bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4414: RhoA activation in diffuse type gastric adenocarcinoma promotes cancer stem cell phenotypes including chemotherapy resistance
Authors: Yoon Changhwan , Cho Soo-Jeong , Aksoy Bulent A. , Park Do Joong , Yoon Sam S. 
Published: August 2015

Abstract
Introduction: The diffuse type of gastric adenocarcinoma (GA) was recently found to frequently harbor activating mutations in RHOA. RhoA is a member of the small GTPase-Ras-like proteins which are involved in cell signaling for cell migration and cell cycle.
Methods: RhoA activity and inhibition was examined in diffuse GA cell lines grown as spheroids (i.e. cancer stem cell conditions) and as monolayers in various in vitro assays. RhoA knockdown combined with chemotherapy was examined in a mouse xenograft model.
Results: RhoA activity was much higher in diffuse GA cell lines MKN-45 and SNU-668 compared to intestinal GA cell lines NCI-N87 and AGS. RhoA activity was further increased in diffuse GA cells when grown as spheroids rather than as monolayers. RhoA inhibition with shRNA or the RhoA inhibitor Rhosin decreased spheroid formation and deceased expression of the stem cell transcription factor, Sox2. Diffuse GA cells when grown as spheroids had significantly greater migration, invasion, and anchorage-independent growth, and these properties could all be blocked with RhoA shRNA or Rhosin. Diffuse GA spheroid cells (compared to monolayer cells) were resistant to 5-fluorouracil and cisplatin chemotherapy, and this chemotherapy resistance could be reversed with RhoA inhibition. In the MKN-45 xenograft model, cisplatin inhibited tumor growth by 50%, RhoA shRNA by 60%, and the combination by 83%. Clinical tumor samples of diffuse GA are currently being analyzed for RhoA expression and correlated with extent of disease and response to chemotherapy.
Conclusions: RhoA signaling is upregulated in diffuse GA cells grown as spheroids and promotes malignant transformation phenotypes such as migration and invasion. RhoA inhibition can reverse chemotherapy resistance in GC spheroid cells and in tumor xenografts, and thus the RhoA pathway is a promising new target of therapy for diffuse GA.
Citation Format: Changhwan Yoon, Soo-Jeong Cho, Bulent A. Aksoy, Do Joong Park, Sam S. Yoon. RhoA activation in diffuse type gastric adenocarcinoma promotes cancer stem cell phenotypes including chemotherapy resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4414. doi:10.1158/1538-7445.AM2015-4414
Abstract 4443: PB-42: Design and characterization of a glutathione pro-drug selectively delivered to normal tissue and not tumor tissue
Authors: Thomas James P. , Geiger Peter G. 
Published: August 2015

Abstract
The vast majority of cancer treatment regimens involve cytotoxic chemotherapy or radiation with a narrow therapeutic index. More than ½ of all approved anticancer drugs are associated with generation of reactive oxygen species. We have developed a molecule that selectively increases glutathione in normal tissues while not protecting cancer cells. Our compound has a backbone of the glutathione (GSH) precursor γ-glutamyl cysteine, with each acid group protected by ethyl ester moieties. The PB-42 molecule then leverages the dramatic differences in endothelial alkaline phosphatase between normal and cancerous tissues, similar to amifostine. Selectivity is based on a phosphorothioate moiety that requires activation by alkaline phosphatase. We have developed a robust, scalable synthetic pathway for PB-42. Cultured cells incubated with PB-42 dramatically increase intracellular GSH and total nonprotein sulfhydral (NPSH) levels several fold over controls. This process is totally dependent on activation with alkaline phosphatase. Increased GSH and NPSH levels translate into dramatic resistance to the cytotoxic effects of common chemotherapeutic agents such as cisplatin or melphalan. GSH increases are not inhibited by prior incubation with the γ-glutamyl cysteine synthase inhibitor buthionine sulfoximine (BSO), demonstrating that PB-42 enters into the GSH synthetic pathway beyond the allosterically controlled step and is not simply providing intracellular cysteine. Cells initially depleted of endogenous GSH with BSO demonstrated dramatic increases in GSH after co-incubation with PB-42 and alkaline phosphatase. PB-42 was well tolerated in vivo and was able to abrogate cisplatin-induced nephrotoxicity. PB-42 could offer several advantages in selective protection against the toxic effects of chemotherapy and radiation therapy as compared to amifostine, in that it generates the natural sulfhydral GSH, that in addition to acting as a bulk thiol, also participates in a number of enzyme based protective systems.
Note: This abstract was not presented at the meeting.
Citation Format: James P. Thomas, Peter G. Geiger. PB-42: Design and characterization of a glutathione pro-drug selectively delivered to normal tissue and not tumor tissue. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4443. doi:10.1158/1538-7445.AM2015-4443
Abstract 4448: Identification of a small molecule inhibitor of aldolase A for the targeting of hypoxic cancer cells
Authors: de Jong Petrus R. , Grandjean Geoffrey V. , Devkota Ashwini K. , Cho Eun Jeong , Dalby Kevin N. , Powis Garth 
Published: August 2015

Abstract
Cancer cells are critically dependent on glycolysis. Currently, there is no effective pharmacotherapy that exploits this metabolic vulnerability. We have uncovered a feed forward cycle of anaerobic glycolysis and hypoxia-inducible factor-1 (HIF-1). Glycolysis under hypoxic conditions normally maintains high ATP levels, which is driven by transcriptional activity of HIF-1. Glycolysis inhibition results in a cellular energy crisis, i.e. an increased AMP:ATP ratio, leading to AMPK-mediated phosphorylation of the HIF-1 co-activator p300/CBP. This prevents HIF-1 activity, although HIF-1 protein levels are unchanged, abrogating the feed forward cycle. We identified fructose-1,6-bisphosphate aldolase A (ALDOA) as a top glycolytic enzyme target for inhibiting hypoxic cancer cell glycolysis and HIF-1 activity. Our aim was to identify small molecule inhibitors for ALDOA that may yield compounds for further preclinical development. To this end, a primary high-throughput screen (HTS) was performed with 65,936 compounds using a fluorescence-based NADH oxidation aldolase (cell-free) assay. 640 compounds were further tested in a cherry-pick confirmation screen, from which 112 hits underwent concentration-response curve validation in cell-free assays. From these, 4 hits were further tested in cell-based assays by using colorectal, breast and pancreatic cancer cell lines. A lead compound that showed micromolar potency in inhibiting ALDOA, induced cell death under hypoxic conditions with IC50 values ranging between 2 - 8 μM in the cancer cell lines tested. It also inhibited extracellular flux in a real-time glycolysis assay, inhibited extracellular lactate production under hypoxic conditions as a measure of glycolysis, and blocked hypoxia responsive element (HRE) HIF-1 reporter activity but not HIF-1 protein levels. No effect of the lead compound was observed on mitochondrial respiration. Thus, this compound provides a valuable chemical probe for inhibiting glycolysis in cancer cells. Furthermore, the work provides proof-of-concept that targeting glycolysis with a small molecule inhibitor exerts potent antitumor effects in vitro and is currently being tested in preclinical models as a first-in-class oncological agent.
Citation Format: Petrus R. de Jong, Geoffrey V. Grandjean, Ashwini K. Devkota, Eun Jeong Cho, Kevin N. Dalby, Garth Powis. Identification of a small molecule inhibitor of aldolase A for the targeting of hypoxic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4448. doi:10.1158/1538-7445.AM2015-4448
Abstract 445: Tumor microenvironment influences survival of mantle cell lymphoma-initiating cells through FGF/FGFR1 signaling
Authors: Sehgal Lalit , Mathur Rohit , Berkova Zuzana , Khashab Tamer , Wang Xin , Romaguera Jorge E. , Rodriguez Alma E. , Neelapu Sattva , Samaniego Felipe 
Published: August 2015

Abstract
Introduction
Mantle cell lymphoma (MCL) represents an aggressive, incurable form of non-Hodgkin's lymphoma (NHL). The health complications associated with advanced age of MCL patients restrict treatment with intense chemotherapy. Translocation t(11;14), responsible for overexpression of cyclin-D1, is the hallmark of MCL. More detailed insight into MCL pathogenesis has been delayed until the recent development of a tissue culture system, using human mesenchymal stromal cells (hMSC), suitable for propagating primary MCL cells. We hypothesized that tumor-initiating cells are responsible for MCL relapse and chemoresistance and thus, identification of signals responsible for survival and maintenance of MCL-initiating cells (MCL-ICs) is essential for design of curative treatment strategies.
Methods
Isolates of primary MCL cells (n = 24) were co-cultured with human mesenchymal stem cells (hMSCs) and the content of MCL-ICs was analyzed by flow-cytometry based on marker expression profile; CD34-CD3-CD45+CD19-. Cytokine array was used to identify the soluble factors enriched in the co-cultures and the expression of these factors was confirmed by RT-PCR analysis. The signaling pathways employed by the newly-identified factors were blocked in 3 MCL cell lines (JVM2, Mino, Z138) to confirm their essential role in survival of MCL cells and, more importantly, for MCL-ICs.
Results
Co-cultures of primary MCL isolates with hMSCs supported the growth of MCL cells for over 4 weeks with continued presence of MCL-ICs (CD34-CD3-CD45+CD19-) representing about 1% of MCL cells. We found that IL-6 produced by hMSCs triggered an FGF/FGFR autocrine loop in MCL-ICs. The extent of FGFR expression correlated tightly with expression of SOX11, a pathology related negative prognostic marker in MCL. MCL cell survival and growth was regulated via the FGFR/mir101/ EZH2/ NF-κB/XIAP axis. Blocking of this signaling pathway with FGFR1 inhibitors consistently induced early reduction in XIAP levels and subsequently MCL cell death.
Conclusion
We established that propagation of primary MCL in co-cultures with hMSCs depends on an FGF/FGFR autocrine loop that enhances XIAP protein expression and thus, supports survival of MCL cells. We identified the factors essential for survival of MCL and MCL-ICs that present new targets for improved MCL treatment strategies.
Citation Format: Lalit Sehgal, Rohit Mathur, Zuzana Berkova, Tamer Khashab, Xin Wang, Jorge E. Romaguera, Alma E. Rodriguez, Sattva Neelapu, Felipe Samaniego. Tumor microenvironment influences survival of mantle cell lymphoma-initiating cells through FGF/FGFR1 signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 445. doi:10.1158/1538-7445.AM2015-445
Abstract 4462: The effects of NT-1044, a novel AMPK activator, on endometrial cancer cell proliferation and apoptosis
Authors: Roque Dario R. , Wysham Weiya W. , Zhou Chunxiao , Batchelor Ken , Brewster Wendy R. , Bae-Jump Victoria L. 
Published: August 2015

Abstract
Objectives: Obesity and diabetes are associated with increased risk and worse outcomes in endometrial cancer (EC). Anti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 (NovaTarg Therapeutics) is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and 3. We sought to compare the effects of NT-1044 on cell proliferation and apoptosis in human EC cell lines.
Methods: Cell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044. Apoptosis was analyzed by Annexin V-FITC assay. Cell cycle progression was evaluated by flow cytometry. Phosphorylated (phos)-S6, phos-AMPK, Cyclin D-1 and CDK-6 were evaluated by Western immunoblotting.
Results: NT-1044 significantly inhibited proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 uM for ECC-1; 87 uM for Ishikawa). Treatment with NT-1044 resulted in G1 cell cycle arrest and apoptosis in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of Cyclin-D1 and CDK-6 also decreased in a dose dependent-fashion in both cell lines.
Conclusions: NT-1044 suppressed EC cell growth through G1 cell cycle arrest, inducing apoptosis, and inhibition of the mTOR pathway. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes.
Citation Format: Dario R. Roque, Weiya W. Wysham, Chunxiao Zhou, Ken Batchelor, Wendy R. Brewster, Victoria L. Bae-Jump. The effects of NT-1044, a novel AMPK activator, on endometrial cancer cell proliferation and apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4462. doi:10.1158/1538-7445.AM2015-4462
Abstract 4465: Sequential combination of docetaxel with a novel SHP-1 agonist enhanced anti-tumor effect in triple negative breast cancer cells
Authors: Tseng Ling-Min , Liu Chun-Yu , Yang Shiu-Ping , Wang Wan-Lun , Su Jung-Chen , Wu Chia-Yun , Shiau Chung-Wai , Chen Kuen-Feng 
Published: August 2015

Abstract
Background: Interfering the oncogenic STAT3 signaling is considered as promising anti-cancer strategy. STAT3 signaling can be negatively regulated by the protein tyrosine phosphatase SHP-1 through direct dephosphorylation of p-STAT3 (Tyr705). Our previous studies have confirmed SC-43 as a novel SHP-1 enhancer which down-regulate p-STAT3 and STAT3-related downstream effectors (Breast Cancer
Research 2013). Here, we tested the efficacy of SC-43 in combination with docetaxel in triple negative breast cancer cells.
Methods: TNBC cell lines (HCC-1937, MDA-MB-468, MDA-MB-231) were used for in vitro studies. Cell viability was examined by MTT assay. Combination index was determined using Calcusyn anaysis. Apoptosis was examined by flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. In vivo efficacy of
SC-43 in combination with docetaxel was tested in nude mice with breast cancer xenografts.
Results: Sequential combination of docetaxel with SC-43 showed enhanced anti-proliferative activity in all tested TNBC cells. Synergistic effect was demonstrated when docetaxel combined with SC-43 at a dose ratio of 1 to 10, showing combination index below 1.0. Sub-G1 and western blot analysis showed that SC-43 enhanced docetaxel-induced apoptosis. In addition, combining SC-43 with docetaxel efficiently suppressed p-STAT3 and downstream effectors. Ectopic expression of STAT3 reduced the enhanced cytotoxicity by the combination therapy. Previous studies has shown SC-43 enhanced SHP-1 activity, here we showed that SC-43 in combination with docetaxel significantly enhanced SHP-1 activity. More importantly, intraperitoneal injection of SC-43 with tri-weekly docetaxel showed enhanced anti-tumor growth in xenografted tumor mice.
Conclusion: Our results suggest that the novel SHP-1 agonist SC-43 enhanced docetaxel-induced cytotoxic killing by SHP-1 dependent STAT3 inhibition in human triple negative breast cancer cells. (Supported by Yen Tjing-Ling Medical Foundation CI-104-07; NSC-102-2325-B-075-006 and MOST 103-2325-B-075-002; and MOHW103-TD-B-111-02)
Citation Format: Ling-Min Tseng, Chun-Yu Liu, Shiu-Ping Yang, Wan-Lun Wang, Jung-Chen Su, Chia-Yun Wu, Chung-Wai Shiau, Kuen-Feng Chen. Sequential combination of docetaxel with a novel SHP-1 agonist enhanced anti-tumor effect in triple negative breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4465. doi:10.1158/1538-7445.AM2015-4465
Abstract 4469: A novel class of inhibitors of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) with potential for the treatment of cancer
Authors: Ching Lai-Ming , Palmer Brian D. , Tomek Petr , Flanagan Jack U. , Henare Kimiora 
Published: August 2015

Abstract
A broad range of cancers express the tryptophan catabolising enzyme indoleamine 2,3-dioxygenase 1 (IDO1) as a mechanism of suppressing the endogenous anti-tumour immunity. High IDO1 expression by their tumours is associated with poor patient prognosis and has prompted the discovery of small molecule inhibitors of the enzyme for development as anti-cancer agents. Towards this end, we carried out a high throughput screen of 42,000 small molecules in the Walter and Eliza Hall Institute for Medical Research compound library and retrieved over 30 good hits with diverse structures that inhibited recombinant human IDO1 with potencies in the low μM range. Initial structure activity relationship studies of the best hits led us to focus on one chemical class, which, although less potent than some of the other hits on the list, exhibited a number of features that make it more favourable for development as a therapeutic agent. SN35837, the non-optimised hit from the high throughput screen is highly cell permeable and displays improved potency in inhibiting cytoplasmic hIDO1 in cell-based assays, compared to that for enzymatic assays. Complete inhibition of IDO1 function is seen at concentrations that has no measurable effects on cell viability. The imidazole lead from New Links Genetics, NLG919 has decreased activity in cells, whilst Incyte's hydroxyamidine inhibitor INCB024360 has similar potency in cellular and enzymatic assays. The maximum tolerated dose SN35837 in C57Bl/6 mice given as a single intraperitoneal bolus dose was 500 mg/kg. Mice tolerated daily intraperitoneal or subcutaneous administrations of SN35837 at 150 mg/kg. Statistically significant inhibition of growth of subcutaneously implanted GL261 gliomas and Lewis Lung carcinomas in syngeneic hosts were achieved after daily administration of 75 mg/kg SN35837. Preliminary studies indicate that the non-optimised hit also synergises when given in combination with anti-PD1 and anti-CTLA-4 antibodies. We conclude that derivatives of SN35837 may provide effective and potent inhibitors of IDO1 suitable for development as anti-cancer agents.
Citation Format: Lai-Ming Ching, Brian D. Palmer, Petr Tomek, Jack U. Flanagan, Kimiora Henare. A novel class of inhibitors of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) with potential for the treatment of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4469. doi:10.1158/1538-7445.AM2015-4469
Abstract 4471: The antitumor activity of hyaluronic acid nimuselide-NH2 bioconjugate (CA102N) in human colorectal cancer (CRC)
Authors: Tchaparian Eskouhie 
Published: August 2015

Abstract
Carrier mediated drug delivery systems are promising next generation therapeutics for targeted delivery and improved efficacy and safety of cytotoxic drugs. Hyaluronic Acid conjugated drugs (HACD) are novel carrier-mediated drug delivery systems (Targeting Carrier™) characterized by CD44-mediated endocytosis of Hyaluronic Acid (HA) and intracellular drug release. The present study investigates the in vitro and in vivo antitumor activity of CA102N, an HA- Cyclooxygenase-2 inhibitor conjugate, HA-Nimesulide, currently in preclinical development. Cyclooxygenase-2 (COX-2) inhibitors are a class of compounds that are associated with anticancer properties. CA102N was able to selectively inhibit HCT116 and HT29, CRC cancer cell growth in vitro with an IC50 of 57.7 and 77.14 μM respectively. In in vivo studies, strong anti-tumor effects and rapid tumor shrinkage was observed within 3 days posttherapy in mice bearing HT-29 xenografts treated with either 1.5 or 4.5 mg/kg of relative amount of the conjugate. Further, full and sustained regression of tumors was also attained during the entire observational period (14 days) after the last dose. No treatment related toxicity was noticed in mice. HACD drug delivery systems may offer great advantages in the development of a new class of bioconjugated drugs for intracellular delivery and enhanced safety of potent cytotoxic drugs.
Citation Format: Eskouhie Tchaparian. The antitumor activity of hyaluronic acid nimuselide-NH2 bioconjugate (CA102N) in human colorectal cancer (CRC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4471. doi:10.1158/1538-7445.AM2015-4471