bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4136: Effect of prorenin receptor PRR knock down and telmisartan on endometrial cancer growth
Authors: Mohammed Riazuddin , Delforce Sarah J. , Wang Yu , Verrills Nicole M. , Lumbers Eugenie R. , Pringle Kirsty G. 
Published: July 2017

Abstract
Endometrial cancer is the most common gynaecological malignancy and its incidence is increasing. Tissue renin angiotensin systems (RAS) are known to stimulate angiogenesis, cell proliferation and migration. All of these actions potentiate cancer growth and spread. We have previously demonstrated that endometrioid endometrial cancers express both prorenin and prorenin receptor ((P)RR) mRNA and have significantly greater levels of these proteins than normal adjacent endometrial tissue. Prorenin acting via the (P)RR can activate both RAS dependent and independent signalling pathways. Therefore we hypothesized that endometrial cancer growth can be inhibited by drugs that block Ang II/AT1R interactions and prorenin/(P)RR mediated signaling pathways. To determine the functional role of (P)RR in endometrial cancer growth, we used siRNA transfection to knock down (P)RR expression in three endometrial cancer cell lines (Ishikawa, HEC-1A and AN3CA) at 24h, 48h, 72h & 96h. The effect of RAS blockers on cell viability was also assessed by Resazurin assay at 48h in the three endometrial cancer cell lines.
All three of the endometrial cancer cell lines examined (Ishikawa, HEC-1A and AN3CA) expressed (P)RR and prorenin mRNA, however levels of (P)RR were much higher in Ishikawa cells. Transfection of the three cell lines with a (P)RR siRNA resulted in 90% knockdown of (P)RR mRNA expression and reduced the cell viability of both Ishikawa and AN3CA but not HEC-1A cells, as measured by a resazurin assay after 48h incubation. Aliskiren (a renin inhibitor) inhibited Ishikawa cell growth by 20%. There was no effect of Aliskiren on cell viability in HEC-1A and AN3CA cell lines. Perindoprilat (an ACE inhibitor) and Losartan (an angiotensin II type 1 receptor (AT1R) inhibitor) had no effect on cell viability in any cell line. Another AT1R antagonist, telmisartan, which also acts as a selective agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), did however significantly reduce cell viability in all cell lines (Ishikawa 75%, HEC-1A 50% and AN3CA 60%).
Removal of the prorenin receptor inhibits the growth and development of some endometrial cancer cell lines. Only telmisartan, which has properties additional to Ang II antagonism, was effective in inhibiting endometrial cancer cell growth. (P)RR knockdown and telmisartan are therefore potential therapeutic drugs for the treatment of endometrial cancer.
Citation Format: Riazuddin Mohammed, Sarah J. Delforce, Yu Wang, Nicole M. Verrills, Eugenie R. Lumbers, Kirsty G. Pringle. Effect of prorenin receptor PRR knock down and telmisartan on endometrial cancer growth [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 4136. doi:10.1158/1538-7445.AM2017-4136
Abstract 4140: Identification of a selective MKLP2/KIF20A inhibitor with high in-vivo antitumor activity
Authors: Collette Yves , Miserey-Lenkei Stephanie , Guillou Catherine , Carniato Denis , Pau Bernard , Goud Bruno , Vey Norbert , Bougeret Cecile E. 
Published: July 2017

Abstract
Mitotic kinesins are essential regulators of cancer cell replication and migration. The mitotic kinesin MKLP2/KIF20A, a member of the kinesin-6 family, plays an essential role during cytokinesis and was identified as a potential new target for cancer chemotherapy1. We have previously identified Paprotrain, a new synthetic compound, as the first selective MKLP2 inhibitor2. Recently, we obtained Paprotrain analogues with higher potency on MKLP23. Herein we describe the identification and characterization of BKS0349, a new potent analogue of Paprotrain.
BKS0349 compound is 10 times more potent than paprotain on MKLP2 inhibition and has shown an even more restricted specificity profile when tested on a large set of kinases. In-vitro this compound is highly cytotoxic on a wide panel of human cancer cell lines (IC50 ranged 10-70 nM, which corresponds to 1000 fold improvement of paprotrain potency) while no toxicity is observed on human normal cells such as peripheral blood mononuclear cells (PBMC) and primary hepatocytes (IC50 &gt;50µM). BKS0349 compound is well tolerated in mice using repeated intravenous administrations (200 mg/kg, twice a week for 4 weeks). In xenografted nude mice, in-vivo treatment with BKS0349 compound demonstrates a high antitumor activity against various human cancer cell models, either sensitive or resistant to some standard-of-care treatments. In addition, human cancer cells treated in-vitro as well as in-vivo with BSK0349 compound display Golgi scattering and a mitotic arrest leading to cell death, as hallmarks of BKS0349’ mode of action.
These findings show that MKLP2 is a potential new target for cancer chemotherapy and BKS0349 a good candidate to be developed for cancer treatment.
1Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance. P. Khongkow et al. Oncogene, 2015, 1-13.
2Relocation of Aurora B and Survivin from centromeres to the central spindle impaired by a kinesin-specific MKLP-2 inhibitor. S. Tcherniuk et al. Angew. Chem. Int. Ed., 2010, 49:8228-8231.
3New MKLP-2 inhibitors in the paprotrain series: design, synthesis and biological evaluations. C. Labrière et al. Bioorg and Med Chem, 2016, 24:731-734.
Note: This abstract was not presented at the meeting.
Citation Format: Yves Collette, Stephanie Miserey-Lenkei, Catherine Guillou, Denis Carniato, Bernard Pau, Bruno Goud, Norbert Vey, Cecile E. Bougeret. Identification of a selective MKLP2/KIF20A inhibitor with high in-vivo antitumor activity [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 4140. doi:10.1158/1538-7445.AM2017-4140
Abstract 4155: Crosstalk of SOX2 and epithelial-to-mesenchymal transition on EGFR-TKI resistance
Authors: Lee An-Chun , Chiu Yu-Fan , Kuo Ming-Han , Wang Yuan-Hung , Chou Yu-Ting 
Published: July 2017

Abstract
EGFR-tyrosine kinase inhibitors (TKIs) have been shown to produce profound therapeutic responses in lung adenocarcinoma harboring EGFR mutations. Despite this initial response, patients with EGFR-mutated lung adenocarcinoma ultimately developed resistance to EGFR-TKIs. Although both SOX2 and epithelial-to-mesenchymal (EMT) have been linked to the EGFR-TKI resistance in lung adenocarcinoma, the interplay between SOX2 and EMT in EGFR-TKI resistance is not known. Here, we report that cancer plasticity switched by SOX2 and EMT regulates EGFR-TKI resistance. We found that the selection of EGFR-TKI resistant cells induced EMT while attenuating SOX2 expression. We observed that EGFR-TKI treatment induced SOX2 expression in EGFR-mutated lung cancer cells, and SOX2 silencing encouraged EGFR-TKI resistance. Preselection of EGFR-mutated lung cancer cells with the EMT feature endowed cells with EGFR-TKI resistance but suppressed SOX2 expression. We found that TGF-β induced EMT but attenuated SOX2 expression, resulting in increased EGFR-TKI resistance. Pharmacological inhibition of HDACs in EGFR-mutated cells attenuated SOX2 expression but induced EMT, causing increased EGFR-TKI resistance. Enriching SOX2 expression in EGFR-mutated cells attenuated EMT and rendered cells more sensitive to EGFR-TKIs. Correlation analysis exhibited negative correlations between SOX2 and EMT markers in primary non-small cell lung cancer. Kaplan-Meier analysis revealed that a SOX2 low/Vimentin high signature predicted a poor survival in EGFR-mutated lung adenocarcinoma. Our findings support the notion that the cancer plasticity regulated by SOX2 and EMT plays a critical role in EGFR-TKI resistance, and SOX2 and Vimentin can function as prognostic biomarkers in lung cancer progression.
Citation Format: An-Chun Lee, Yu-Fan Chiu, Ming-Han Kuo, Yuan-Hung Wang, Yu-Ting Chou. Crosstalk of SOX2 and epithelial-to-mesenchymal transition on EGFR-TKI resistance [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 4155. doi:10.1158/1538-7445.AM2017-4155
Abstract 4158: Targeting the imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia through a novel BCR-ABL inhibitor
Authors: Gupta Pranav , Kathawala Rishil , Wei Liuya , Wang Fang , Wang XiaoKun , Druker Brian J. , FU Li-Wu , Chen Zhe-Sheng 
Published: July 2017

Abstract
Chronic Myeloid Leukemia (CML), a hematological malignancy, is largely caused by the Philadelphia (Ph) chromosome carrying the Break point Cluster Region-Abelson (BCR-ABL) oncogene. Imatinib is a BCR-ABL-targeted therapy and considered the standard of care in CML management. Resistance to imatinib therapy often develops because of mutations in the BCR-ABL kinase domain. In this study, we evaluated PBA2, a novel BCR-ABL inhibitor, for its anti-cancer activity against BCR-ABL expressing BaF3 cells. PBA2 shows potent activity against wild-type and T315I mutated BaF3 cells as compared with imatinib. PBA2 inhibited the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. PBA2 inhibited the mRNA expression of BCR-ABL in BaF3/WT and BaF3/T315I cells. Mechanistically, PBA2 increased the cell population in sub G1 phase of the cell cycle, induced apoptosis and elevated ROS production in both BaF3/WT and BaF3/T315I cells. Taken together, our results indicate that PBA2 exhibits anti-proliferative effects and inhibits the imatinib-resistant T315I BCR-ABL mutation. PBA2 may be a novel drug candidate for overcoming the resistance to imatinib in CML patients.
Note: This abstract was not presented at the meeting.
Citation Format: Pranav Gupta, Rishil Kathawala, Liuya Wei, Fang Wang, XiaoKun Wang, Brian J. Druker, Li-Wu FU, Zhe-Sheng Chen. Targeting the imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia through a novel BCR-ABL inhibitor [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 4158. doi:10.1158/1538-7445.AM2017-4158
Abstract 4159: In vitro drug response (IVDR) and tumor-associated biomarker (BM) expression profiles in lung carcinoma (LC)
Authors: Parker Ricardo J. , Schiltz Patric M. , Myers Michael P. 
Published: July 2017

Abstract
Assessing IVDR to Chemo and BM expression in tumors of patients (Pts) before treatment can stratify therapy and improve outcome. Historical IVDR and BM data were analyzed retrospectively on 582 human LC specimens including 311 adenocarcinomas (ADCA), 131 non-small cell lung carcinomas (NSCLC), and 140 squamous cell carcinomas (SQCC) resected from Pts diagnosed with primary (PD), recurrent (RD) or metastatic disease (MD), and tested at a single clinical reference lab between March 2004 and July 2006. Pt and specimen information were unlinked directly and anonymized. IVDR was determined in prepared aliquots of Pts’ viable tumor cell suspensions after 5-day exposures to single physiologic doses of Chemo (CARBO, CPLAT, GMCB, NVBL, TAXOL, TXTR, VP16, TOPO). IVDR was bifurcated into extreme resistance (ER, non-response) or low resistance (LR, response). Standard immunohistochemistry (IHC) was performed on the same Pts’ paraffin-embedded LC sections to detect BMs mutant-p53 (mp53; n=322), EGFR (n=250), and BCL-2 (n=270), and results showed 57% overexpressed mp53, 91% overexpressed EGFR, and 32% expressed BCL-2. IVDR profiles for ADAC and NSCLC were similar, while SQCC was comparatively less resistant. IVDR profiles for PD, RD and MD of a given histology were relatively dissimilar. In ADCA, RD was more resistant than PD and MD. In NSCLC and SQCC, MD was more resistant. Significant portions of LCs showed prevalent ER to CARBO, TAXOL, TXTR, and VP16; and cross resistance to combinations, suggesting no clinical benefit from toxic ineffective Chemo. In such settings, disease progression may negatively impact a Pt’s tolerance to further Chemo. Pre-assessment of IVDR and BMs may identify ER factors, stratify treatment, and potentially improve clinical outcomes.
Citation Format: Ricardo J. Parker, Patric M. Schiltz, Michael P. Myers. In vitro drug response (IVDR) and tumor-associated biomarker (BM) expression profiles in lung carcinoma (LC) [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 4159. doi:10.1158/1538-7445.AM2017-4159
Abstract 416: Identification of therapeutic combinations in glioblastoma using personalized gene expression networks
Authors: Stathias Vasileios , Forlin Michele , Allen Bryce , Schürer Stephan , Ayad Nagi G. 
Published: July 2017

Abstract
The goal of our study was to identify patient-specific gene expression networks from Glioblastoma Patient-Derived Xenografts (PDXs) and determine novel therapeutic compound combinations using those networks.
Glioblastoma is the most common malignant primary adult brain tumor with a standard of care consisting of maximal surgical resection followed by radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. However, despite medical advances in the field, recurrence is almost universal, suggesting the need for more personalized and targeted therapeutic approaches.
For this, we obtained, transcriptional data from Glioblastoma PDXs and used them to identify their respective differentially expressed genes. Patient-specific gene expression networks were then created and their biological relevance was supplemented by integrating them with TCGA Glioblastoma transcriptional data. In order to identify compound combinations specific for those networks, we used the extensive chemical perturbation signatures from the Library of Network-based Cellular Signatures (LINCS). From the large number of L1000 transcriptional data we extracted gene expression signatures that were indicative of specific LINCS compounds. We then compared those signatures to the patient-specific networks in order to prioritize compound combinations that were inducing discordant transcriptional changes in distinct sub-networks of the PDXs transcriptome. The most orthogonal compound combinations were then chosen and used in in-vitro cell viability assays of Glioblastoma PDXs in order to evaluate their effectiveness. The above process can be used to prioritize compound combinations with potential therapeutic effect in a patient-specific manner.
Citation Format: Vasileios Stathias, Michele Forlin, Bryce Allen, Stephan Schürer, Nagi G. Ayad. Identification of therapeutic combinations in glioblastoma using personalized gene expression networks [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 416. doi:10.1158/1538-7445.AM2017-416
Abstract 4166: Role of CD44 as a regulator of adaptive plasticity in pancreatic cancer cells
Authors: Chen Chen , Zhao Shujie , Zhao Xiangru , Freeman James W. 
Published: July 2017

Abstract
Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) may show an initial objective response to chemotherapy that is usually of short duration. Our research goal is to understand the molecular mechanisms for this short duration response and to more fully define differences between chemosensitive and chemoresistant cells. Cancer cells that undergo an EMT and metastatic tumors show an increase in CD44s expression. In this study, we use CD44 Low and CD44 High isogenic cell models to identifying key molecular networks and potential targets that could benefit therapy.
Experiments design: CFPAC1-CD44 Hi and Low cells were sorted by flowcytometry and single clone selection. Isogenic model systems were generated by overexpression CD44s in CF-Low cells. Western blot, MTT, migration and invasion assays had been used to characterize cell growth, invasiveness and gemcitabine sensitivity. Receptor Tyrosine Kinase arrays were used to identify the CD44 regulated molecular networks in these isogenic cell models treated with/without CD44 ligand hyaluronan acid (HA).
Summary: CD44s high cells show an EMT phenotype (increase of vimentin and loss of E-cadherin) and increase invasion. Expression of CD44s in CD44 low cells was sufficient to drive EMT partially and drive invasion. By in vitro testing over expressing CD44s is not sufficient to decrease sensitivity to gemcitabine. By Receptor Tyrosine Kinase arrays, CD44 Hi clone cells show increase in IGF-1R phosphorylation. Preliminary data had shown that HA may stimulate ROR2, VEGFR1, and EphB2 phosphorylation in CD44 Hi clone cells.
Conclusion: Our previous study suggested that CD44 could be a therapeutic target in Gemcitabine resistant PDAC cells. The current study will further identify the molecular targets that regulated by CD44 pathways. These newly identified targets could be hopefully used for the optimized multimodality therapy to sensitize the PDAC cells to therapy and to benefit the pancreatic cancer patients.
Citation Format: Chen Chen, Shujie Zhao, Xiangru Zhao, James W. Freeman. Role of CD44 as a regulator of adaptive plasticity in pancreatic cancer cells [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 4166. doi:10.1158/1538-7445.AM2017-4166
Abstract 4168: Altering cisplatin sensitivity by manipulating the cellular metallome
Authors: Amable Lauren , Shide Eric 
Published: July 2017

Abstract
The cellular metallome serves as an important reservoir to meet the biological needs of the cell, serving as enzyme co-factors and ensuring proper protein folding. Recent studies have suggested that cancer cells adapt their metallome in order to accommodate rapid cellular growth and metabolism pathways. Thus, altering the cancer metallome may yield new avenues to target cancer and change the responsiveness to chemotherapy. Here, we aim to characterize and understand how changes in the ovarian cancer metallome affect sensitivity to the chemotherapy drug cisplatin. Five ovarian cancer cell lines were used in experiments: A2780, A2780/CP70, SKOV3, OVCAR3, and CAOV3. The metallome was manipulated by treating cells with either zinc, copper, magnesium, calcium, iron, manganese, or the metal chelator tetrathiomolybdate. Cisplatin sensitivity after metal treatment was measured by WST-1 cell proliferation assays. Metallomes were quantitated by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) by measuring the following metals: zinc, copper, magnesium, calcium, molybdenum, manganese, iron, phosphorous, and sulfur. Cellular metal concentrations were normalized to sulfur levels. Changes in cisplatin sensitivity were evaluated by measuring cellular cisplatin uptake by ICP-MS. Treatment of ovarian cancer cells with various metals resulted in differences in cellular proliferation and metallome composition. The changes in the metallome were not singular in nature because altering one metal resulted in changes in multiple metals. Cisplatin sensitivity was additionally affected under different metal treatments. Preliminary data suggest that cisplatin uptake was altered as a mechanism to mediate the cellular response to cisplatin, however other mechanisms such as DNA repair might also play a role. In conclusion, we demonstrate that perturbations of the cancer metallome result in changes of various metals, cellular proliferation, and sensitivity to the chemotherapy drug cisplatin. The data lend further insight into how an individual’s metallomic status, a combination of nutritional and harmful metal exposure, might result in the development and progression of cancer and affect the response to chemotherapy.
Citation Format: Lauren Amable, Eric Shide. Altering cisplatin sensitivity by manipulating the cellular metallome [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 4168. doi:10.1158/1538-7445.AM2017-4168
Abstract 4173: Drug target mutations as a mechanism of acquired resistance to small molecules activators of protein phosphatase 2a
Authors: Tohme Rita , Sangodkar Jaya , Kiselar Janna , Leonard Daniel , O'Connor Caitlin , Gandhe Sai , Xu Wenqing , Brautigan David , Chance Mark , Ohlmeyer Michael , Narla Goutham 
Published: July 2017

Abstract
The sustainable activation of the RAS/MAPK and PI3K/AKT signaling pathways in cancer is promoted by a reduction in the activity of the tumor suppressor protein phosphatase 2A (PP2A). Therefore, a novel therapeutic strategy consists of directly activating PP2A, leading to the simultaneous inhibition of these oncogenic pathways. PP2A is a heterotrimeric complex, consisting of a scaffolding A subunit, catalytic C subunit, and one of many regulatory B subunits responsible for substrate specificity. Our lab has successfully developed first-in-class Small Molecule Activators of PP2A (SMAPs), which induce tumor growth inhibition in both transgenic and patient derived xenograft mice models. However, alterations to the drug binding site is one of the most common mechanisms of acquired resistance, and we hypothesized that point mutations of the drug binding amino acid residues of PP2A would lead to decreased sensitivity to SMAP treatment. Determining potential mechanisms responsible for the development of resistance to SMAPs would guide the development of novel therapeutic strategies to improve patients’ prognosis. In silico docking calculations, photo affinity labeling, and hydroxyl radical footprinting studies were used to identify K194, E197, and L198 as the putative residues of PP2A-Aα that were interacting with SMAPs. K194R, E197K, and L198V mutations were generated by site-directed mutagenesis. H358, a KRAS-driven lung adenocarcinoma cell line, was used to create isogenic cell lines stably overexpressing mutated and wild type PP2A-Aα. These mutations did not affect the phosphatase activity or its ability to form holoenzymes in a cell-free system. SMAP response was investigated in vivo using a xenograft model of H358 isogenic cell lines and it was determined that tumors harboring mutant K194R and L198V PP2A-Aα were resistant to SMAPs treatment. Together, our results suggest that residues K194 and L198 are required for drug binding and subsequent target engagement. These findings shed light on possible mechanisms of acquired resistance to SMAPs in patients and have potential to guide the design of second-generation drugs.
Citation Format: Rita Tohme, Jaya Sangodkar, Janna Kiselar, Daniel Leonard, Caitlin O'Connor, Sai Gandhe, Wenqing Xu, David Brautigan, Mark Chance, Michael Ohlmeyer, Goutham Narla. Drug target mutations as a mechanism of acquired resistance to small molecules activators of protein phosphatase 2a [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 4173. doi:10.1158/1538-7445.AM2017-4173