bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2086: Dominant role of receptor tyrosine kinase in the activation of MAPK signaling in BRAF non-V600 mutant cancers
Authors: Ebi Hiromichi , Kotani Hiroshi , Kitai Hidenori , Adachi Yuta , Yano Seiji 
Published: July 2017

Abstract
BRAF mutations are found in ~8% of all cancers. In addition to the commonest mutation in kinase domain at the V600, a wide range of other missense mutations (non-V600) have been reported. Non-V600 mutant BRAF protein was also shown to enhance MAPK signaling, suggesting the effectiveness of MEK inhibitors. However, the existence of feedback mechanism in MAPK singling and the roles of receptor tyrosine kinases (RTKs) in these cells are not fully understood. To interrogate this, BRAF non-V600 cell lines with intermediate/impaired kinase activity were treated with MEK inhibitor. RTKs involved in the upregulation of P-MEK following MEK inhibition in BRAF non-V600E mutant cell lines were determined by phosphor-RTK arrays. The effect of combinatorial inhibition of RTKs and MEK in BRAF non-V600 cancer was assessed in vitro and in vivo. By analyzing drug screen data, we first found cells with BRAF non-V600E mutation were less sensitive to MEK inhibition compared with BRAF V600E mutant cell lines and almost comparable to RAS/RAF wild-type cell lines. MEK inhibition did not induce P-MEK suppression and it resulted in significant upregulation of p-MEK compared to BRAF V600E mutant cell lines. Phospho-RTK arrays in the presence or absence of trametinib displayed basal phosphorylation of RTKs including EGFR, MET, and IGF1R, although the phosphorylation level was not consistently changed following MEK inhibition. Among these RTKs, treatment with the EGFR inhibitor erlotinib led to more complete suppression of P-ERK upon trametinib treatment. Furthermore, we found that erlotinib monotherapy downregulated P-ERK in BRAF non-V600 mutant cell lines in contrast that inhibition of RTKs had no effect on MAPK signaling in BRAF V600 mutant cells. While erlotinib treatment led to MAPK inhibition both in intermediate active and impaired kinase active BRAF mutant cells, p-MEK and p-ERK were more strongly suppressed in impaired type BRAF non-V600 mutant cells. The combination of EGFR inhibitor and MEK inhibitor suppressed cell growth and achieved tumor shrinkage in mice xenograft. These results suggest that RTKs, especially EGFR, are dominantly involved in the regulation of MAPK signaling in BRAF non-V600 cancer cells.
Note: This abstract was not presented at the meeting.
Citation Format: Hiromichi Ebi, Hiroshi Kotani, Hidenori Kitai, Yuta Adachi, Seiji Yano. Dominant role of receptor tyrosine kinase in the activation of MAPK signaling in BRAF non-V600 mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2086. doi:10.1158/1538-7445.AM2017-2086
Abstract 2099: In vitro characterization of the effect of nazartinib against non-small cell lung cancer activating clinically relevant EGFR mutants
Authors: Masuzawa Keita , Yasuda Hiroyuki , Hirano Toshiyuki , Nukaga Shigenari , Hasegawa Hanako , Hamamoto Junko , Naoki Katsuhiko , Soejima Kenzo , Betsuyaku Tomoko 
Published: July 2017

Abstract
Purpose: Multiple EGFR-TKIs are available and under development to treat patients with lung cancer harboring EGFR mutations. Nazartinib is one of the 3rd generation EGFR-TKIs targeting EGFR T790M as well as common mutations such as L858R and exon 19 deletions. Today, there is no clear guideline regarding which EGFR-TKIs should be used for which mutations. The purpose of this study is to clarify which EGFR-TKIs including nazartinib are best for each EGFR mutation, especially exon 20 insertion mutations using in vitro modeling.
Experimental design: We evaluated drug sensitivity and downstream signaling of human lung cancer cell lines (PC9, H3255, H1975, PC9ER, BID007) and Ba/F3 cells harboring multiple types of EGFR mutations for 1st- (erlotinib), 2nd- (afatinib) and 3rd- (osimertinib and nazartinib) generation EGFR-TKIs by MTS assay and western blotting. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFRs.
Results: The model of mutation specificity identified a wide therapeutic window of each EGFR-TKIs for exon 19 deletions and L858R. On the other hand, osimertinib and nazartinib have wide therapeutic window for T790M positive mutations in human cell lines and Ba/F3 cells. In human cell lines and Ba/F3 cells harboring exon 19 deletions or L858R, afatinib dramatically inhibited the phosphorylation of EGFR, AKT, and ERK. Afatinib and 3rd generation EGFR-TKIs, osimertinib and nazartinib, effectively inhibited the phosphorylation of EGFR, AKT, and ERK in T790M positive cells. For EGFR exon 20 insertion mutations, althogh afatinib, osimertinib and nazartinib effectively inhibited the phosphorylation of EGFR, AKT, and ERK in several exon 20 insertion mutations, osimertinib and nazartinib were potent and presented a wide therapeutic window.
Conclusion: Nazartinib as well as osimertinib has wide therapeutic windows for exon 19 deletions, L858R, T790M and some exon 20 insertions .
Citation Format: Keita Masuzawa, Hiroyuki Yasuda, Toshiyuki Hirano, Shigenari Nukaga, Hanako Hasegawa, Junko Hamamoto, Katsuhiko Naoki, Kenzo Soejima, Tomoko Betsuyaku. In vitro characterization of the effect of nazartinib against non-small cell lung cancer activating clinically relevant EGFR mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2099. doi:10.1158/1538-7445.AM2017-2099
Abstract 2102: ONC201 targets AR and AR-V7 signaling pathways, reduces PSA and synergizes with everolimus in castration resistant prostate cancer
Authors: Lev Avital , Lulla Amriti R. , Dicker David T. , El-Deiry Wafik S. 
Published: July 2017

Abstract
Androgen receptor (AR) signaling plays a key role in prostate cancer progression; thus Androgen Deprivation Therapy (ADT) is a mainstay therapy for patients with advanced prostate cancer. However, in most cases the tumor becomes androgen-independent and resistant to ADT with patients ultimately progressing to metastatic castration resistant prostate cancer (mCRPC). Constitutively activated AR splice variants (AR-Vs) have emerged as major mediators of resistance to AR-targeted therapy and progression of mCRPC, representing an important therapeutic target for mCRPC. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant in prostate cancer and its expression correlates with ADT resistance. ONC201 is the founding member of the imipridone class of small molecules that induces apoptosis in a variety of tumor types tested. It is currently in Phase I/II clinical trials for advanced solid tumors and hematological malignancies, including mCRPC with encouraging activity observed in patients in early clinical testing (Stein et al., ASCO, 2016). We demonstrate here that ONC201 treatment induces apoptosis in both castration-resistant and –sensitive human prostate cancer cell lines. Furthermore, an in-vitro synergistic effect is observed with ONC201 and FDA approved drugs for prostate cancer such as enzalutamide, docetaxel and everolimus. Mechanistically, we found that ONC201 inhibits both AR and AR-V7 signaling pathways. Analysis of AR+ cell lines stimulated with DHT showed a significant decrease in both RNA and protein levels of AR, AR-V7, PSA and other AR-target genes following ONC201 treatment. Ongoing experiments are aimed at better understanding the molecular and cellular mechanisms that enable ONC201 to inhibit the AR signaling pathway. In-vivo studies with AR-negative hormone refractory prostate cancer xenografts demonstrate single agent ONC201 anti-tumor efficacy. Ongoing studies are further evaluating the in-vivo efficacy of ONC201 as a single agent or in combination with enzalutamide and everolimus using mouse models of both castration-resistant and -sensitive prostate cancer. These preclinical results indicate that ONC201 is well suited to address mCRPC, including tumors that harbor AR-V7, as a single agent that may be combined synergistically with enzalutamide or everolimus . With these observations we envision further development a combination of ONC201 plus everolimus in CRPC with or without enzalutamide resistance.
Citation Format: Avital Lev, Amriti R. Lulla, David T. Dicker, Wafik S. El-Deiry. ONC201 targets AR and AR-V7 signaling pathways, reduces PSA and synergizes with everolimus in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2102. doi:10.1158/1538-7445.AM2017-2102
Abstract 2103: NVP-FGF401: Cellular and in vivo profile of a novel highly potent and selective FGFR4 inhibitor for the treatment of FGF19/FGFR4/KLB+ tumors
Authors: Weiss Andreas , Porta Diana Graus , Reimann Flavia , Buhles Alexandra , Stamm Christelle , Fairhurst Robin A. , Kinyamu-Akunda Jacqueline , Sterker Dario , Murakami Masato , Wartmann Markus , Wang Youzhen , Engelman Jeffrey A. , Hofmann Francesco , Sellers Wiliam R. 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a deadly disease. Treatment options are limited and prognosis generally is poor. Aberrant signaling through the fibroblast growth factor 19 (FGF19) - fibroblast growth factor receptor 4 (FGFR4) axis has been implicated in the development of HCC, and recently FGF19 has been determined as a specific driver gene amplification in a subset of liver tumors and cancer cell lines. Here, we describe the cellular and in vivo profile of NVP-FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. NVP-FGF401 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. We show that among the FGF19-amplified liver cancer cells in the cancer cell line encyclopedia (CCLE), only those with concomitant expression of β-klotho (KLB), a co-receptor for FGF19 that facilitates its binding to FGFR4, are sensitive to NVP-FGF401. NVP-FGF401 has good oral PK properties and shows an excellent in vivo PK/PD relationship. NVP-FGF401 has remarkable anti-tumor activity in mice bearing HCC tumor xenografts and PDX models that are positive for FGF19, FGFR4 and KLB. NVP-FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a PhI/II study is currently ongoing in HCC and other types of solid tumors.
Citation Format: Andreas Weiss, Diana Graus Porta, Flavia Reimann, Alexandra Buhles, Christelle Stamm, Robin A. Fairhurst, Jacqueline Kinyamu-Akunda, Dario Sterker, Masato Murakami, Markus Wartmann, Youzhen Wang, Jeffrey A. Engelman, Francesco Hofmann, Wiliam R. Sellers. NVP-FGF401: Cellular and in vivo profile of a novel highly potent and selective FGFR4 inhibitor for the treatment of FGF19/FGFR4/KLB+ tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2103. doi:10.1158/1538-7445.AM2017-2103
Abstract 2105: Evaluation of antitumor properties of metformin over human multidrug-resistant chronic myeloid leukemia cells
Authors: Oliveira Ligia P. , Renó Débora L. , Curvello Rodrigo S. , Lima Luana P. , Galvão Ana Carolina S. 
Published: July 2017

Abstract
Besides the progress in the knowledge of cancer biology, the rates of mortality due to this disease are still considerably elevated. Therefore, application of new drugs in antitumor therapies has been constantly studied. However, any of them have achieved a considerable success so far. In this work we evaluated the ability of metformin, a traditional hypoglycemic prescribed to treatment of type II diabetes along decades, over programmed cell death and modulation of metastatic potential in multidrug resistant (MDR) human myeloid chronic leukemia cells (Lucena), through MTT reduction test, flow cytometry, western blotting and gelatin zymography. Metformin was able to reduce the cell viability in a concentration and time-dependent manner, but was not able to induce Lucena cells to apoptosis or necrosis, though activation of the apoptotic machinery. Indeed, it was not observed activation of caspase 3, in contrast to an expressive activation of PARP. Interestingly, proteins associated to autophagy were overexpressed by Lucena cells, and an arrest of cell cycle was observed after exposition to the drug. Finally, it was verified that metformin was able to modulate activity of MMP2 and MMP9, enzymes associated to the metastatic process. Taken together these results suggest that the hypoglycemic is able to acts over the first steps of cancers in more aggressive stages. Finally, inhibition of MMPs indicates a promissory action of metformin for the treatment of metastatic disease.
Note: This abstract was not presented at the meeting.
Citation Format: Ligia P. Oliveira, Débora L. Renó, Rodrigo S. Curvello, Luana P. Lima, Ana Carolina S. Galvão. Evaluation of antitumor properties of metformin over human multidrug-resistant chronic myeloid leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2105. doi:10.1158/1538-7445.AM2017-2105
Abstract 2110: Anti-invasive and antimetastatic actions of omega-3 polyunsaturated fatty acids in glioblastoma cells
Authors: Kim Soyeon , Shin Soyeon , Jeong Soyeon , Han Seung-Hyeon , Yoo Yoon-Seon , Silwal Prashanta , Jeon Young-Joo , Heo Jun-Young , Kweon Gi-Ryang , Park Seung-Kiel , Park Jong-Il , Lim Kyu 
Published: July 2017

Abstract
Glioblastoma (GBM) is the most aggressive and deadliest brain malignancy in adults. Despite of surgical techniques, radiotherapy and chemotherapy, GBM has remained an invariably lethal tumor with a median survival less than 15 months. Although the anticancer mechanisms of omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been reported in several cancers, it is still unclear in brain cancer. Here, our data show the anti-invasive and anti-metastatic effects of ω3-PUFAs in GBM. Invasiveness using transwell chamber was inhibited by docosahexaenoic acid (DHA) treatment in D54MG and GL261 cells. In zymography, MMP-2 activity was suppressed by DHA in a dose dependent manner. MMP-2 promoter activity was also decreased. DHA inhibited both p-STAT3 and β-catenin levels that contribute to invasion by stimulating pro-invasion factors such as MMP-2. Additionally, fat-1 (ω3-desaturease) stable D54MG cell was established and the effect of the high level of ω3-PUFAs was investigated endogenously. The invasiveness were significantly inhibited in the fat-1 stable cells compared to control cell. Moreover, the metastasis in vivo was significantly reduced when GL261 mouse glioma cells were injected through tail vein into the fat-1 transgenic mice. In immunohistochemistry, intensity of p-STAT-3 and β-catenin were significantly weak in metastatic lung tumor from Fat-1 mice compared to wild type mice. These results indicate that anti-invasive and anti-metastatic actions of ω3-PUFA may be correlated with inhibition of MMP-2 through decrease of STAT3 and β-catenin in GBM cells. Thus, these findings provide important preclinical evidence and molecular insight for utilization of ω-3 PUFAs for the chemoprevention and treatment of human GBM. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2007-0054932, NRF-2015R1D1A1A01056887) and by the framework of international cooperation program managed by National Research Foundation of Korea (2015K2A2A6002008)].
Citation Format: Soyeon Kim, Soyeon Shin, Soyeon Jeong, Seung-Hyeon Han, Yoon-Seon Yoo, Prashanta Silwal, Young-Joo Jeon, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim. Anti-invasive and antimetastatic actions of omega-3 polyunsaturated fatty acids in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2110. doi:10.1158/1538-7445.AM2017-2110
Abstract 2115: Therapeutic potential of fingolimod against prostate cancer cells is partly attributed to interrupting the cross talk between estrogen and sphingolipid metabolisms
Authors: Allam Rasha M. , Al-Abd Ahmed M. , Khedr Alaa , Sharaf Ola A. , Nofal Salwa M. , Khalifa Amani E. , Mosli Hisham A. , Abdel-Naim Ashraf B. 
Published: July 2017

Abstract
Sphingolipids influence tumor microenvironment in different malignancies. Estrogen and estrogen metabolites are involved in prostate cancer. Fingolimod is Sphingokinase-1 (SphK1) inhibitor which possesses anticancer properties in various tumor types. The aim of the current study is to investigate the interference of Fingolimod with the cross talk between sphingolipid and estrogen metabolisms within prostate cancer cells as a novel therapeutic strategy. The design is based on determining the mutual influence between estrogen metabolism/signaling and sphingolipid metabolism within prostate cancer cells. Cytotoxicity using SRB-U assay; cell cycle analysis using DNA cytometry and intracellular caspase-3 concentration were assessed. Estrogen metabolites and estrogen metabolizing enzymes were determined using LC/MS and RT-PCR, respectively. Estrogen receptor (ERα and ERβ) expression and their downstream signaling (CXCR4 and Cyclin-D1, respectively) were measured using immunocytochemical staining and RT-PCR, respectively. Fingolimod showed antiproliferative/cytotoxic effects against different prostate cancer cells (LNCaP, DU145 and PC3) with IC50 ranging from 3.0±0.3 to 6.8±1.7 µM. Fingolimod induced significant decrease in estradiol, estrone, 4-hydroxyestradiol and 16α-hydroxyestrone concentrations with reciprocal increase in 2-methoxyestrone and 2-methoxyestradiol concentrations. This was mirrored by significant down expression for the enzymes, aromatese, CYP1A1 and CYP1B1 and over expression for the enzyme COMT. Additionally, Fingolimod suppressed the expression of ERα and ERβ within prostate cancer cells as well as their downstream signaling (CXCR4 and Cyclin-D1, respectively). Reciprocally, it was found that estradiol and catechol estrogens induce the expression of SphK1 while methoxylated catechol estrogen suppresses its expression. Our results give compelling evidence that Fingolimod has therapeutic potential by modulating the estrogenic micromilieu and interrupting its cross talk with sphingolipid metabolism in prostate cancer cells.
Citation Format: Rasha M. Allam, Ahmed M. Al-Abd, Alaa Khedr, Ola A. Sharaf, Salwa M. Nofal, Amani E. Khalifa, Hisham A. Mosli, Ashraf B. Abdel-Naim. Therapeutic potential of fingolimod against prostate cancer cells is partly attributed to interrupting the cross talk between estrogen and sphingolipid metabolisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2115. doi:10.1158/1538-7445.AM2017-2115
Abstract 2125: Flavokawain A, a kava chalcone, inhibits growth and invasion of human osteosarcoma cells by targeting Skp2
Authors: Zhang Yidan , Zhang Wendong , Zaphiros Nikolas , Du Xiuquan , Koirala Pratistha , Roth Michael , Gill Jonathan , Piperdi Sajida , Geller David , Yang Rui , Zhang Jinghang , Gorlick Richard , Zi Xiaolin , Ji Tao , Hoang Bang H. 
Published: July 2017

Abstract
Purpose: Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Flavokawain A (FKA), a major chalcone from kava extract, has been reported to have antitumor effects on multiple cancer cell lines. The consumption of kava-containing beverage has been associated with a low cancer incidence. In a previous report, mice treated with high-dose FKA did not demonstrate any significant major organ toxicity. However, the efficacy and anticancer mechanisms of FKA in OS is still to be elucidated.
Experimental Design: OS cell lines were treated with increasing dosage of FKA and tested for cell motility, proliferation, and invasion by MTT assay and Matrigel invasion assay. Cell cycle analysis was performed using flow cytometry. We examined Skp2 expression in several OS cell lines using western blot and in patient tissue array by immunostaining. Kaplan-meier analysis and log rank test were used to compare overall survival. Both Skp2-dependent cell cycle progression and Skp2-related RhoA expression were also examined after FKA treatment. The effects of FKA on lung metastasis were evaluated after orthotopic injection of OS cells into the tibia.
Results: We show that FKA inhibits the growth and motility of multiple OS cell lines in vitro. Flow cytometry analysis confirms cellular apoptosis and arrest in G2/M phase after FKA treatment, whereas cellular invasion is also inhibited in a dose-dependent manner. Skp2 is expressed in several OS cell lines and is associated with a poor prognosis in OS patients. Skp2 levels in OS cell lines decreased after FKA treatment. The expression of cell cycle regulators including p21 and p27, which are downstream of Skp2, was upregulated. Moreover, Skp2-related RhoA expression is inhibited by FKA and confirmed at protein level.
Conclusions: Taken together, the evidence suggests FKA exerts anti-invasive effects in association with Skp2-dependent cell cycle progression and Skp2-related RhoA expression. Since Skp2 is a negative prognostic factor for OS patients, FKA should be investigated further as an anti-Skp2 therapeutic strategy for OS.
Citation Format: Yidan Zhang, Wendong Zhang, Nikolas Zaphiros, Xiuquan Du, Pratistha Koirala, Michael Roth, Jonathan Gill, Sajida Piperdi, David Geller, Rui Yang, Jinghang Zhang, Richard Gorlick, Xiaolin Zi, Tao Ji, Bang H. Hoang. Flavokawain A, a kava chalcone, inhibits growth and invasion of human osteosarcoma cells by targeting Skp2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2125. doi:10.1158/1538-7445.AM2017-2125