bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 675: Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia
Authors: Kuenzi Brent M. , Remsing Rix Lily L. , Kunigal Sateesh S. , Kinose Fumi , Knezevic Claire E. , Wright Gabriela , Kroeger Jodi L. , Lancet Jeffrey E. , Padron Eric , Rix Uwe 
Published: August 2015

Abstract
GSK3 alpha has been shown to be a new target in the treatment of acute myeloid leukemia (AML); however current GSK3 inhibitors are unselective and target both GSK3 alpha and GSK3 beta. Interestingly, a known pan-GSK3 inhibitor LiCl has been previously investigated for the treatment of AML yet has met limited clinical success. This could be partly due to the fact that pan-GSK3 inhibition results in beta-catenin stabilization, which has been shown to mediate hematopoietic self-renewal and leukemogenesis. As beta-catenin stabilization requires inhibition of both kinases and most GSK3 inhibitors target GSK3 alpha and GSK3 beta with equal potency, these compounds may possess some significant limitations. We have previously shown GSK3 alpha to be a prominent target of the intended MET inhibitor tivantinib (ARQ197) and that tivantinib shows some specificity for GSK3 alpha over GSK3 beta. We thus hypothesized that tivantinib would be an effective therapy for the treatment of AML. Consistently, tivantinib potently inhibited cellular viability across several AML cell lines. Using an unbiased, mass-spectrometry based chemical proteomics approach; we confirmed GSK3 alpha (and to a slightly lesser extent GSK3 beta) to be targeted by tivantinib in AML. Tivantinib strongly induced apoptosis as compared to the pan-GSK3 inhibitor LiCl in these cells while LiCl showed larger effects on cell differentiation. Interestingly tivantinib caused less stabilization of beta-catenin as compared to LiCl. Subsequent drug combination studies identified the Bcl-2 inhibitor ABT-199 to synergize with tivantinib and to amplify apoptosis as seen by PARP1 cleavage. Furthermore, the combination of tivantinib with ABT-199 completely abrogated beta-catenin stabilization. Tivantinib was able to significantly inhibit colony formation of primary AML patient bone marrow mononuclear cells (BMNCs) and ABT-199 combination showed significant benefit over tivantinib or ABT-199 alone. In summary, tivantinib has potent anticancer activity in AML based on targeting GSK3 alpha; and tivantinib single agent or combination with ABT-199 may represent a novel and exciting opportunity for the treatment of AML.
Citation Format: Brent M. Kuenzi, Lily L. Remsing Rix, Sateesh S. Kunigal, Fumi Kinose, Claire E. Knezevic, Gabriela Wright, Jodi L. Kroeger, Jeffrey E. Lancet, Eric Padron, Uwe Rix. Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia. [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 675. doi:10.1158/1538-7445.AM2015-675
Abstract 682: Targeting heat shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer
Authors: Liu Hanqing , Lu Jian , Hua Ye , Zhang Peishan , Liang Zhiquan , Ruan Lingling , Lian Caixia , Shi Haifeng , Chen Keping , Tu Zhigang 
Published: August 2015

Abstract
Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, due to its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib dramatically reduced growth of MGC-803 and also significantly inhibited growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected EGFR signaling cascades by dramatically decreasing levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, while SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Though SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of H&E staining, TUNEL assays, and immunohistochemistry staining of pCDK1, EGFR, and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR.
Note: This abstract was not presented at the meeting.
Citation Format: Hanqing Liu, Jian Lu, Ye Hua, Peishan Zhang, Zhiquan Liang, Lingling Ruan, Caixia Lian, Haifeng Shi, Keping Chen, Zhigang Tu. Targeting heat shock protein 90 with ganetespib for molecularly targeted therapy of gastric 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 682. doi:10.1158/1538-7445.AM2015-682
Abstract 701: A novel class of Ras selective inhibitors
Authors: Canzoneri Joshua C. , Chen Xi , Keeton Adam B. , Lee Kevin , Gary Bernard , Butler Ethan B. , Grizzle William E. , Wilson Landon , Barnes Stephen , Boyd Michael R. , Piazza Gary A. 
Published: August 2015

Abstract
Despite the fact that activating mutations in the various forms of Ras were identified as driving factors in oncogenesis over thirty years ago, there are still no effective therapeutics which act on this target. We recently synthesized and characterized a novel class of compounds that show striking potency and selectivity to inhibit the growth of tumor cells with mutant Ras. Through iterative structure-activity studies, we selected for and optimized Ras selectivity to achieve high potency with IC50 values in the low nanomolar range and selectivity indices of nearly 100-fold. For example, ADT-062 inhibited the growth of human HCT116 colon tumor cells that harbor mutant K-Ras with an IC50 value of 8.4 + 3.6 nM,. In contrast, human HT29 colon tumor cells that have wild type Ras displayed an IC50 value of 521 + 253 nM in response to ADT-062 treatment. When surveying a larger panel of colon tumor cell lines, we observed a direct correlation between potency and Ras activation status. Further, ADT-062 induced cell cycle arrest only in the Ras-mutant cell line. To study the mechanism by which this class of compounds selectively inhibits the growth of tumor cells with mutant K-Ras, we profiled lysates from treated HCT116 and HT29 colon tumor cells using high resolution LC-MS/MS. Over 100 ions were identified that were differentially affected by treatment with ADT-062 at its IC50 value in the respective cell line. Among the ions of interest, a component of the purine biosynthetic pathway, 5′-phosphoribosyl-N-formylglycinamide (FGAR), was found to be induced 200-fold (p = .0031) in K-Ras mutant cells compared with Ras wild type cells. Together, these findings suggest that this compound may cause a Ras selective disruption of purine metabolism and cell cycle progression which contributes to the selectivity by which this novel class of compounds inhibit the growth of tumor cells with mutant Ras. These findings may enable us to develop this compound class as a novel therapeutic which targets Ras driven tumors and tumors which may become resistant to other targeted therapeutics through secondary Ras mutations.
Citation Format: Joshua C. Canzoneri, Xi Chen, Adam B. Keeton, Kevin Lee, Bernard Gary, Ethan B. Butler, William E. Grizzle, Landon Wilson, Stephen Barnes, Michael R. Boyd, Gary A. Piazza. A novel class of Ras selective inhibitors. [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 701. doi:10.1158/1538-7445.AM2015-701
Abstract 710: CRP induction in tamoxifen-resistant breast cancer cells
Authors: Choi Min Chang , Moon Aree , Kang Keon Wook 
Published: August 2015

Abstract
Breast cancer is one of the most common cancer types among post-menopausal women. Tamoxifen has been known as the most effective therapeutic option for estrogen receptor-positive breast cancer. One of the main issues of breast cancer is acquisition of tamoxifen resistance, and if it does, the way to treat tamoxifen-resistant breast cancer has not been discovered. It has been recently suggested that c-reactive protein (CRP), inflammatory marker found in many diseases may be related to breast cancer progression. Here, we found that tamoxifen-resistant breast cancer (TAMR-MCF-7) cells expresses much higher protein and mRNA level of CRP compared to parent breast cancer (MCF-7) cells. CRP knock-down by lentiviral shRNA did not affect cell proliferation rate of TAMR-MCF-7 cells. One of the main characteristics of tamoxifen-resistant breast cancer is higher migratory ability. Through trans-well migration assay, we have discovered that CRP alone increases migratory function of MCF-7 cells. Moreover, CRP knock-down significantly reduced cell migration of TAMR-MCF-7 cells. It has been recently reported that sphingosine-1-phosphate (S1P) induces CRP in mammary epithelial cells and ultimately causes cancer cell transformation. S1P treatment increased CRP expression in MCF-7 cells. Protein expression of sphingosine kinase (Sphk) 1 and 2, which catalyzes conversion of sphingosine to S1P, was also increased in TAMR-MCF-7 cells. Among five S1P receptors, we also discovered that S1P receptor 3 (S1Pr3) is related with CRP induction in TAMR-MCF-7 cells. Taken together, tamoxifen-resistant breast cancer expresses high level of CRP and S1P-S1Pr3 plays a key role in CRP induction in TAMR-MCF-7 cells. Higher levels of CRP increases migratory function of tamoxifen-resistant breast cancer cells. CRP may be an important therapeutic target for the treatment of tamoxifen-resistant breast cancer.
Citation Format: Min Chang Choi, Aree Moon, Keon Wook Kang. CRP induction in tamoxifen-resistant 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 710. doi:10.1158/1538-7445.AM2015-710
Abstract 714: Cbl-b Inhibits p-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers
Authors: Zhang Ye , Qu Xiujuan , Teng Yuee , Xu Ling , Liu Jing , Li Zhi , Hu Xuejun , Liu Yunpeng 
Published: August 2015

Abstract
Background The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown.
Methods Immunofluorescence microscopy and proximity ligation assays were used to analyze the translocation of P-gp into caveolae. Nude mice (n = 7 mice per group) were injected with SGC7901/Adr vector, SGC7901/Adr + Cbl-b cells and/or Dox and tumor growth was assessed. Immunoprecipitation and western blotting were used to examine the effects of Cbl-b mediated ubiquitination and degradation of c-Src. Immunochemistry was performed on primary tumor specimens from breast cancer patients (n = 319) to determine the relationship of Cbl-b with overall survival.
Results c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance (MDR) in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae, resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy.
Conclusions Our findings reveal a new regulatory mechanism of P-gp transport function.
Citation Format: Ye Zhang, Xiujuan Qu, Yuee Teng, Ling Xu, Jing Liu, Zhi Li, Xuejun Hu, Yunpeng Liu. Cbl-b Inhibits p-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers. [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 714. doi:10.1158/1538-7445.AM2015-714
Abstract 729: The role of skp2 in paclitaxel-resistant prostate cancer cells
Authors: Yang Yeguo , Song Qiong , Lu Yi , Zhang Jian , Fu Jiejun 
Published: August 2015

Abstract
Prostate cancer is the most common cancer and the second most frequent cause of cancer-related death of men in the United States. It has been shown that the F-box protein Skp2(S-phase kinase associated protein 2) plays an important role in the development and progression of prostate cancer. The molecular mechanism responsible for paclitaxel-resistant in prostate cancer cells remain unclear. Interestingly, we found that the expression of Skp2 is higher in the paclitaxel-resistant prostate cancer cells DU145-TXR or PC-3-TXR compared with their parental cells DU145 or PC-3 respectively.This study was aimed to investigate the role of Skp2 in prostate cancer cell resistance to paclitaxel and the progress of epithelial-to-mesenchymal transition(EMT). Skp2 encoding plasmid was stably transfected into PC-3 and DU145 cells. Meanwhile, Skp2 was silenced by shRNA in DU145-TXR or PC-3-TXR cells. MTS assay was used to measure the cytotoxicity effect of Skp2 overexpression or knockdown of Skp2 in cells after treatment with paclitaxel. We found that when downregulating Skp2 in DU145-TXR and PC-3-TXR, the cells showed a more sensitive response to paclitaxel. Moreover, Overexpression of Skp2 enhances prostate cancer cells resistance to paclitaxel. EMT markers E-cadherin was decreased while vimentin was increased in PC-3-TXR or DU145-TXR cells. The further study showed that when downregulating Skp2 in PC-3 or DU145, the expression of E-cadherin was increased. However, E-cadherin has no significant change when knockdown of Skp2 in PC-3-TXR or DU145-TXR cells. CyclinD1, P21 and P27 were found to increase while CyclinB1 and CyclinE2 to decrease when downregulating Skp2 in PC-3-TXR or DU145-TXR cells. These data provide evidence that Skp2 is associated with prostate cancer cell resistance to paclitaxel. Skp2 could be a potential therapeutic target for prostate cancer. This study is supported by NSFC key project 81130046, NSFC projects 81201669, 81171993 and 81272415.
Note: This abstract was not presented at the meeting.
Citation Format: Yeguo Yang, Qiong Song, Yi Lu, Jian Zhang, Jiejun Fu. The role of skp2 in paclitaxel-resistant prostate 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 729. doi:10.1158/1538-7445.AM2015-729
Abstract 732: Using functional and chemical genomics to identify mechanisms of Enzalutamide resistance in prostate cancer
Authors: Jeganathan Sujeeve , Zoubeidi Amina , Gleave Martin , Wouters Brad G. , Joshua Anthony M. 
Published: August 2015

Abstract
Introduction: Enzalutamide is a recently approved potent androgen receptor antagonist for prostate cancer both in the pre- and post-docetaxel settings. Its action relies upon 3 defined mechanisms of action: 1) blocking testosterone binding to the androgen receptor (AR), 2) preventing nuclear translocation of AR, and 3) inhibiting AR-DNA binding. However, despite its utility in prolonged overall survival in both these settings, disease relapse is inevitable, suggesting that resistance to the drug is somehow being acquired and is of vital concern.
Methods: Using a combination of high-throughput functional genomic (kinome-shRNA) and chemical genomic (pharmacological inhibitor) screens, along with various in vitro / in vivo assays (proliferation, apoptosis, necrosis, soft agar growth, etc.) we have identified the IkB kinase (IKK) / IkB / NFkB signaling axis as important for acquisition of, and continued resistance to, Enzalutamide.
Results: Using a panel of Enzalutamide-resistant and -sensitive cell lines, we show that targeting this signaling axis will selectively kill Enzalutamide-resistant cells while not affecting the proliferation of sensitive cells. Moreover, our data shows that the pharmacological inhibitors and shRNAs are effective even without Enzalutamide administration, negating any potential drug-drug interaction issues. Finally, we have found that our cells are resistant to Enzalutamide in an AR-V7-independent manner, suggesting that NFkB signaling is acting in a novel manner to bring about the resistance phenotype.
Conclusions: Through in vitro and in vivo experiments, we provide evidence that targeting activators of NFκB signalling can be a strategy to help patients with Enzalutamide-resistant prostate cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Sujeeve Jeganathan, Amina Zoubeidi, Martin Gleave, Brad G. Wouters, Anthony M. Joshua. Using functional and chemical genomics to identify mechanisms of Enzalutamide resistance in prostate 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 732. doi:10.1158/1538-7445.AM2015-732
Abstract 739: Tumor cell plasticity with transition to a mesenchymal phenotype is a mechanism of chemoresistance that is reversed by Notch pathway inhibition in lung adenocarcinoma
Authors: Hassan Khaled A. 
Published: August 2015

Abstract
Background: Lung cancer is the leading cause of cancer death in the world, mainly due to complex genetic events that characterize lung cancer, tumor heterogeneity and resistance to traditional and targeted treatments. Resistance may be explained by passive clonal selectivity, however, the propensity and variability of resistance suggests an active process of tumor plasticity. We hypothesize that tumor cells undergo an epithelial to mesenchymal transition as a mechanism of resistance to chemotherapy.
Results: The lung adenocarcinoma cell lines NCI-H1299, NCI-H358, and NCI-H441 were exposed to gradually increasing doses of docetaxel over 12-16 weeks. Chemoresistance emerged with a 10-15X increase in IC50 as compared to parental cells. With each treatment dose increase more than 50% of cells remained alive, suggesting bulk cell transformation. This resistance has been maintained for more than 20 generations after withdrawal of docetaxel. Morphologically, NCI-H358 and NCI-H441 chemoresistant cell lines lost their cobblestone architecture becoming more spindle-shaped. Using RT-PCR assays, there was increased expression of mesenchymal-related genes, vimentin (2.5-3.5X), twist (2-4X) and decreased expression of epithelial-related genes such as E-CAD (2-5X). Our previous data suggested that Notch activity plays a significant role in the EMT process, thus we evaluated Notch downstream genes expression by RT-PCR. We detected increase expression of Hey2 (2.5-3.5X), in NCI-H358 and NCI-H441 resistant cell lines as compared to parental cells. When chemoresistant cell lines were exposed to gamma secretase inhibitor, a Notch inhibitor, they became less invasive, epithelial-like and sensitive to docetaxel.
Conclusion: These data suggest that tumor cell plasticity with transition to a mesenchymal phenotype is a mechanism of chemotherapy resistance that is controlled through the Notch pathway. Inhibiting Notch activity induces mesenchymal to epithelial transition and re-sensitizes cells to chemotherapy. Notch inhibition in combination with standard chemotherapy represents a potential approach to achieve better disease control.
Citation Format: Khaled A. Hassan. Tumor cell plasticity with transition to a mesenchymal phenotype is a mechanism of chemoresistance that is reversed by Notch pathway inhibition in lung adenocarcinoma. [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 739. doi:10.1158/1538-7445.AM2015-739
Abstract 741: Anti-tumor activity and acquired resistance mechanism of dovitinib in RET-rearranged lung adenocarcinoma
Authors: Kang Chan Woo , Jang Kang Won , Cho Byoung Chul 
Published: August 2015

Abstract
Background:
RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib, a potent inhibitor of FGFR, VEGFR, and PDGFR, on RET-rearranged LADC is not known. This aims of the study are to explore anti-tumor effects and mechanism of acquired resistance of dovitinib in RET-rearranged LADC.
Results:
Dovitinib potently induced cell cycle arrest in G1 phase and dose-dependent suppression of phosphorylation of RET and ERK in LC-2/ad LADC cells harboring CCDC6-RET rearrangement. Selective inhibition of dovitinib on autophosphorylation of RET kinases was confirmed in HEK293 cells expressing KIF5B-RET or CCDC6-RET. In Human RTK array, dovitinib did not show significant inhibition of phosphorylation on FGFR or VEGFR in LC-2/ad cells. Dovitinib exhibited growth inhibition of LC-2/ad cells more efficiently than vandetanib, sunitinib, and sorafenib, which was confirmed in vivo xenograft models. To identify the acquired resistance mechanism, we established resistant cells to dovitinib (LC-2/ad DR) from LC-2/ad cell line. Knockdown of RET or dovitinib did not inhibit RET-induced ERK phosphorylation in LC-2/ad DR cells. Using microarray and immunoblotting, we confirmed aberrant focal adhesion kinase signaling, including c-Src. Dasatinib, a Src inhibitor, suppressed ERK phosphorylation and growth of LC-2/ad DR cells.
Conclusion:
Dovitinib can be a potential therapeutic option for RET-rearranged LADC. Acquired resistance to dovitinib can be overcome by targeting SRC.
Citation Format: Chan Woo Kang, Kang Won Jang, Byoung Chul Cho. Anti-tumor activity and acquired resistance mechanism of dovitinib in RET-rearranged lung adenocarcinoma. [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 741. doi:10.1158/1538-7445.AM2015-741