bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 869: PTEN/PI3K oncogenic pathway profiling informs an in vivo synergistic therapeutic model for basal-like breast cancer.
Authors: Saal Lao H. , She Qing-Bai , Gruvberger-Saal Sofia K. , Maurer Matthew , Jumppanen Mervi , Su Tao , Dendy Meaghan , Lau Ying-Ka I. , Memeo Lorenzo , Ringner Markus , Isola Jorma , Hibshoosh Hanina , Rosen Neal , Parsons Ramon 
Published: August 2014

Abstract
The basal-like breast cancer (BBC) subtype is generally characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis, however, are not fully elucidated. In an analysis of phosphoinositide 3-kinase (PI3K) pathway-activating molecular aberrations in 116 unselected breast tumors, we find that three-quarters of cases had a potential oncogenic alteration to PIK3CA, PTEN, HER2, INPP4B, or EGFR, including 97% of estrogen receptor (ER)-negative tumors compared to 65% of ER-positive tumors (P&lt;0.001). Interestingly, nearly all p53 mutant tumors had one or more of these alterations (93%, P=0.001). Loss of PTEN was significantly associated to EGFR overexpression, positivity for the BBC marker cytokeratin 5/14, and the BBC molecular subtype by mRNA gene expression profiling (all P&lt;0.001), informing a potential therapeutic combination targeting the PTEN/PI3K and EGFR pathways in BBC. In BBC cell lines, combination treatment with the EGFR-inhibitor gefitinib plus PI3K-inhibitor LY294002 was synergistic and increased apoptosis. Similarly, in an in vivo BBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy. Our study supports the future clinical evaluation of EGFR and PI3K pathway inhibitors for the treatment of BBC.
Citation Format: Lao H. Saal, Qing-Bai She, Sofia K. Gruvberger-Saal, Matthew Maurer, Mervi Jumppanen, Tao Su, Meaghan Dendy, Ying-Ka I. Lau, Lorenzo Memeo, Markus Ringner, Jorma Isola, Hanina Hibshoosh, Neal Rosen, Ramon Parsons. PTEN/PI3K oncogenic pathway profiling informs an in vivo synergistic therapeutic model for basal-like breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 869. doi:10.1158/1538-7445.AM2013-869
Abstract 886: OCT6 expression is associated with the resistance to cisplatin in lung cancer.
Authors: Kasai Daishi , Oguri Tetsuya , Uemura Takehiro , Hijikata Hisatoshi , Yokoyama Midori , Kunii Eiji , Takakuwa Osamu , Ohkubo Hirotsugu , Miyazaki Mikinori , Maeno Ken , Niimi Akio 
Published: August 2014

Abstract
Organic cation transporters (OCTs) of the solute carrier family 22 have been identified as uptake transporters for the charge state of a substrate such as cationic drugs. The OCTs have an isoform of OCT1, OCT2, OCT3, and OCT6. Previously OCT1-3 have shown to related with intracellular uptake of anticancer platinum drugs such as cisplatin (CDDP) and oxaliplatin; however an association of OCT6 and platinum drugs is not well elucidated. We found decreased gene and protein expressions of OCT6 in CDDP resistant PC14/CDDP cells compared to those in parental lung adenocaricinoma PC14 cells. In contrast, the expression levels of OCT1-3 were not changed between PC14 and PC-14/CDDP cells. The intracellular concentration of CDDP also decreased in PC14/CDDP compared with the parental cell. To elucidate the OCT6 for uptake of CDDP, we established a forced expression of OCT6 cell line by a transfection an OCT6 vector to PC14/CDDP cells. We found that intracellular CDDP concentration are increased concomitant with decreased resistance to CDDP in OCT6 overexpressed PC14/CDDP cells. These results indicate that OCT6 is related with uptake of CDDP, and that the expression of OCT6 could be one of the resistant factors against CDDP in lung cancer cells.
Citation Format: Daishi Kasai, Tetsuya Oguri, Takehiro Uemura, Hisatoshi Hijikata, Midori Yokoyama, Eiji Kunii, Osamu Takakuwa, Hirotsugu Ohkubo, Mikinori Miyazaki, Ken Maeno, Akio Niimi. OCT6 expression is associated with the resistance to cisplatin in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 886. doi:10.1158/1538-7445.AM2013-886
Abstract 894: Melanoma fights cisplatin with NO: S-nitrosation as a mechanism supporting drug-resistance.
Authors: Godoy Luiz C. , Anderson Chase C.T. , Chowdhury Rajdeep , Trudel Laura J. , Wogan Gerald N. 
Published: August 2014

Abstract
Melanoma patients experience inferior survival after bio-chemotherapy when their tumors contain numerous cells expressing the inducible isoform of NO synthase (iNOS), and elevated levels of nitrotyrosine, a product derived from nitric oxide (NO). Although several lines of evidence suggest that NO promotes tumor growth and increases resistance to chemotherapy, it is unclear how it shapes these outcomes. Here we demonstrate that modulation of NO-mediated S-nitrosation of cellular proteins is strongly associated with the pattern of response to the anti-cancer agent cisplatin in human melanoma cells in vitro. Cells were shown to express iNOS constitutively, and to generate sustained nanomolar levels of NO intracellularly. Inhibition of NO synthesis or scavenging of NO enhanced cisplatin-induced apoptotic cell death. Additionally, pharmacologic agents disrupting S-nitrosation markedly increased cisplatin toxicity, whereas treatments favoring stabilization of S-nitrosothiols decreased its cytotoxic potency. Activity of the pro-apoptotic enzyme caspase-3 was higher in cells treated with a combination of cisplatin and chemicals that decreased NO/S-nitrisothiols, whereas lower activity resulted from cisplatin combined with stabilization of S-nitrisothiols. Constitutive protein S-nitrosation in cells was detected by analysis with biotin switch and reduction/chemiluminescence techniques. Moreover, intracellular NO concentration increased significantly in cells that survived cisplatin treatment, resulting in augmented S-nitrosation of caspase-3 and prolyl-hydroxylase-2 (PHD2), the enzyme responsible for targeting the pro-survival transcription factor HIF-1α for proteasomal degradation. Because activities of these enzymes are inhibited by S-nitrosation, our data thus indicate that modulation of intrinsic intracellular NO levels substantially affects cisplatin toxicity in melanoma cells. The underlying mechanisms may thus represent potential targets for adjuvant strategies to improve the efficacy of chemotherapy.
Citation Format: Luiz C. Godoy, Chase C.T. Anderson, Rajdeep Chowdhury, Laura J. Trudel, Gerald N. Wogan. Melanoma fights cisplatin with NO: S-nitrosation as a mechanism supporting drug-resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 894. doi:10.1158/1538-7445.AM2013-894
Abstract 910: Synergistic combinations of targeted therapy and chemotherapy for neuroendocrine cancer.
Authors: Dinnen Richard D. , Mao Yuehua , Petrylak Daniel P. , Fine Robert L. 
Published: August 2014

Abstract
We previously developed and reported a novel laboratory-derived chemotherapeutic regimen of capecitabine and temozolomide (TMZ) (CapTem). The CapTem regimen is highly active, well-tolerated with minor toxicities and may prolong survival and palliate symptoms in patients with well differentiated neuroendocrine tumors (NET).
Further studies with CapTem in our laboratory indicated that sunitinib, a tyrosine kinase inhibitor (TKI), was highly synergistic with 5-Fluorouracil (5-FU) in killing BON (NET) cells. (Capecitabine is enzymatically converted to 5-FU in the tumor). Synergy was observed at a low concentration of 1.0 μM 5-FU and 1 nM sunitinib. Addition of 100 nM sunitinib resulted in a 4.5 fold increase in cell death (14.2 vs 64.5%). In addition, if sunitinib was combined with the CapTem regimen, (5-FU followed by TMZ), a synergistic response was observed with both 5-FU and TMZ over a range of concentrations, giving a maximal cell death of 74.4%. This contrasts with the cell death obtained with 5-FU, TMZ and sunitinib alone, resulting in 9.0, 6.8 and 10.2% annexin V+ cells, respectively.
Sorafinib, a TKI closely related to sunitinib, not only did not synergize with 5-FU or TMZ, it inhibited cell death observed with sunitinib and 5-FU/ TMZ. In addition, K-252a, a potent inhibitor of tyrosine kinases, reduced the cell death induced by 5-FU/sunitinib suggesting a tyrosine kinase was involved. Considering the IC-50 of sunitinib for PDGF β is 75 nM, whereas for sorafinib it is 1129 nM, a difference of 15 fold, we hypothsized that the PDGF-β pathway might be involved. Addition of the PDGF-ββ form resulted in an enhancement of 5-FU/TMZ (CapTem) cell death. However, there was no effect on sunitinib-induced cell death, suggesting that the PDGF-β pathway may be involved but to an unknown extent in the cell death pathway induced by CapTem.
Exposure of BON cells to TMZ and 5-FU may mimic the in vivo exposure to these drugs in patients and the resulting cell line resistance may be similar to resistance in tumors. Preliminary studies with four resistant BON cell lines: TMZ-Resistant, 5-FU-Resistant, TMZ+5FU-Resistant, (concurrent exposure to TMZ and 5-FU) and TMZ -&gt; 5FU-Resistant, (sequential exposure to 5FU and TMZ) found that cells resistant to CapTem still retain sensitivity to sunitinib. This suggests that addition of sunitinib can overcome CapTem resistance in BON cells.
Citation Format: Richard D. Dinnen, Yuehua Mao, Daniel P. Petrylak, Robert L. Fine. Synergistic combinations of targeted therapy and chemotherapy for neuroendocrine cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 910. doi:10.1158/1538-7445.AM2013-910
Abstract 916: Preclinical responses of the MEK inhibitor AZD6244 in a genetically modified mouse model of prostate cancer.
Authors: Uemura Hirotsugu , Kura Yurie , Ando Naomi , Fukushima Emiko , Hatanaka Yuji , Yamamoto Yutaka , Shimizu Nobutaka , Nozawa Masahiro , Yoshimura Kazuhiro , Yoshikawa Kazuhiro , Nishio Kazuto , De Velasco Marco A. 
Published: August 2014

Abstract
The mitogen-activated protein kinase (MAPK) pathway is involved in a broad range of cellular processes that include proliferation, survival, apoptosis, and cellular differentiation. MAPK has also been shown to increase the transcription of androgen-dependent (AR) genes, independently of androgens by phosphorylation of the AR or its cofactors. Thus, MAPK signal inhibition has the potential to be a therapeutic target for prostate cancer. To determine the clinical benefit of MAPK inhibition, we used the highly selective MEK inhibitor, AZD6244, in a prostate-specific PTEN-conditional knockout mouse model of prostate cancer. In this model, prostate tumors from mice exhibit increased levels of p-Erk1/2 expression that correlates with tumor progression. Acute pharmacodynamic responses, after a single dose of AZD6244, showed a strong inhibition of Erk1/2 phosphorylation that was maintained for at least 24 hours after drug administration. Levels of cellular proliferation decreased, and apoptosis was induced shortly after the administration of AZD6244. However, apoptosis was suppressed after 8 hours. To further characterize the responses to MAPK signal inhibition, we examined the activity of downstream molecules of the PI3K/Akt and JAK/STAT3 signaling pathways. While PI3K/Akt activity decreased mildly, activation of JAK/STAT3 was transiently but strongly increased. To determine tumor responses to chronic administration of AZD6244, Pten-mutant mice harboring prostate tumors were treated with AZD6244 for 4 a period of 4 weeks. 2-D morphometric analysis of tumor surface area showed a reduction of 10.9% (P =0.035) in treated mice. Furthermore, inhibition of p-Erk was maintained and tumor cell proliferation was reduced by 25.24% (P =0.005). The apoptotic index increased from 3.9% in controls to 7.2% (P=0.004) in mice receiving AZD6244. Our findings suggest that inhibition of MAPK signaling can contribute to decreased tumor progression and may represent a promising therapeutic alternative.
Citation Format: Hirotsugu Uemura, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Marco A. De Velasco. Preclinical responses of the MEK inhibitor AZD6244 in a genetically modified mouse model of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 916. doi:10.1158/1538-7445.AM2013-916
Abstract 921: Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents.
Authors: Sharma Sharad , Zeng Jun-Yin , Zhunag Chunmei , Zhang Ruiwen , Wang Ming-hai 
Published: August 2014

Abstract
The RON receptor tyrosine kinase is a therapeutic target for cancer treatment. Here we report therapeutic effect and phenotypic change of breast cancer cells in response to BMS-777607, a RON tyrosine kinase inhibitor. Treatment of breast cancer cells with BMS-777607 at therapeutic doses inhibited cancerous clonogenic growth but had only minimal effect on cell apoptosis. Significantly, BMS-777607 induced extensive polyploidy with multiple sets of chromosomes in cancer cells. This effect is independent of RON expression. Knockdown of RON in T-47D and ZR-75-1 cells by specific siRNA did not prevent polyploid formation. Immunofluorescent analysis of α-tubulin and γ-tubulin expression in polyploid cells revealed that BMS-777607 disrupts bi-polar spindle formation and causes multi-polar-like microtubule assembly. Also, both metaphase equatorial alignment and chromosomal segregation were absent in polyploid cells. These results suggest that cellular mitosis arrests at prophase/pro-metaphase and fails to undergo cytokinesis. By analyzing kinase-inhibitory profiles, aurora kinase B was identified as the target molecule inhibited by BMS-777607. In BMS-777607 treated cells, aurora kinase B was inhibited followed by protein degradation. Moreover, BMS-777607 inhibited Ser10 phosphorylation of histone H3, a substrate of aurora kinase B. Chemosensitivity analysis indicated the resistance of polyploid cells towards chemotherapeutics. Treatment with doxorubicin, bleomycin,cisplatin, methotrexate, and paclitaxel significantly increased cellular IC50 values. These findings highlight the theory that BMS-777607 acts as a multi-kinase inhibitor at therapeutic doses and is capable of inducing polyploidy by inhibiting aurora kinase B. Increased resistance of polyploid cells to cytotoxic chemotherapeutics could have a negative impact on targeted cancer therapy using BMS-777607.
Citation Format: Sharad Sharma, Jun-Yin Zeng, Chunmei Zhunag, Ruiwen Zhang, Ming-hai Wang. Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 921. doi:10.1158/1538-7445.AM2013-921
Abstract 929: Caboxylic acid esters as inhibitors of the MEK1/2 and MEK5 signaling cascades.
Authors: Cavanaugh Jane E. , Monlish Darlene A. , Chakrabarty Suravi , Qin Si , Flaherty Patrick T. 
Published: August 2014

Abstract
The purpose of the current study is to examine how structural variation on methyl anthranilates can differentially affect specific branches of the MAPK signaling cascade. The specific goal is to correlate the role of MEK1/2 versus MEK5 in breast cancer proliferation and migration modeled by the profile of pERK isoforms in treated BT-474 (ER+/PR+/HER2high) and MDA-MB-231 (ER−/PR−/HER2low) human breast cancer cell lines. The MAPK signaling pathway is a complex interconnected signaling cascade activated by extracellular stimuli, including growth factors, cytokines, and mechanical and chemical stressors, to elicit appropriate cellular responses including cell survival, proliferation, differentiation, and apoptotic cell death. The interconnected nature of these pathways permits a single external stimulus to be interpreted in the context of the immediate metabolic demands of the cell. The singularly specific and parallel event is phosphorylation of ERK by its corresponding activating kinase or MEK. In the course of examining small molecules with the design goal of developing selective inhibitors of the MEK5 isoform, we identified a simple substituted methyl anthranilate derivative that unexpectedly and specifically inhibited ERK1/2 activation but had little effect on ERK5 activation. We subsequently explored structural variations and prepared structure assisted new compounds from this initial find. In the BT-474 and MDA-MB-231 cell lines, western blot analysis was performed to determine the expression and activation of ERK1/2 and ERK5 following treatment with the novel MEK-specific inhibitors. An MTT assay was used to assess changes in cell proliferation following kinase inhibition, while scratch and invasion assays were performed to assess the effect of the carboxylic acid esters on cell migration and invasion in these cell lines. The data obtained from these studies indicate methyl anthranilate derivatives warrant further investigation as potential inhibitors of tumor proliferation and migration in breast cancer.
Citation Format: Jane E. Cavanaugh, Darlene A. Monlish, Suravi Chakrabarty, Si Qin, Patrick T. Flaherty. Caboxylic acid esters as inhibitors of the MEK1/2 and MEK5 signaling cascades. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 929. doi:10.1158/1538-7445.AM2013-929
Abstract 933: Modeling acquired resistance to EGFR-directed therapies in mouse models of lung cancer.
Authors: Pirazzoli Valentina , de Stanchina Elisa , Xia Jungfeng , Zhao Zhongming , Pao William , Politi Katerina A. 
Published: August 2014

Abstract
Seventy percent of patients with Epidermal Growth Factor Receptor (EGFR) mutant lung cancer respond to treatment with the tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib. Despite this high response rate, patients almost inevitably develop resistance to these drugs on average within a year of starting drug treatment. Acquired resistance to EGFR TKIs is most commonly due to the emergence of a secondary mutation (T790M) in EGFR (in 50% of cases), amplification of the genes encoding the ERBB2 and MET receptor tyrosine kinases in 12 and 5% of cases, respectively, and phenotypic transformation of the adenocarcinomas to small cell lung cancer (5% of cases). Previously, in an effort to develop strategies to overcome T790M-mediated resistance, we generated tetracycline-inducible transgenic mice that express the EGFRL858R+T790M in the lung epithelium. Upon administration of doxycycline these mice develop lung adenocarcinomas that are resistant to TKIs. However, the combination of the irreversible TKI afatinib and the EGFR antibody cetuximab showed dramatic responses in these transgenic mice. These preclinical studies led to a clinical trial of these agents, which has showing a promising 30% response rate in patients with EGFR mutant tumors resistant to TKIs. However, tumors also acquire resistance to this drug combination and the mechanisms of resistance to afatinib+cetuximab are currently unknown. We set out to identify these mechanisms using xenograft and transgenic mouse models of EGFR mutant lung cancer. Transgenic mice with EGFRL858R+T790M-induced tumors were treated with afatinib+cetuximab using an intermittent dosing strategy that we had previously used to generate erlotinib-resistant tumors in mice with EGFRL858R and EGFRDEL-induced tumors. 75% of mice develop afatinib+cetuximab resistant tumors after three month-long rounds of treatment. The same treatment strategy applied to xenografts harboring subcutaneous tumors induced by EGFRDEL+T790M gave rise to resistant tumors in 20% of cases. Analysis of the afatinib+cetuximab resistant tumors performed to date has not revealed additional mutations in the EGFR transgene, the ERBB2 kinase domain or KRAS. Additional sequencing studies and examination of signaling pathway alterations in the resistant tumors are ongoing. Uncovering mechanisms of resistance to this drug combination will allow the development of strategies to treat tumors that acquire resistance to EGFR-directed therapies.
Citation Format: Valentina Pirazzoli, Elisa de Stanchina, Jungfeng Xia, Zhongming Zhao, William Pao, Katerina A. Politi. Modeling acquired resistance to EGFR-directed therapies in mouse models of lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 933. doi:10.1158/1538-7445.AM2013-933
Abstract 985: Design of a model for the development of cisplatin resistance in H526 human small cell lung cancer xenografts.
Authors: Caffrey Paula B. , Frenkel Gerald D. 
Published: August 2014

Abstract
Treatment of Small Cell Lung Cancer (SCLC) often fails due to the rapid development of resistance to chemotherapy drugs. Reversal of resistance has proven to be difficult to achieve; thus, we have suggested an alternative strategy - prevention of its development [Frenkel & Caffrey, Current Pharmaceutical Design, (2001) 7: 1595-1614]. In order to investigate this possibility we previously designed a model of the development of cisplatin resistance in ovarian cancer xenografts, which mimics the development of clinical resistance in ovarian cancer patients [Caffrey & Frenkel, Cancer Chemotherapy Pharmacology (2000) 46: 74-78]. We used this model to identify compounds which are able to prevent resistance; these are being further investigated in a Phase I clinical trial. We have now designed an analogous model of the development of resistance in SCLC xenografts. Mice were injected sc with H526 SCLCL cells. Those bearing visible tumors were injected i.p. with a single “pretreatment” dose of cisplatin ranging from 0.75 - 3.0 mg/kg. On the 3rd, 5th or 7th day after this pretreatment, mice were injected i.p. with a single “high” dose of cisplatin (3.0 mg/kg). This high dose decreased the growth rate of control (PBS pretreated) tumors by 40%. Tumors whose growth curve was decreased by less than 40% were considered resistant. Our results indicated that several potential models resulted in a low incidence of resistance. However, pretreatment with 1.5 mg/kg followed seven days later by high dose treatment of 3.0 mg/kg consistently resulted in the development of cisplatin-resistant tumors. This model can be used to screen a variety of agents for their ability to prevent the induction of platinum resistance in SCLC tumors. Supported by a grant from the PA State System of Higher Education.
Citation Format: Paula B. Caffrey, Gerald D. Frenkel. Design of a model for the development of cisplatin resistance in H526 human small cell lung cancer xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 985. doi:10.1158/1538-7445.AM2013-985