bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4541: Dual targeting of CDK4 and MEK as a combination treatment strategy for metastatic colorectal cancer
Authors: Ziemke Elizabeth , Dosch Joseph , Shettigar Amrith , Wan Shanshan , Welling Theodore , Hardiman Karin , Sebolt-Leopold Judith 
Published: May 2015

Abstract
Aberrant hyperactivation of KRAS plays a prominent role in tumor initiation and progression of a broad spectrum of human malignancies. The incidence of KRAS mutations is especially high in colorectal cancers, where it occurs at a frequency of roughly 50%. The present study addresses the hypothesis that dual targeting of CDK4 and MEK represents a viable treatment strategy for the subpopulation of colorectal cancers exhibiting hyperactivated KRAS signaling. We have generated both in vitro and in vivo data in highly passaged colorectal xenograft models to provide compelling support for further exploration of this combination treatment strategy. We have now turned to the study of primary human models that are anticipated to be more predictive of ultimate clinical activity in patients. A heterogeneous panel of low passage colorectal patient-derived xenografts (PDX) has been established from biospecimens procured during patient surgeries conducted at our institution (n=12). All xenograft models have been genomically profiled and their histologies mimicked those observed in the original samples. As anticipated, approximately half of these models harbor an oncogenic KRAS mutation and exhibit widely differing histologies, consistent with the heterogeneity encountered in the clinic. Immunoblotting analysis has further revealed that that the majority (&gt;80%) are positive for both phosphorylated RB and constitutive pERK expression and are therefore candidates for treatment regimens combining inhibitors of CDK4 and MEK. Employing the CDK4 inhibitor palbociclib and multiple MEK inhibitors, in vivo efficacy studies are ongoing against our colorectal PDX panel. Preliminary data have shown a higher frequency of regressions in the combination arm compared to either single agent arm at the respective maximum tolerated doses. Our results therefore suggest that combined inhibition of CDK4 and MEK may provide an attractive therapeutic strategy for the treatment of colorectal cancer.
Citation Format: Elizabeth Ziemke, Joseph Dosch, Amrith Shettigar, Shanshan Wan, Theodore Welling, Karin Hardiman, Judith Sebolt-Leopold. Dual targeting of CDK4 and MEK as a combination treatment strategy for metastatic colorectal 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 4541. doi:10.1158/1538-7445.AM2014-4541
Abstract 4545: Anticancer effects and mechanism of VR23, a novel chloroquine derivative
Authors: Vu Hai-Yen Thi , Pundir Sheetal , Solomon Raja V. , Lee Hoyun 
Published: May 2015

Abstract
Chloroquine, a worldwide used drug in treatment of malaria, rheumatoid and other human diseases, has recently been focused as a potential anti-cancer drug as well as a chemo-sensitizer when given in combination with other anti-cancer drugs. In cancer treatment, chloroquine possesses a major potential therapeutic advantage in which it specifically targets cancer cells. Unfortunately, however, its anticancer activity is rather low. To further improve its efficacy and specificity in killing cancer cells, we created and characterized several chloroquine derivatives using a hybrid pharmacophore approach, which led us to identify VR23 as the most promising compound. Our in-vitro model of cancer cells shows that VR23 functions as a novel proteasome inhibitor. It also deregulates activity of cyclin E and other centrosomal proteins, resulting in induction of multiple centrosome amplification, abnormal spindle formation, uneven cytokinesis, irreversible mitotic arrests, and eventually apoptosis. These VR23-induced phenomena occur in cancer-specific manner and cause massive death in a variety of cancer cell types. The treatment of engrafted animals with VR23 (30 mg/kg) twice per week for three weeks effectively inhibits tumor growth. Interestingly, administration of VR23 following 24 hours pre-treatment with paclitaxel (20mg/kg/week) enhances paclitaxel's anti-tumor activity by 70%. Our histological data shows that VR23 causes substantial decrease in mitotic index, inhibition of tumor infiltration into surrounding tissues and remarkable reduction of tumor cell proliferation and angiogenesis. Most importantly, VR23 shows very low toxicity to vital organs (liver, spleen, kidney and lung) of non-tumor-bearing nude mice. In addition, VR23 seems to reduce paclitaxel-induced toxicity when used in combination. Taken together, VR23, our novel chloroquine derivative and newly discovered proteasome inhibitor, appears to be an effective and safe anticancer therapeutic alone or in combination with other anticancer agents.
Citation Format: Hai-Yen Thi Vu, Sheetal Pundir, Raja V. Solomon, Hoyun Lee. Anticancer effects and mechanism of VR23, a novel chloroquine derivative. [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 4545. doi:10.1158/1538-7445.AM2014-4545
Abstract 4554: Downstream effects of rigosertib (ON 01910.Na) in cancer cells involves impairment of protein translation via eIF2 and eIF4
Authors: Merali Salim , Perez-Leal Oscar , Barrero Carlos 
Published: May 2015

Abstract
Purpose: Rigosertib, a novel synthetic styryl benzyl sulfone, is cytotoxic against a variety of human tumor cell lines in vitro and in vivo. Significantly, rigosertib is currently being tested in a randomized phase III clinical trial in patients with higher risk myelodysplastic syndrome (MDS) who have failed treatment with hypomethylating agents. Previous studies have shown that rigosertib interacts with both the phosphoinositide 3-kinase (PI3K) and polo-like kinase (PLK1) pathways. Because these pathways can affect several cellular functions, we used a combination of unbiased global proteomics and interactomics approaches to assemble a rigosertib target profile. Here, we confirm and elaborate the pathways modulated by rigosertib.
Experimental Design: Stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics was used to identify the differentially expressed proteins in HeLa cells with and without 8 hours of treatment with 10 μM rigosertib. In addition, rigosertib protein interaction (interactomics) studies were performed to validate the proteomics observations.
Results: Using a combination of SILAC and subcellular fractionation we were able to quantify more than 1500 proteins, among which 125 were significantly altered by rigosertib treatment. Quantified proteins were selected and clustered by biological function. We performed pathway and network analysis using Ingenuity® Systems computational pathway analysis. The pathways that were identified at statistically significant levels (p &lt; 0.05) were eukaryotic initiation factor (eIF2) signaling, eIF4 signaling and nuclear erythroid factor 2 (Nrf2)-mediated oxidative stress response. In total, 19 proteins were down-regulated and 2 proteins were up-regulated in the eIF2 signaling pathway, suggesting that rigosertib represses protein translation in tumor cells. These observations have been noted in other experimental systems using different experimental approaches. To validate these findings and to determine extent of interaction of these proteins with rigosertib, we used drug affinity pull-down followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis to confirm that rigosertib interacts with eIF2 and eIF4 via Raf and p70S6K, respectively.
Conclusions: Collectively, these results demonstrate that a terminal effect of rigosertib in cancer cells is the inhibition of protein translation mediated by eIF2 and eIF4.
Citation Format: Salim Merali, Oscar Perez-Leal, Carlos Barrero. Downstream effects of rigosertib (ON 01910.Na) in cancer cells involves impairment of protein translation via eIF2 and eIF4. [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 4554. doi:10.1158/1538-7445.AM2014-4554
Abstract 4562: Ginkgetin inhibits the growth of cancer cells via the cell cycle arrest at G2-phase
Authors: Kwon Byoung-Mog , Lee Yu-Jin 
Published: May 2015

Abstract
Ginkgetin, isolated from herbal medicines, has been reported to play a role in antitumor activity. However, the relevant pathway integrating cell cycle regulation and signaling pathways involved in growth inhibition in cancer cells remains to be identified. In the present study, ginkgetin treatment of colon cancer cells resulted in significant dose-dependent growth inhibition together with apoptosis, G2-phase cell cycle arrest at a 5 μM (IC50) dose in HCT116colon cancer cells and ginkgetin also inhibits tumor growth in a mouse xenograft model of HCT116 cells. We found that ginkgetin regulated the expression of genes which are critically involved in cell cycle, cell signaling transduction, and cell proliferation using DNA microarray analysis. Furthermore, we provided evidence that ginkgetin inhibited BUB3, cyclin B, CDC2, and b-Myb expression. Especially ginkgetin induced G2-phase arrest by down-regulates expression of b-Myb Our data have suggested that ginkgetin exerts its anticancer effects through induction of cell cycle arrest at G2 phase as well as inhibition cell proliferation.
Note: This abstract was not presented at the meeting.
Citation Format: Byoung-Mog Kwon, Yu-Jin Lee. Ginkgetin inhibits the growth of cancer cells via the cell cycle arrest at G2-phase. [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 4562. doi:10.1158/1538-7445.AM2014-4562
Abstract 487: The Integrated Stress Response kinase GCN2 regulates cell proliferation and survival through combined transcriptional and translational control of p21 (Cip1/Waf1)
Authors: Lehman Stacey L. , Ye Jiangbin , Koumenis Constantinos 
Published: May 2015

Abstract
The tumor microenvironment is often characterized by deficiencies in nutrients, such as oxygen, glucose, and amino acids. Activation of the nutrient-sensing kinase GCN2, which constitutes one arm of the Integrated Stress Response (ISR), is one mechanism by which tumor cells cope with and adapt to nutrient stress. GCN2 phosphorylates the alpha subunit of eukaryotic translation initiation factor eIF2, leading to global downregulation of translation to conserve amino acids and initiation of a transcriptional program through ATF4 to promote recovery from nutrient deprivation. Loss of GCN2 results in decreased tumor cell survival in vitro under conditions of amino acid deprivation and attenuated tumor growth in vivo in a variety of implanted animal tumor models. Our recent studies have shown that amino acid deprivation induces the cell cycle inhibitor p21 in a GCN2-dependent manner. GCN2 regulates p21 at both the transcriptional and translational level. Upregulation of p21 results in cell cycle arrest and promotes survival under amino acid deprivation. In agreement with a pro-survival role, we observe p21 upregulation concomitant with ISR activation in a genetically engineered mouse model of soft tissue sarcoma. These findings point to a novel mechanism of p21 regulation in order to coordinate cell division with nutrient availability.
Research supported by NCI R01CA094214.
Citation Format: Stacey L. Lehman, Jiangbin Ye, Constantinos Koumenis. The Integrated Stress Response kinase GCN2 regulates cell proliferation and survival through combined transcriptional and translational control of p21 (Cip1/Waf1). [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 487. doi:10.1158/1538-7445.AM2014-487
Abstract 5010: Osteoblasts-derived WISP-1 increases prostate cancer metastasis through VCAM-1 upregulation
Authors: Chang An-Chen , Wang Shih-Wei , Tang Chih-Hsin 
Published: May 2015

Abstract
The skeleton is the most common metastatic site for prostate cancer, and increases the risk of intractable bone pain. Therefore, study of the interactions between prostate cancer and the bone microenvironment is very important. Wnt-1 induced secreted protein 1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV), which plays an important role in bone formation and many cellular processes. However, the effects of WISP-1 on the prostate cancer metastasis are not clearly understood. First, we found that WISP-1 presents in osteoblast-condition medium (OB-CM), which increases prostate cancer cell migration and invasion. In addition, OBs were infected with lentivirus containing human WISP-1 shRNA which reduced OB-CM-mediated prostate cancer metastasis. We also demonstrated that OB-derived WISP-1 enhanced cell migration via vascular cell adhesion molecule 1(VCAM-1) up-regulation in prostate cancer. Transfection of cells with VCAM-1 siRNA reduced OB-CM and WISP-1-mediated cell migration. The incresing of prostate cancer cell migration by OB-derived WISP-1 is associated with FAK and p38 activation, as well as mir-126 downregulation. Pretreatment of cells with FAK and p38 inhibitors reduced WISP-1-mediated cell migration. In contrast, WISP-1-mediated migration activity was inhibited by mir-126 mimic. Over all, we characterized an important role for OB-derived WISP-1 which regulates cell migration and invasion by increasing VCAM-1 expression in human prostate cancer via the activation of FAK, p38 and downregulation of mir-126 signaling pathway.
Citation Format: An-Chen Chang, Shih-Wei Wang, Chih-Hsin Tang. Osteoblasts-derived WISP-1 increases prostate cancer metastasis through VCAM-1 upregulation. [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 5010. doi:10.1158/1538-7445.AM2014-5010
Abstract 5466: The Mdm2 inhibitor, NVP-CGM097, in combination with the BRAF inhibitor NVP-LGX818 elicits synergistic antitumor effects in melanoma
Authors: Wang Hui Qin , Zubrowski Matthew , Emerson Erling , Pradhan Elina , Jeay Sébastien , Wiesmann Marion , Caponigro Giordano , Wuerthner Jens , Schlegel Robert , Cao Z. Alexander , Huang Alan , Halilovic Ensar 
Published: May 2015

Abstract
RAF kinase inhibitors have shown substantial therapeutic effects in patients with BRAF-mutant melanoma. However, despite impressive initial responses, therapeutic effects are often temporary due to acquired resistance. This resistance highlights the need to identify therapeutic approaches to improve the durability of responses to RAF inhibitors. In this study, we demonstrate that a novel inhibitor of p53-Mdm2 interaction, NVP-CGM097, causes marked reduction of melanoma cell viability. The activation of p53 signaling and consequent reduction in cell viability required wild-type p53, but was independent of BRAF status. Moreover, combined inhibition of Mdm2, using NVP-CGM097, and BRAF using NVP-LGX818, synergistically inhibited the viability of BRAF mutant melanoma cells in vitro and tumor growth in vivo. NVP-CGM097 caused induction of p21 and Bax, while NVP-LGX818 did not. Instead, NVP-LGX818 caused induction of p27 and Bim. Therefore, together they induced a complementary set of anti-proliferative and apoptosis stimulating molecules, which resulted in strong synergistic antitumor effects. In vivo, the combination treatment resulted in sustained tumor regressions and markedly prolonged survival relative to either single agent. Collectively, these data show that activation of p53, through inhibition of Mdm2, leads to antitumor effects in melanoma. Furthermore, the data show that concomitant activation of tumor suppressor p53 and inhibition of BRAF synergistically suppresses melanoma growth. Therefore, combined inhibition of Mdm2 and BRAF in melanoma may provide an effective therapeutic modality capable of overcoming the resistance observed with the BRAF inhibitor monotherapy and thus lead to more durable responses in the clinic.
Citation Format: Hui Qin Wang, Matthew Zubrowski, Erling Emerson, Elina Pradhan, Sébastien Jeay, Marion Wiesmann, Giordano Caponigro, Jens Wuerthner, Robert Schlegel, Z. Alexander Cao, Alan Huang, Ensar Halilovic. The Mdm2 inhibitor, NVP-CGM097, in combination with the BRAF inhibitor NVP-LGX818 elicits synergistic antitumor effects in melanoma. [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 5466. doi:10.1158/1538-7445.AM2014-5466
Abstract 5544: Patient-derived xenograft study reveals the pharmacology and the role of ESR1 gene aberrations in endocrine therapy resistance of ER positive breast cancer
Authors: Sen Triparna , Li Shunqiang , Shao Jieya , Crowder Robert , Kitchens Robert , Ellis Matthew J. 
Published: May 2015

Abstract
Background: The study of estrogen-receptor-positive patient-derived xenografts (PDXs) from patients with disease progression despite endocrine therapy has revealed recurrent ESR1 mutation, gene amplification and ESR1 gene translocations as likely drivers of resistance. We addressed this hypothesis further using pharmacological and genetic approaches in the PDX system.
Methodology: ER positive PDXs that harbored one of four recurrent ligand binding domain (LBD) mutations (Y537S/N/C and D538G) as well as a ESR1/YAP1 translocation were studied in parallel with T47D and MCF7 cells expressing these mutants through lentivirus constructs. Single cell suspensions generated from PDX models were using for in vitro experiments using with a panel of endocrine inhibitors and ESR1 shRNA constructs. In vitro effects were confirmed using in vivo tumor response.
Results: Cell suspensions from ER+ PDX models in short-term culture successfully reproduced the endocrine therapy resistant phenotypes exhibited by the donor patient, thereby facilitating drugs screens designed to identify new endocrine approaches for ESR1 mutant breast cancer using authentic models rather than an exclusive reliance on models derived by transfection of mutant constructs into standard indicator cell lines. We were also able to demonstrate that that lentivirus-driven shRNA mediated knockdown of ESR1-YAP1 caused inhibition of PDX tumor growth in in vivo and reduced cell growth in vitro, confirming that this chimeric protein is a driver of estradiol-independent growth.
Conclusion: ER+ PDX can be manipulated in vitro and in vivo to successfully model ESR1 mutation and gene-rearrangement driven endocrine therapy resistance. PDX studies complement standard ectopic expression systems for the study of ESR1 mutation-driven resistance and, we hypothesize, will provide pharmacological data that will predict the activity of pharmacological agents designed to improve outcomes for patients with ESR1 mutant driven endocrine therapy resistance.
Citation Format: Triparna Sen, Shunqiang Li, Jieya Shao, Robert Crowder, Robert Kitchens, Matthew J. Ellis. Patient-derived xenograft study reveals the pharmacology and the role of ESR1 gene aberrations in endocrine therapy resistance of ER positive breast 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 5544. doi:10.1158/1538-7445.AM2014-5544
Abstract 556: Interleukin 32 is an independent prognostic biomarker of human gastric cancer correlated with tumor progression and metastasis
Authors: Wang Chia-Siu , Tsai Chung-Ying , Lin Kuan-Huei 
Published: May 2015

Abstract
Background: The pro-inflammatory cytokine, interleukin 32 (IL-32), is a novel tumor marker highly expressed in various human carcinomas including gastric cancer (GC).
Materials and Methods: A total of 120 patients with gastric cancer undergoing gastrectomy were enrolled into this study. Real-time quantitative RT-PCR, western blot analysis and immunohistochemistry (IHC) on resected specimens were used to confirm the IL-32 overexpression in surgical patients. The clinicopathological correlation and survival outcome of IL-32 were analysed for clinical significance in these patient. In vitro study, using ectopic overexpression and knockdown of IL-32 in GC cell lines, was established to investigate the invasiveness and the signaling pathway of IL-32 in GC.
Results: IL-32 was significantly upregulated in GC and positively correlated with aggressiveness of cancer and poor prognosis. Stable suppression or overexpression of IL-32 revealed marked influence of cell migration and invasion by modulating phosphorylation of AKT and glycogen synthase kinase 3β (GSK3β), leading to activation of β-catenin. Expression of IL-32 was accompanied by the induction of interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2) and 9 (MMP9) in vitro and in vivo.Conclusion: Our results clearly suggest that IL-32 is an important mediator for GC metastasis and an independent prognostic predictor of GC.
Citation Format: Chia-Siu Wang, Chung-Ying Tsai, Kuan-Huei Lin. Interleukin 32 is an independent prognostic biomarker of human gastric cancer correlated with tumor progression and metastasis. [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 556. doi:10.1158/1538-7445.AM2014-556