bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1703: Nicotine-induced gemcitabine resistance is reversed by gamma-aminobutyric acid but enhanced by baclofen in pancreatic cancer xenografts and in pancreatic cancer cells in vitro
Authors: Banerjee Jheelam , Al-Wadei Hussein A. N , Al-Wadei Mohammed H. , Dagnon Koami , Schuller Hildegard M. 
Published: May 2015

Abstract
Pancreatic cancer is frequently resistant to cancer therapeutics. Smoking and alcoholism are risk factors and pancreatic cancer patients often undergo nicotine replacement therapy (NRT) and treatment for alcohol dependence. Based on our report that low dose nicotine within the range of NRT causes gemcitabine resistance in pancreatic cancer, our current study has tested the hypothesis that GABA or the selective GABA-B-R agonist baclofen used to treat alcohol dependence reverse nicotine-induced gemcitabine resistance in pancreatic cancer. Using pancreatic cancer cell lines BXPC-3 and PANC-1, our data show that GABA significantly reversed gemcitabine resistance induced by low dose nicotine in xenografts whereas baclofen did not. This effect of GABA was accompanied by decreases in cAMP, p-CREB, p-AKT, p-Src, p-ERK metalloproteinases-9 and -2 and EGR-1 and increases in cleaved caspase-3 in xenografts whereas baclofen had the opposite effects. In vitro exposure of cells to single doses or seven days of nicotine induced the protein expression of MMP-2, MMP-9 and EGR-1 and these responses were blocked by GABA. Baclofen downregulated the protein expression of GABA-B-Rs in xenograft tissues and in cells exposed to baclofen for seven days in vitro. This response was accompanied by inversed baclofen effects from inhibition of cAMP formation after single dose exposures to stimulation of cAMP formation in cells pretreated for seven days. These findings suggest GABA as a promising agent to overcome nicotine-induced gemcitabine resistance in pancreatic cancer whereas treatment of alcoholism by baclofen may increase gemcitabine resistance.
Supported by grants RO1CA130888 and RO1CA042829 with the National Cancer Institute.
Citation Format: Jheelam Banerjee, Hussein A. N Al-Wadei, Mohammed H. Al-Wadei, Koami Dagnon, Hildegard M. Schuller. Nicotine-induced gemcitabine resistance is reversed by gamma-aminobutyric acid but enhanced by baclofen in pancreatic cancer xenografts and in pancreatic cancer cells in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1703. doi:10.1158/1538-7445.AM2014-1703
Abstract 1704: Combination of Pirfenidone and Cisplatin as a potential therapeutic strategy in NSCLC
Authors: Mediavilla-Varela Melanie , Noyes David , Boateng Kingsley , Antonia Scott 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer death in the United States. Due to limited efficacy of current conventional chemotherapy, the majority of patients face poor prognosis and eventually succumb the disease. Therefore, the study of combination therapy using traditional anticancer drugs with novel therapeutic approaches is needed. Pirfenidone is a small molecule that is being used in Phase II and III clinical trials for idiopathic pulmonary fibrosis (IPF). Although it has already been approved for IPF in Europe, there is no known mechanism of action known for the drug. Recently we discovered that Pirfenidone has a detrimental effect on cancer associated fibroblasts (CAFs) as well as in non-small cell lung cancer (NSCLC) cells. Our hypothesis is that Pirfenidone, in combination with standard chemotherapy, will act synergistically and proffer a more potent therapeutic strategy for NSCLC. Our studies show that in a co-culture model there is a decrease in viability on CAFs and NSCLC cells when the combination of Pirfenidone and Cisplatin is used. Furthermore, Pirfenidone and Cisplatin were able to have an anti-tumor effect in a xenograft model of NSCLC and CAFs. In addition, insights in the mechanism by which Pirfenidone and Cisplatin induce synergy in NSCLC cells are being elucidated. Our studies show that the combination of drugs leads to an increase in phosphorylated ERK as well as a decrease in phosphorylated Akt. Thus, involving the PI3K and MAPK/ERK pathways in Pirfenidone/Cisplatin induced cell death. Our lab is the first to recognize the therapeutic potential of combining Pirfenidone and Cisplatin, as well as elucidating the mechanism of action for both drugs in NSCLC.
Citation Format: Melanie Mediavilla-Varela, David Noyes, Kingsley Boateng, Scott Antonia. Combination of Pirfenidone and Cisplatin as a potential therapeutic strategy in NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1704. doi:10.1158/1538-7445.AM2014-1704
Abstract 1708: Heparanase regulates response to chemotherapy in myeloma
Authors: Ramani Vishnu Prakash C. , Zhan Fenghuang , Tricot Guido , Sanderson Ralph D. 
Published: May 2015

Abstract
Following therapy, essentially all multiple myeloma patients relapse due to a population of chemoresistant cells leading to eventual patient death. Our lab has identified heparanase, an endoglycosidase, as a master regulator of aggressive myeloma disease. In the present study that was designed to probe the role of heparanase in chemoresistance, we made the striking finding that heparanase promotes survival of tumor cells post-therapy. Using an array of cellular viability assays, we tested for differences in viability and apoptosis between myeloma cells engineered to express high levels of heparanase (HPSE-high) and cells expressing low levels of heparanase (HPSE-low) following their exposure to frontline anti-myeloma drugs (bortezomib, carfilzomib). Results revealed a much smaller apoptotic fraction and higher cell viability following treatment of the HPSE-high cells compared to HPSE-low cells. In addition to promoting tumor survival, we also discovered that myeloma cell expression and secretion of heparanase is dramatically enhanced in response to chemotherapy. Using small molecule inhibitors, we were able to pinpoint that activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was driving the heparanase expression upon chemotherapy. The secreted heparanase generated by chemotherapy was readily taken up by tumor cells growing in culture, consistent with previous studies demonstrating that heparanase is taken up by myeloma tumor cells and that this activates aggressive tumor behavior. Extending our findings to the clinic revealed that in tumor cells from seven out of nine myeloma patients examined, there was a dramatic increase in heparanase gene expression following chemotherapy. Together, these results demonstrate a pivotal role for heparanase in regulating myeloma response to therapy and indicate that the use of heparanase inhibitors may inhibit or delay relapse in myeloma.
Citation Format: Vishnu Prakash C. Ramani, Fenghuang Zhan, Guido Tricot, Ralph D. Sanderson. Heparanase regulates response to chemotherapy in myeloma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1708. doi:10.1158/1538-7445.AM2014-1708
Abstract 1727: Development of novel TAK1 inhibitors for pancreatic cancer
Authors: Chiao Paul J. , Zhuang Zhuonan , Xia Qianghua , Schuber Paul T. , Sun Duoli , Peng Zhenghong , Maxwell David S. , Bornmann William G. 
Published: May 2015

Abstract
Transforming growth factor- (TGF-) activation kinase (TAK1, MAP3K7) is a member of MAPKKK family [1]. It was well established that TAK1 plays a key role in both TNFα and IL-1 pathway. Knock down of TAK1 impaired the activation of IKK and JNK by TNFα and IL-1 [2, 3]. NF-B activation induced by TNFα and IL-1 are severely impaired in TAK1 knock out MEF cells [4]. TAK1 acts as the kinase of IKK and therefore regulates NF-κB activation. Our previous work has demonstrated that TAK1 is upregulated and plays an important role in chemotherapeutic drug resistance in pancreatic cancer cells. Block TAK1 activity can reverse pancreatic cancer cell resistance to chemotherapeutic drug and reduce tumor size in Orthotopic Xenograft models [5]. These findings underscore the significance of TAK1 in mediating drug resistance. Strategies to target TAK1 may play a critical role in the treatment of this deadly malignancy.
Utilizing computational-based structural modeling and a recently published crystal structure of TAK1, compounds were designed to inhibit the ATP-binding pocket of the TAK1. Synthetic templates were proposed for building a urea based library of potential inhibitors. A multiple stage docking involving both pre- and post-filtering and progressively more stringent docking criteria led to approximately 1,000 structures. The resulting scores from two docking programs were fed into workflow software that combined the results and calculated ADME properties. To provide better consistency in scoring and less bias in setting the filtering cutoffs, we also included docking decoys and utilized a more statistically relevant Z-score. After application of a final binding mode filter, there were 22 structures that were selected and ranked. A seven-step synthesis was developed and a focused library of compounds was synthesized from those top-ranked compounds.
Note: This abstract was not presented at the meeting.
Citation Format: Paul J. Chiao, Zhuonan Zhuang, Qianghua Xia, Paul T. Schuber, Duoli Sun, Zhenghong Peng, David S. Maxwell, William G. Bornmann. Development of novel TAK1 inhibitors for pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1727. doi:10.1158/1538-7445.AM2014-1727
Abstract 1739: Preclinical profile of BAY 1163877 - a selective pan-FGFR inhibitor in phase 1 clinical trial
Authors: Heroult Melanie , Ellinghaus Peter , Sieg Christian , Brohm Dirk , Gruenewald Sylvia , Collin Marie-Pierre , Boemer Ulf , Lobell Mario , Huebsch Walter , Ocker Matthias , Ince Stuart , Haegebarth Andrea , Jautelat Rolf , Hess-Stumpp Holger , Brands Michael , Ziegelbauer Karl 
Published: May 2015

Abstract
Fibroblast growth factors (FGFs) orchestrate a variety of cellular functions by binding to their transmembrane tyrosine-kinase receptors (FGFR1-4) and activating downstream signaling pathways. FGF signaling has been demonstrated to be altered in a high proportion of cancers, with activating mutations and/or overexpression of FGFRs frequently observed in lung, gastric, breast and urothelial tumors. Therefore, targeting FGFRs using selective FGFR inhibitors is an attractive therapeutic approach to treat cancer patients.
BAY 1163877 is as an orally available, selective and potent inhibitor of FGFR-1, -2 and -3 kinase activity. BAY 1163877 has been advanced through preclinical development and we disclose here the first details of its preclinical profile.
BAY 1163877 inhibited FGFR-1, -2, -3 kinase activity in the nanomolar range and demonstrated a kinase selectivity profile for FGFR-1, -2 and -3 over 222 kinases tested. BAY 1163877 inhibited proliferation of various cancer cell lines in vitro and phosphorylation of downstream signaling molecules. BAY 1163877 was also tested in vivo in monotherapy and combination therapy on various human xenografts and syngeneic tumors and inhibited growth of tumors presenting at least one FGFR alteration.Overall, the in vitro and in vivo studies confirm that the FGFR inhibitor BAY 1163877 is a potent and selective inhibitor of altered FGFRs pathways in cancer models. A Phase 1 clinical trial (NCT01976741) has been initiated.
Citation Format: Melanie Heroult, Peter Ellinghaus, Christian Sieg, Dirk Brohm, Sylvia Gruenewald, Marie-Pierre Collin, Ulf Boemer, Mario Lobell, Walter Huebsch, Matthias Ocker, Stuart Ince, Andrea Haegebarth, Rolf Jautelat, Holger Hess-Stumpp, Michael Brands, Karl Ziegelbauer. Preclinical profile of BAY 1163877 - a selective pan-FGFR inhibitor in phase 1 clinical trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1739. doi:10.1158/1538-7445.AM2014-1739
Abstract 1746: Novel and selective Axl inhibitors
Authors: Zhang Zaihui , Li Rick , Lee Erica , Hu Yuxiang , Yan Jun , Sanghera Jasbinder 
Published: May 2015

Abstract
Axl is a member of the TAM tyrosine kinase family and is activated by products of Gas6 and Protein S genes. Axl is overexpressed or overactive in breast, renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma, uveal melanoma as well as in myeloid leukemias. It has also been demonstrated that Axl expression is upregulated in drug-resistant cancer cells. Knock-down of Axl by RNAi repressed tumor formation in MDA-231 breast carcinoma model. Downregulation of Axl expression by RNAi led to a decrease of K562/ADR and MCF-7/ADR cells invasion, proliferation, and increased cell chemosensitivity in vitro. In a xenograft model of MDR cells, downregulation of Axl enhanced the anticancer activity of chemotherapeutic drugs. Therefore, Axl is a potential target for the development of chemotherapeutic agents for cancer therapy. During our endeavor of discovering and developing Axl kinase inhibitors for cancer therapy, we have discovered a series of potent and selective Axl inhibitors. These new compounds have demonstrated nM potency against Axl and good selectivity against other kinases in a selected panel of kinases. Many of these new compounds can reduce the pAkt levels in several cancer cell lines in a dose dependent manner and demonstrated inhibition of cell proliferation at sub-micromolar concentration in thymidine incorporation assay. Several selected compounds have demonstrated efficacy in colony formation assays. The most promising compounds are now being selected for in vivo proof-of-concept studies. The pharmaceutical properties of these compounds together with ADME profile were also evaluated and will be reported. These new Axl inhibitors represent a new approach for cancer therapy.
Citation Format: Zaihui Zhang, Rick Li, Erica Lee, Yuxiang Hu, Jun Yan, Jasbinder Sanghera. Novel and selective Axl inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1746. doi:10.1158/1538-7445.AM2014-1746
Abstract 1750: Combined blockade of Aurora A and JAK2 kinase is highly effective at inhibiting malignant transformation
Authors: Sebti Said M. , Yang Hua , Lawrence Harshani , Kazi Aslamuzzaman , Gervaria Harsukh , Patel Ronil , Luo Yunting , Rix Uwe , Schonbrunn Ernst , Lawrence Nicholas 
Published: May 2015

Abstract
Our ongoing efforts to validate kinases for cancer therapy led to the novel finding that ectopic expression of JAK2 and Aurora A together is more effective than each alone at inducing normal cells to grow in an anchorage-independent manner and to invade. In addition, siRNA silencing or pharmacological inhibition of JAK2 and Aurora A with Ruxolitinib and Alisertib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-dependent and -independent growth and invasion as well as at inducing apoptosis. This led us to develop dual Aurora and JAK inhibitors, AJI-214 and AJI-100, which potently inhibit the activities of Aurora A, Aurora B and JAK2 in vitro. In human cancer cells, these dual inhibitors block the auto-phosphorylation of Aurora A (Thr-288) and the phosphorylation of the Aurora B substrate histone H3 (Ser-10) and the JAK2 substrate STAT3 (Tyr-705). Furthermore, AJI-214 and AJI-100 inhibit anchorage dependent and independent cell growth and invasion and induce G2/M cell cycle accumulation and apoptosis. Finally, the more soluble AJI-100 was effective at inducing tumor regression of human xenografts in mice. Taken together, our genetic and pharmacological studies indicate that targeting Aurora A and JAK2 together is a more effective approach than each alone at inhibiting malignant transformation and warrant further advanced pre clinical investigations of dual Aurora A/JAK2 inhibitors as potential anti tumor agents.
Citation Format: Said M. Sebti, Hua Yang, Harshani Lawrence, Aslamuzzaman Kazi, Harsukh Gervaria, Ronil Patel, Yunting Luo, Uwe Rix, Ernst Schonbrunn, Nicholas Lawrence. Combined blockade of Aurora A and JAK2 kinase is highly effective at inhibiting malignant transformation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1750. doi:10.1158/1538-7445.AM2014-1750
Abstract 1755: CT053PTSA, a novel c-MET and VEGFR2 inhibitor, potently suppresses angiogenesis and tumor growth
Authors: Xi Ning , Zhang Yingjun , Wang Zhaohe , Wu Yanjun , Wang Tingjin 
Published: May 2015

Abstract
Background: In many human cancers, c-Met is activated via receptor overexpression, amplification, mutation and/or a ligand-dependent autocrine/paracrine loop. c-MET-driven tumor growth and metastasis may be further stimulated by hypoxic conditions in the tumor microenvironment, which are often exacerbated by the VEGF-pathway inhibition. Therefore, blockades of c-Met and VEGFR2 simultaneously may yield synergistic inhibition on tumor growth.
Methods and Results: CT053PTSA is a potent, orally bioavailable small molecule tyrosine kinase inhibitor (TKI) against c-Met, VEGFR2 as well as Axl, Mer, and FLT3, all of which have been implicated in tumor pathogenesis. In cell-based assays, CT053PTSA showed IC50s of 6.7, 1.9 and &lt; 1.0 nM against c-Met, VEGFR-2 and Axl. In cell-based functional assays, CT053PTSA inhibited HGF and VEGF-stimulated HUVEC proliferation and microvascular angiogenesis in rat aortic rings with IC50 values of 8.6 and 6.3 nM, respectively. When single dosed orally (3mg/kg) to U87MG tumor-bearing nude mice, CT053PTSA potently inhibited the phosphorylation of c-Met and its downstream signaling kinases AKT and ERK1/2 for up to 6 hours in tumor tissues.
The antitumor efficacy of CT053PTSA was evaluated in human tumor subcutaneous xenograft models in athymic mice, which included Caki-1 (kidney carcinoma), U-87MG (glioblastoma), NCI-H441 (lung adenocarcinoma), MDA-MB-231 (breast adenocarcinoma), SMMC-7721 (hepatoma), 5637 (bladder carcinoma) and SK-OV-3 (ovarian carcinoma). The ED50s of CT053PTSA to inhibit tumor growth in these studies ranged from &lt; 1mg/kg (NCI-H441) to ∼ 6 mg/kg (SMMC-7721). In orthotopic U87MG human glioblastoma xenograft model, CT053PTSA prolonged the median survival time (MST) and yielded significant increase in life-span value (ILS = 32%, p = 0.003) at an oral dose of 20 mg/kg/day (dosed 21 days) versus the vehicle-treated group.
Conclusions: CT053PTSA displayed excellent oral bioavailability (&gt; 60% across animal species) and desirable drug exposures in mice, rats, dogs and monkeys. Based on its potent antitumor activity, favorable PK profile and toxicological data, CT053PTSA was granted to enter clinical trials in China and is currently under phase I evaluation as a potential treatment for human malignancies.
Citation Format: Ning Xi, Yingjun Zhang, Zhaohe Wang, Yanjun Wu, Tingjin Wang. CT053PTSA, a novel c-MET and VEGFR2 inhibitor, potently suppresses angiogenesis and tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1755. doi:10.1158/1538-7445.AM2014-1755
Abstract 1764: Inhibition of R-spondin (RSPO) signaling reduces the growth of multiple human tumors
Authors: Gurney Austin , Axelrod Fumiko , Bond Chris , Cain Jennifer , Chartier Cecile , Fischer Marcus , Ji May , Murriel Chris , Raval Janak , Shah Jalpa , Wang Min , Yen Wan-Ching , Kapoun Ann , Lewicki John , Hoey Timothy 
Published: May 2015

Abstract
Deregulation of the canonical Wnt/beta-catenin signaling pathway has long been associated with cancer. Intracellular components of this pathway, including Axin, APC, and beta-catenin are frequently mutated in a range of human tumors. The identity of specific extracellular ligands that contribute to human cancer development through this signaling axis has remained unclear. Molecular characterization of the secreted beta-catenin signaling activities produced by minimally passaged human tumor xenograft models identified RSPO family members produced by multiple tumor types including ovarian, pancreatic, colon, breast and non-small cell lung cancer. In human tumor xenograft models that had RSPO overexpression, in some instances due to genomic translocation, anti-RSPO treatment markedly inhibited tumor growth. In addition, striking combination activity with standard of care chemotherapy agents resulted in regression of established tumors. These results highlight the potential for therapeutic intervention with this newly appreciated signaling axis.
Citation Format: Austin Gurney, Fumiko Axelrod, Chris Bond, Jennifer Cain, Cecile Chartier, Marcus Fischer, May Ji, Chris Murriel, Janak Raval, Jalpa Shah, Min Wang, Wan-Ching Yen, Ann Kapoun, John Lewicki, Timothy Hoey. Inhibition of R-spondin (RSPO) signaling reduces the growth of multiple human tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1764. doi:10.1158/1538-7445.AM2014-1764