bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2805: Protein oxidation in pancreatic neoplasia and cancer
Authors: Schultz Michelle , Diaz Andrew , Smite Sharon , DeCant Brian , Bentrem David , Grippo Paul 
Published: July 2016

Abstract
Rationale- Peroxiredoxin-1 (Prdx1) is overexpressed in pancreatic cancer patient serum and correlates with worse prognosis. Prdx1 is an important antioxidant protein whose deletion causes the formation of malignant lesions in mice. Prdx1's redox function depends on its reduction by two other Thioredoxin system members, Thioredoxin (Txn) and Sulfiredoxin (Srxn). Prdx1 may also contribute to tumorigenesis by oligomerizing and becoming a nuclear chaperone when it's overoxidized and its redox function is inhibited.
Objective- Our objective was to investigate disruptions in the Txn system during pancreatic neoplasia and to determine how that affects phosphorylation of Kras effectors.
Findings- Prdx1 expression was elevated and Srxn expression was reduced in pancreatic lesions of El-Kras, Pdx1-Cre/LSL-Kras (KC-Pdx1), and P48-Cre/LSL-Kras (KC-P48) mice. Txn was absent in lesions of KC-Pdx1 and KC-P48 mice but present and differentially located in EL-Kras lesions. In primary pancreatic acinar cells, oxidation of the Txn system with auranofin increased ERK and AKT phosphorylation in EL-Kras mice, but not in KC-P48 mice, indicating differential regulation of the Txn system in KC-P48 mice. This could be due to the presence of a higher molecular weight Prdx1 being present in KC-p48 mice and not in EL-Kras mice. This suggests that the effect of mutant Kras on the thioredoxin system in these two models may be different. Prdx1 and (p)ERK also interacted in vitro and inhibition of ERK and AKT phosphorylation modified the expression of Txn and Srxn in pancreatic cell lines. We also found that in human pancreatic cancer patient tissue, Prdx1 was overexpressed in pancreatic cancer as compared to adjacent normal tissue.
Conclusions- The Txn system is disrupted during pancreatic neoplasia and may be associated with modified ERK and AKT regulation in Kras mutant pancreatic tissue.
Citation Format: Michelle Schultz, Andrew Diaz, Sharon Smite, Brian DeCant, David Bentrem, Paul Grippo. Protein oxidation in pancreatic neoplasia and cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2805.
Abstract 2813: The synergistic anticancer activity of 1’-acetoxychavicol acetate and sodium butyrate in human hepatocellular carcinoma cells
Authors: Matsui-Yuasa Isao , Kojima-Yuasa Akiko 
Published: July 2016

Abstract
Introduction: It has been suggested that the combined effect of natural products may improve the effect of treatment against the proliferation of cancer cells. We evaluated the combination of 1’-acetoxychavicol acetate (ACA), obtained from Alpinia galangal, and sodium butyrate (NaB), a major short chain fatty acid, on the growth of HepG2 cells. ACA exhibits chemopreventive effects on chemically induced tumors in mouse skin as well as on rat oral, colonic, esophangeal, and pancreatic tumors. ACA also exerts antitumor activity by inducing apoptosis in various tumor cells. On the other hand, sodium butyrate has multiple effects on tumor cells cultured in vitro, including, most notably, inhibition of cell proliferation and induction of apoptosis, as well as initiating the differentiation of various carcinoma cells. The aim of our study was to elucidate the synergistic interaction of ACA and NaB on cell viability in the human hepatocellular carcinoma cell line HepG2 and to examine the mechanism of the anti-cancer effect of combined ACA and NaB treatment.
Methods: HepG2 cells or HT-29 cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% FBS.
Results: The number of HepG2 cells was synergistically decreased via apoptosis induction with the combined treatment of ACA and NaB. In ACA- and NaB-treated cells, intracellular reactive oxygen species (ROS) levels and NADPH oxidase activities were increased significantly. The decrease in cell number after combined treatment of ACA and NaB was improved with the treatment of catalase. These results suggest that an increase in intracellular ROS levels is involved in cancer cell death. AMP-activated protein kinase (AMPK) plays an essential role in controlling processes related to tumor development. In ACA- and NaB-treated cells, AMPK phosphorylation was induced significantly, and this induction improved when cells were pretreated with catalase. These results suggest that the increase in intracellular ROS is involved in the increase of AMPK phosphorylation.
Conclusion: These findings are consistent with the hypothesis that combination treatments can sensitize cancer cells more effectively than individual treatments. We reported that combination treatment of ACA and NaB synergistically induced apoptotic cell death via an increase in intracellular ROS and an increase in pAMPK levels. Our findings may provide new insight into the development of novel combination therapies against hepatocellular carcinoma.
Citation Format: Isao Matsui-Yuasa, Akiko Kojima-Yuasa. The synergistic anticancer activity of 1’-acetoxychavicol acetate and sodium butyrate in human hepatocellular carcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2813.
Abstract 2834: Antitumor effect of AGM 130 (5’-OH-5-nitro-Indirubin oxime), a cyclin-dependent kinase inhibitor in colorectal cancer cells
Authors: Shim Hyun-Jeong , Hwang Jun-Eul , Bae Woo-Kyun , Park Myung-Sook , Yun Hyo-Jeong , Lee Ji-Hee , Cho Sang-Hee , Chung Ik-Joo 
Published: July 2016

Abstract
The AGM 130 (5’-OH-5-nitro-Indirubin oxime) compound is derived from Indirubin, which is an ingredient of Danggui Longhui Wan and used in traditional Chinese medicine. AGM 130 can inhibit the proliferation of a variety cells by arresting the cell in the G2/M phase of the cell cycle, it is a cyclin-dependent kinase (CDK) inhibitor that has anti-proliferative activity and apoptotic effects on cancer cells. AGM 130 has improved water solubility compared to Indirubin, however still displays a low solubility in biologic fluids and a poor bioavailability. This poor water solubility limits the clinical application of AGM 130 to treat cancer. In this study, we decided to develop and evaluate a SNEDDS (self-nanoemulsifying drug delivery systems) formulation containing AGM130 for improving its solubility, dissolution rate, and bioavailability.
To check the anti-proliferative effect of the AGM 130 compound on colon cancer cell line, we performed the MTT assay with the CT-26 cancer cell. We also performed cell cycle analysis, apoptotic assays and western blotting. The CT-26 cell bearing mice were treated intraperitoneally with AGM 130 loaded PPG-cRGD, 5-fluorouracil (5-FU) or AGM 130 loaded PPG-cRGD combined with 5-FU. We measured tumor volume and tumor progression of each groups.
In vitro, AGM 130 showed significant anti-proliferative activity in CT-26 cell (IC 50, 1.9 μM). Cells treated with AGM 130 showed G2/M cell cycle arrest and also induced apoptosis compared to untreated cells. The western blotting analysis showed that AGM 130 inhibited CKD1/cyclin B1 and also CKD2/cyclin E. The greatest tumor regression (percentage tumor growth inhibition) was observed in the group treated with AGM 130 loaded PPG-cRGD combined with 5-FU. When 5-FU was administrated alone, the anti-tumor effect was inferior to the group treated with AGM 130 loaded PPG-cRGD alone.
These results suggest that intraperitoneal administration of AGM 130 loaded PPG-cRGD inhibits tumor progression in a mouse colon cancer. Thus, AGM 130, a cyclin-dependent kinase inhibitors may provide a new therapeutic approach in the treatment of colon cancer.
Citation Format: Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Myung-Sook Park, Hyo-Jeong Yun, Ji-Hee Lee, Sang-Hee Cho, Ik-Joo Chung. Antitumor effect of AGM 130 (5’-OH-5-nitro-Indirubin oxime), a cyclin-dependent kinase inhibitor in colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2834.
Abstract 285: Disulfiram, a dual MGMT and aldehyde dehydrogenase inhibitor, sensitizes ER-positive breast cancer cells to temozolomide and cyclophosphamide
Authors: Bobustuc George C. , Donohoe Deborah , Holmuhamedov Alisher , Kalkunte Srivenugopal , Konduri Santhi D. 
Published: July 2016

Abstract
Background: O6 methylguanine DNA methyltransferase (MGMT) is overexpressed in a majority of cancers, including breast cancer. MGMT is a DNA repair protein leading to chemo resistance. MGMT expression directly correlates with ER expression and tamoxifen resistance. Aldehyde Dehydrogenase (ALDH) activity, as a progenitor/stem cell marker, while it has been reported to inversely correlate with MGMT expression in other cancers, has also been linked to chemotherapy and radiation resistance.
Methods: We have tested the effect of Antabuse (disulfiram, DSF), as a dual MGMT and ALDH inhibitor, at nontoxic doses, in combination with Temozolomide (TMZ) or/and Cyclophosphamide (CP) on ER+ breast cancer cells.
Results: DSF at very low doses (achievable in human serum with standard DSF clinical dosing) decreases ER+ breast cancer cell growth (MCF7, T47D and ZR75) in a dose-dependent manner. DSF further sensitizes breast cancer cells to TMZ or/and CP and significantly inhibits breast cancer growth without causing unwanted side effects on the normal breast epithelial cells. Dose effect and isobologram studies confirm synergistic activity of DSF + CP and moderate synergism for DSF + TMZ. DSF, alone or in combination with TMZ (DSF ± TMZ) and/or CP (DSF ± CP), significantly inhibits expression of MGMT, aldehyde dehydrogenase, ERα, E2F and BIRC5 gene (survivin) - all involved in breast cancer tumorigenesis. DSF, alone or in combination with TMZ (DSF ± TMZ) and/or CP (DSF ± CP) caused significant apoptosis in breast cancer cells. In a dose dependent manner, DSF inhibited colony formation, effect which was further enhanced by addition of TMZ/CP (DSF ± TMZ/CP). Similarly, DSF alone or in combination with TMZ (DSF ± TMZ) and/or CP (DSF ± CP) decreased the metastatic potential of breast cancer cells.
Conclusions: Our findings suggest that DSF as dual inhibitor of MGMT and ALDH significantly enhances the antitumor effect of alkylators as CP and TMZ in ER+ breast cancer
Citation Format: George C. Bobustuc, Deborah Donohoe, Alisher Holmuhamedov, Srivenugopal Kalkunte, Santhi D. Konduri. Disulfiram, a dual MGMT and aldehyde dehydrogenase inhibitor, sensitizes ER-positive breast cancer cells to temozolomide and cyclophosphamide. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 285.
Abstract 2970: MEDI4276, a HER2-targeting antibody tubulysin conjugate, displays potent in vitro and in vivo activity in preclinical studies
Authors: Li John , Toader Dorin , Perry Samuel R. , Muniz-Medina Vanessa , Wetzel Leslie , Rebelatto Marlon C. , Masson Hinrichs Mary Jane , Fleming Ryan , Bezabeh Binyam , Thompson Pamela , Dimasi Nazzareno , Lam Brandon , Yu Xian-Qing , Gao Changshou , Dixit Rakesh , Coats Steven , Osbourn Jane , Wu Herren 
Published: July 2016

Abstract
Antibody drug conjugates (ADCs) combine the specificity of antibodies with the potent cytotoxicity of small molecule drugs and have shown to provide therapeutic options for various cancers. We report herein the discovery of a HER2-targeting ADC MEDI4276 that showed potent cell killing activity in vitro in cancer cell lines that express the HER2 receptor. The observed in vitro activity translated into in vivo tumor growth inhibition in various xenograft mouse models. MEDI4276 is a homogeneous molecule with precise control of drug loading following site specific conjugation of a cytotoxic drug. The drug in MEDI4276 is MMETA, a fully synthetic analog of the tubulysin family that showed pM potency in a panel of cancer cell lines. MMETA was conjugated to the antibody via engineered cysteines with a maleimide-bearing mc-Lys protease cleavable linker. The antibody in MEDI4276 is a bivalent biparatopic antibody targeting two distinct non-overlapping epitopes on HER2 that leads to antibody-receptor clustering following binding and thus promoting internalization, lysosomal trafficking and degradation. The combination of enhanced internalization and potent cytotoxic drug allows for this ADC to kill tumor cell populations with a broader range of HER2 expression. Preclinical studies showed that MEDI4276 induced tumor regression in HER2-positive tumor models that had developed acquired resistance to T-DM1 and in a number of models with lower HER2 expression that are refractory to T-DM1 treatment. Overall, our findings underscore the potential application of MEDI4276 to treat a large patient population that is ineligible for or relapsed/refractory to current HER2-targeted therapies. MEDI4276 is currently being investigated in a Phase I clinical trial.
Citation Format: John Li, Dorin Toader, Samuel R. Perry, Vanessa Muniz-Medina, Leslie Wetzel, Marlon C. Rebelatto, Mary Jane Masson Hinrichs, Ryan Fleming, Binyam Bezabeh, Pamela Thompson, Nazzareno Dimasi, Brandon Lam, Xian-Qing Yu, Changshou Gao, Rakesh Dixit, Steven Coats, Jane Osbourn, Herren Wu. MEDI4276, a HER2-targeting antibody tubulysin conjugate, displays potent in vitro and in vivo activity in preclinical studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2970.
Abstract 2973: CD269 - A promising target for amanitin based ADCs
Authors: Palfi Aniko , Hechler Torsten , Mueller Christoph , Pahl Andreas , Kulke Michael 
Published: July 2016

Abstract
Antitumor activity of monoclonal antibodies can be dramatically enhanced by conjugation to toxic small molecules. Beside the recent approval of Kadcyla (T-DM1) and Adcetris (SGN-35) more than 30 antibody-drug conjugates (ADC) have entered clinical trials, promising to strengthen the therapeutic capabilities for cancer treatment in the next decade. Surprisingly most ADCs are based on one of few toxic compounds only and on an even smaller number of toxicity mechanisms: Most antibodies are coupled to the microtubuli-targeting auristatins and maytansines. Toxins that operate through such a mechanism could suffer from limited activity in different cancer indications and in cells expressing resistance mechanisms. Accordingly the use of new drugs that function via alternative toxicity mechanisms could enhance the therapeutic potential of ADCs. Heidelberg Pharma focuses on Amanitin, the most well-known toxin of the amatoxin family. Amanitin binds to the eukaryotic RNA pol II and thereby inhibits the cellular transcription at very low concentrations.
In the current study, in vitro and in vivo Data of Amanitin-ADCs targeting CD269 (B cell maturation antigen) are presented. CD269 is expressed on cells of the B cell lineage, predominantly on plasma blasts and plasma cells. It is not expressed on naïve B cells, germinal center B cells and memory B-cells (Darce et al. (2007) J Immunol 179:7276-7286). CD269 is highly expressed on malignant plasma cells like multiple myeloma, a B cell non Hodgkin lymphoma of the bone marrow (Novak et al. (2004) Blood 103:689-94). Since multiple myeloma is a usually incurable malignancy of plasma cells, new therapies are urgently needed. Using ADCs in the cure of multiple myeloma could be a promising approach, especially by using a toxin whose mode of action was not applied before, like amanitin based ADCs.
In vitro data of anti-CD269-amanitin ADC showed cytotoxicity on CD269 positive cell lines in picomolar range, while up to micromolar concentrations, no cytotoxic activity on CD269 negative cells was observed. In mouse xenograft models, anti-CD269-amanitin showed clear anti-tumorigenic potential. A comprehensive data package will be presented.
Citation Format: Aniko Palfi, Torsten Hechler, Christoph Mueller, Andreas Pahl, Michael Kulke. CD269 - A promising target for amanitin based ADCs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2973.
Abstract 2995: Mechanisms of high dose ascorbate inhibiting pancreatic cancer growth and metastasis
Authors: Chen Qi , Polireddy Kishore , Dong Ruochen , Chen Ping 
Published: July 2016

Abstract
Purpose:
High-dose intravenous ascorbate (IVC) bypasses bioavailability barriers of oral ingestion and provides pharmacologic concentrations in tissues, and exhibits pro-oxidant anti-cancer activities. In pancreatic cancer pre-clinical models, ascorbate has been shown to sensitize the tumor to the 1st line chemotherapeutic drug gemcitabine. Here, we investigated the possible mechanisms of actions of ascorbate on pancreatic cancer growth and metastasis.
Methods
Orthotopic pancreatic cancer mouse model was utilized for evaluation of the effects of ascorbate in inhibiting tumor growth and metastasis. Molecular biological approaches were used in investigation the mechanisms of these effects.
Results
In the orthotopic mouse tumor model, ascorbate treatment alone decreased pancreatic cancer growth and metastasis. Ascorbate treatment enhanced expressions of epithelial markers and suppressed expression of mesenchymal markers in pancreatic cancer cells. MMP-2 expression and activity were decreased dose-dependently. Tumor tissues from ascorbate-treated mice had markedly increased collagen and desmoplasia in the extracellular matrix. Such fibrosis was not seen in normal tissues from the same mouse. In addition, ascorbate decreased the protein level of deacetylase HDAC6, and inhibited activity of the deacetylase Sirt-2 through depletion of NAD+. As a result, ascorbate robustly increased α-tubulin acetylation in pancreatic cancer cells. Acetylation promoted tubulin polymerization and stabilization, mimicking the cellular outcome of paclitaxel, resulted in inhibition of cell motility and mitosis.
Conclusion
Pharmacological concentrations of ascorbate affected pancreatic tumor cells and the tumor microenvironment, led to inhibition of tumor growth and metastasis.
Citation Format: Qi Chen, Kishore Polireddy, Ruochen Dong, Ping Chen. Mechanisms of high dose ascorbate inhibiting pancreatic cancer growth and metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2995.
Abstract 3207: Influence of tumor mutation burden on response to anti-PD-1 treatment in murine models of melanoma
Authors: Galvani Elena , Hogan Kate , Gremel Gabriela , Viros Amaya , Mandal Amit K. , Smith Matthew , Swan Jacqueline , Banyard Antonia , Ashton Garry , Dhomen Nathalie , Marais Richard 
Published: July 2016

Abstract
Therapeutic antibodies directed against immune checkpoints, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), have recently shown remarkable clinical benefits, particularly in metastatic melanoma and non-small cell lung cancer (NSCLC), cancers largely caused by chronic exposure to mutagenic agents. Recent studies have focused on identifying genomic and immune predictors of response, but consistent, robust biomarkers have yet to be fully characterized. However, some data suggests a high non-synonymous tumour mutation burden is associated with clinical benefit in melanoma patients who received anti-CTLA-4 therapy. A similar correlation was also found in NSCLC patients treated with anti-PD-1.
Using mouse models of BRAFV600E-driven melanoma, we examined the relationship between tumour mutation burden and response to the immune checkpoint inhibitor anti-PD-1. Chronic exposure to ultraviolet radiation (UVR) was used to increase the number of tumour non-synonymous single nucleotide variants (SNVs), and thus mutational load. Responses to PD-1 blockade were compared between tumours having low (∼10 SNVs) and high (&gt;100 SNVs) mutation burden and tumours were subsequently subjected to comprehensive molecular and immune profiling using whole exome sequencing, immunohistochemistry, and flow cytometry.
Our initial data suggest there is no significant correlation between tumour mutation burden and response in our model of BRAFV600E-driven melanoma, and we will present a detailed analysis of low- and high-mutation burden tumours in light of their response to PD-1 blockade. Consistent with previous studies, our results highlight that integrated molecular characterization of tumour tissue and associated microenvironment in larger cohorts is needed to identify robust determinants of response to immune checkpoint inhibitors.
Citation Format: Elena Galvani, Kate Hogan, Gabriela Gremel, Amaya Viros, Amit K. Mandal, Matthew Smith, Jacqueline Swan, Antonia Banyard, Garry Ashton, Nathalie Dhomen, Richard Marais. Influence of tumor mutation burden on response to anti-PD-1 treatment in murine models of melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3207.
Abstract 3216: Anti-PD-1, Anti-PD-L1 and Anti-CTLA-4 checkpoint inhibitor treatment leads to different responses in syngeneic tumor models
Authors: Jantscheff Peter , Schaefer-Obodozie Cynthia , Moor Sandra , Weber Holger 
Published: July 2016

Abstract
Checkpoint inhibitor treatment has already become a common therapy of various cancer types. Still there is a growing need for well-characterized preclinical mouse models, as clinical data indicate that patients only partially respond to this regiment. We examined the efficacy of anti-CTLA-4, anti-PD-1 and anti-PD-L1 therapy on 4T1, B16.F10, Clone M-3, CT26wt, LL/2, MC38-CEA and RENCA syngeneic tumor models. The outcome demonstrates a large variation in the response to the immune checkpoint therapy among the analyzed tumor models. Poorly immunogenic models like the LL/2 tumor did not respond to any given therapy, whereas highly immunogenic tumor models like CT26wt or MC38-CEA tumors were inhibited by all tested immunotherapies.
The CT26wt tumor model was further characterized in a re-challenge experiment. Growth retardation was observed in CT26wt-tumor bearing mice treated with anti-PD-L1 antibody. A fraction of mice responded with a complete regression of the tumor. These mice were repeatedly challenged subcutaneously with a high number of fresh CT26wt tumor cells. No re-growth of CT26 tumors was observed, whereas challenging with fresh 4T1 tumor cells resulted in a rapid 4T1 growth in these mice, demonstrating a specific immune protection against CT26wt tumors.
In addition all syngeneic tumor models were analyzed for the distribution of immune cells such as Treg cells, M1/M2 macrophages and M/PMN-MDSCs in tumor tissue based on multi-color flow-cytometric analysis.
These data may help to select a suitable model for testing new drug candidates and define a sensitive combination therapy to support the anti-tumor immune defense in addition to checkpoint inhibitor treatment.
Citation Format: Peter Jantscheff, Cynthia Schaefer-Obodozie, Sandra Moor, Holger Weber. Anti-PD-1, Anti-PD-L1 and Anti-CTLA-4 checkpoint inhibitor treatment leads to different responses in syngeneic tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3216.