falciani C. et al. J Med Chem. 2013; 56:5009-18.
Citation Format: Chiara Falciani, Jlenia Brunetti, Lorenzo Depau, Alessandro Pini, Giulia Riolo, Elisabetta Mandarini, Luisa Bracci. Heparan sulfate proteoglycans as novel target in cancer precise therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1153. doi:10.1158/1538-7445.AM2017-1153