bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 906: Therapeutic potential of JAK/STAT signal inhibition in prostate cancer by the JAK inhibitor AZD1480.
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Fukushima Emiko , Hatanaka Yuji , Yamamoto Yutaka , Shimizu Nobutaka , Nozawa Masahiro , Yoshimura Kazuhiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2014

Abstract
Signal transducers and activators of transcription (STAT) were originally identified as components of cytokine signal transduction pathways but are now also recognized as key regulators of apoptosis, proliferation, angiogenesis and immune responses in many malignant diseases. Activation of STAT3 occurs by the binding of various cytokines to its receptors leading to the activation of the JAK/ STAT3 signaling pathway. Of these cytokines, interleukin-6 (IL-6) has been implicated in regulating growth of various malignant tumors. Activated IL-6 has also been shown to be elevated in the sera from patients with metastatic prostate cancer, and persistent activation of STAT3 is a common feature. To better characterize the potential role of JAK/STAT3 as a therapeutic target for advanced prostate cancer, we used the JAK1/2 inhibitor, AZD1480 to suppress the transcriptional activation of STAT3 in a PTEN-conditional knockout mouse model of prostate cancer. Prostate tumors from homozygous PTEN-mutant mice share many characteristics of human prostate cancer, including increased activation of the JAK/STAT3 signaling cascade. Our pharmacodynamic studies show that AZD1480 elicited a strong inhibition of STAT3 signal activation leading to decreased tumor cell proliferation, and induction of apoptosis. Our drug intervention studies show that persistent suppression of STAT3 signaling results in a reduction of tumor growth characterized by a decrease in tumor cell proliferation, induction of apoptosis, and decreased angiogenesis. However, PI3K/Akt and MAPK signaling were upregulated in response to STAT3 signal inhibition. Our findings show a strong antitumor effect for STAT3 signal inhibition and may be a promising therapeutic option for prostate cancer; however, it still requires further optimization in order to maximize its clinical potential.
Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Therapeutic potential of JAK/STAT signal inhibition in prostate cancer by the JAK inhibitor AZD1480. [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 906. doi:10.1158/1538-7445.AM2013-906
Abstract 913: Natural product sulforaphane selectively inhibits breast cancer stem cells in basal and trastuzumab resistant Her2+ breast cancer.
Authors: Burnett Joseph , Korkaya Hasan , Newman Bryan , Conley Sarah , Connarn Jamie , Sun Lichao , Lee Hsiu-Fang , Ouzounova Maria , Wicha Max , Sun Duxin 
Published: August 2014

Abstract
The natural product sulforaphane (SF) has demonstrated efficacy against multiple forms of cancers and cancer stem cells. However, it is unclear what are the molecular targets for sulforaphane to inhibit breast cancer stem cells and how efficacy varies among four subtypes of breast cancers. In vitro assay showed that sulforaphane preferentially inhibited triple negative (TNBC) breast cancers, but did not show any efficacy to inhibit Her2+ breast cancer cells (even at &gt;100 uM). However, when Her2+ breast cancer cells (with PTEN deletion) developed resistance to trastuzumab, sulforaphane showed more than 20-fold higher activity. Low concentration of sulforaphane (1 uM) also preferentially eliminates breast cancer stem cells from triple negative breast cancers. Her2+ breast cancer cells (with PTEN deletion and long term treatment of trastuzumab) induced resistance to trastuzumab and increase breast cancer stem cell populations by activating a positive feedback loop of IL-6 and NF-kB. Luciferase reporter assay and immunostaining showed that sulforaphane (1 uM) disrupted NF-kB translocation from cytosol to nucleus and inhibited its activity. Sulforaphane (1 uM) also inhibited endogenous IL-6 production by 50%. Sulforaphane (50 mg/kg, adjuvant therapy) reduced tumor formation rate by 70% and inhibit tumor volume by more than 90% of trastuzumab resistant Her2+ breast cancers in mouse fat pad. These data suggest that sulforaphane inhibits trastuzumab-resistant Her2+ breast cancers and breast cancer stem cells by disrupting NF-kB and IL6 positive feedback loop.
Citation Format: Joseph Burnett, Hasan Korkaya, Bryan Newman, Sarah Conley, Jamie Connarn, Lichao Sun, Hsiu-Fang Lee, Maria Ouzounova, Max Wicha, Duxin Sun. Natural product sulforaphane selectively inhibits breast cancer stem cells in basal and trastuzumab resistant Her2+ 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 913. doi:10.1158/1538-7445.AM2013-913
Abstract 918: ASP3026, a selective ALK inhibitor, shows anti-tumor activity in a mouse model xenografted with NCI-H2228 intracranially.
Authors: Konagai Satoshi , Fushiki Hiroshi , Sakagami Hideki , Ueno Yoko , Mori Masamichi , Shimada Itsuro , Kondoh Yutaka , Miyoshi Sousuke , Nishimura Shintaro , Kuromitsu Sadao 
Published: August 2014

Abstract
EML4-ALK translocation has been validated as a therapeutic target in a subset of non-small cell lung cancer (NSCLC) patients. Crizotinib, an FDA-approved ALK inhibitor, is effective against several types of human cancers with ALK abnormalities including EML4-ALK, RANBP2-ALK and ALK mutations. However, long-term treatment is often limited by the development of resistant tumors and distant metastases. Multiple brain metastases are a critical issue because of their poor prognosis despite the standard radiotherapy. The reason for metastases and development of tumor in the brain could be attributable to the poor penetration of crizotinib into central nervous system, as previously reported. ASP3026 is a selective ALK inhibitor which shows antitumor activities in several crizotinib-refractory models including gate keeper mutants.
Here, we established an intracranial xenograft model by implanting NCI-H2228 cells directly in the brain of immunocompromised mice. Xenografted cells develop intracranial tumors which grow in murine brain and eventually become lethal, resembling the clinical tumors that metastasized in the brain.
To determine the anti-tumor activity against tumors in the brain, mice were treated with ASP3026 or crizotinib for 2 weeks and held to observe survival duration. Ten, 30 and 100 mg/kg daily oral administration of ASP3026 dose dependently inhibited tumor growth in brain, and tumor regression was achieved in 30 and 100 mg/kg groups confirmed by MR imaging. These results were supported by the observation that Ktrans and IAUC (90s) were significantly decreased in 30 and 100 mg/kg groups using dynamic contrast enhanced MR imaging (DCE-MRI). Furthermore, ASP3026 significantly prolonged the survival of tumor bearing mice compared to vehicle treatment group. On the other hand, 30mg/kg daily oral administration of crizotinib inhibited the tumor growth during the treatment period but did not produce significant survival benefit.
Taken together, these results indicate that ASP3026 shows better efficacy than crizotinib and improves overall survival in an intracranial mouse xenograft model, suggesting that ASP3026 may have potential to benefit EML4-ALK positive NSCLC patients with brain metastases.
Citation Format: Satoshi Konagai, Hiroshi Fushiki, Hideki Sakagami, Yoko Ueno, Masamichi Mori, Itsuro Shimada, Yutaka Kondoh, Sousuke Miyoshi, Shintaro Nishimura, Sadao Kuromitsu. ASP3026, a selective ALK inhibitor, shows anti-tumor activity in a mouse model xenografted with NCI-H2228 intracranially. [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 918. doi:10.1158/1538-7445.AM2013-918
Abstract 94: Identifying biomarkers of estrogen response in models of serous ovarian cancer.
Authors: Andersen Courtney L. , Sikora Matthew J. , Haluska Paul , Oesterreich Steffi 
Published: August 2014

Abstract
Ovarian cancer is the fifth leading cause of cancer death among women in the United States. Despite advances in treatment for other cancers, ovarian cancer patient prognosis has not improved significantly since the advent of platinum-based chemotherapy. It is a highly heterogeneous disease with at least four distinct histological subtypes: serous, mucinous, endometrioid, and clear cell. However, no subtype- or biomarker-specific therapies are approved for ovarian cancer. Identifying targeted therapies is crucial to improving clinical outcomes. Specific therapies will likely vary based on tumor histology and biomarkers.
Expression of estrogen receptor alpha (ER) is a well established biomarker of response to endocrine therapies in breast cancer. Despite the success of anti-estrogen therapies in treating breast cancer, little attention has been given to their potential in ovarian cancer. However, epidemiologic studies show that approximately 70% of epithelial ovarian tumors express ER, particularly serous and endometrioid subtypes, and that estrogen plays a role in ovarian cancer etiology. Further, clinical data suggest that a subset of ovarian cancer patients can be successfully treated with endocrine therapy. We hypothesize that some ovarian tumors require estrogen for growth and that predictive biomarkers will identify patients who will benefit from endocrine therapy.
Using cell line models, we examined the response of ovarian cancer cells to estrogen (E2) and anti-estrogens with regard to gene expression and cell proliferation. E2 induces expression of canonical ER target genes (e.g. GREB1) in these cells, suggesting that they are estrogen-responsive. We observe that 4-hydroxytamoxifen and fulvestrant inhibit growth of ovarian cancer cells including the chemo-resistant line PEO4. Gene expression microarray studies identified additional E2-regulated genes in ovarian cancer cells that may be utilized as biomarkers of ER activity. We are expanding our studies to in vivo models (human primary tumor xenografts) to evaluate the role of E2 in driving tumor progression and determine the efficacy of anti-estrogens in treating serous ovarian cancer.
There is a critical need for targeted therapies in ovarian cancer. Our studies will determine if endocrine responsiveness correlates with gene expression of specific biomarkers, which may lead to the identification of predictive clinical markers of response to endocrine therapy.
Citation Format: Courtney L. Andersen, Matthew J. Sikora, Paul Haluska, Steffi Oesterreich. Identifying biomarkers of estrogen response in models of serous ovarian 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 94. doi:10.1158/1538-7445.AM2013-94
Abstract 949: miR-634 restores drug sensitivity in tumor cells derived from patients with terminal drug-resistant ovarian cancer.
Authors: van Jaarsveld Marijn TM , van Kuijk Patricia F. , Boersma Antonius WM , Helleman Jozien , van Ijcken Wilfred F. , Mathijssen Ron HJ , Pothof Joris , Berns Els MJJ , Verweij Jaap , Wiemer Erik AC 
Published: August 2014

Abstract
The development of drug resistance is still a major impediment for the successful treatment of cancer. This is particularly pressing in the case of advanced ovarian cancer, which has a 5-year survival rate of 30%. Ovarian cancer is treated with paclitaxel and platinum (e.g cisplatin or carboplatin) combination chemotherapy. Despite an initial high chemo-responsiveness, most ovarian cancer patients will relapse and ultimately die of drug-resistant disease. The molecular processes that contribute to resistance have been extensively studied, however, not much is known about the role of microRNAs (miRNAs), small non-coding RNAs that regulate gene expression.
We compared miRNA expression profiles of isogenic cisplatin sensitive and resistant cell line pairs. The only miRNA that was consistently downregulated in all three resistant cell lines was miR-634 (FDR&lt;1%). Overexpression of miR-634 in ovarian cancer cell lines gave rise to a minor, but reproducible, cell cycle block and reduced cellular viability by 20-50%. In addition, miR-634 transfection resensitized cisplatin-resistant ovarian cancer cell lines. We next investigated whether miR-634 overexpression could enhance therapy response in a more clinical setting. We isolated and cultured tumor cells from 7 patients that had become refractory to carboplatin-paclitaxel combination chemotherapy. We show that miR-634 overexpression causes a ∼two-fold decrease in IC50 for cisplatin and carboplatin treatment. In addition, a ∼1.3-fold decrease in doxorubicin sensitivity was observed upon miR-634 overexpression. Finally, overexpression of miR-634 resulted in downregulation of its predicted targets Cyclin D1 and GRB2, ERK2, RSK1 and RSK2, components of the Ras-MAPK pathway. The combined effect on these miR-634 targets may explain the effects on the cell cycle, cellular viability and response to chemotherapy.
Altogether, our findings suggest that miR-634 modulates important cancer relevant targets and that raising miR-634 levels can be a means to resensitize chemotherapy resistant ovarian tumors.
Citation Format: Marijn TM van Jaarsveld, Patricia F. van Kuijk, Antonius WM Boersma, Jozien Helleman, Wilfred F. van Ijcken, Ron HJ Mathijssen, Joris Pothof, Els MJJ Berns, Jaap Verweij, Erik AC Wiemer. miR-634 restores drug sensitivity in tumor cells derived from patients with terminal drug-resistant ovarian 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 949. doi:10.1158/1538-7445.AM2013-949
Abstract 952: Stemofoline is a potent natural product modulator of the multidrug resistance-linked P-glycoprotein (ABCB1).
Authors: Ohnuma Shinobu , Chanmahasathien Wisinee , Miura Koh , Unno Michiaki , Abudkar Suresh V. , Limtrakul Pornngarm 
Published: August 2014

Abstract
Background: Stemofoline is a plant alkaloid isolated form Stemona, which is native to southeastern Asia. P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter superfamily is implicated in multidrug resistance (MDR) in cancer cells. Aim: To investigate the effect of stemofoline on Pgp function.
Methods and Results: Stemofoline stimulated Pgp-mediated ATP hydrolysis (conc. required for 50% stimulation= 10-12, μM), suggesting that this alkaloid seems to interact with drug-binding site of Pgp. Consistent with this view, stemofoline inhibited the photo-crosslinking of Pgp with [125I]-iodoarylazidoprazosin (IAAP), which is a transport substrate. Interestingly, stemofoline instead of inhibiting verapamil-stimulated ATP hydrolysis, it further enhanced the ATPase activity suggesting that stemofoline and verapamil bind simultaneously to Pgp in the drug-binding pocket. In addition, the efflux of the fluorescent substrate calcein-AM from P-gp expressing cervical cancer cells (KB-V1) was blocked by stemofoline in a concentration-dependent manner.
Conclusion: These studies indicate that stemofoline could be developed as a potent modulator to overcome MDR in cancer cells.
Citation Format: Shinobu Ohnuma, Wisinee Chanmahasathien, Koh Miura, Michiaki Unno, Suresh V. Abudkar, Pornngarm Limtrakul. Stemofoline is a potent natural product modulator of the multidrug resistance-linked P-glycoprotein (ABCB1). [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 952. doi:10.1158/1538-7445.AM2013-952
Abstract 963: Characterizing acquired resistance mechanisms to targeted therapy in FGFR1-amplified lung squamous cell carcinoma.
Authors: Liao Rachel G. , Sivachenko Andrey , Getz Gad , Dutt Amit , Hammerman Peter S. , Meyerson Matthew 
Published: August 2014

Abstract
Inhibitors targeting specific genomic alterations have revolutionized cancer therapy and dramatically improved patient outcomes; nonetheless, after a period response, patient tumors almost universally develop resistance to these inhibitors and recur. In the case of squamous cell carcinoma of the lung, it has been demonstrated that focal amplifications of the FGFR1 gene occur in at least 10% of patients and that a subset of these events are sensitive to FGFR targeted therapies. Here, we describe the generation of resistant clones of the cell line NCI-H2077 to several FGFR inhibitors with clinical potential. This cell line is a squamous lung line with a focal amplification of FGFR1 that demonstrates dependency in the presence of both small molecule inhibitors and knockdown of the FGFR1 protein. After generation of resistant clones, we performed RTK phosphorylation arrays in the presence and absence of inhibitor to determine whether there were changes in the activity of other kinases, and the lines were sequenced to determine whether secondary mutations in FGFR1 had arisen. Follow-up experiments were performed to determine alternative sensitivities of the resistant clones. These experiments contribute to our growing understanding of the resistance mechanisms that arise in response to kinase inhibitors, and it is our hope that they will benefit patients undergoing treatment for FGFR1-amplified lung squamous cell carcinoma.
Citation Format: Rachel G. Liao, Andrey Sivachenko, Gad Getz, Amit Dutt, Peter S. Hammerman, Matthew Meyerson. Characterizing acquired resistance mechanisms to targeted therapy in FGFR1-amplified lung squamous cell carcinoma. [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 963. doi:10.1158/1538-7445.AM2013-963
Abstract 969: The anti-apoptotic impact of neurotrophic factor GDNF on breast cancer cells pre-treated with trastuzumab.
Authors: Gardaneh Mossa , Shojaei Sahar 
Published: August 2014

Abstract
Reports on breast cancer resistance to hormone/antibody therapy indicate molecular switches between membrane or non-membrane tyrosine kinase receptors may be key players. We investigated the impact of glial cell line-derived neurotrophic factor (GDNF) on the activity of these receptors in breast cancer cell lines pre-treated with trastuzumab that blocks her2. We found by RT-PCR and Western blot analyses that GDNF activates SRC via GDNF-specific receptor Ret leading to SRC-AKT interaction in the lipid raft of the cell membrane. Consequently, p53 is phosphorylated and interacts with MDM2 that ultimately inhibits apoptosis. Phosphorylation and activation events occurred more robustly in SKBR3, a cell line with strong her2 expression, than in MCF-7 and MDA-MB-231 both having lower expression levels of her2. Inhibition of the SRC-AKT interaction using an SRC-specific antibody blocked GDNF-promoted anti-apoptotic effects. We found similar changes when we replaced cell lines with her2-positive tumor cells collected from breast cancer patients. GDNF is introduced a molecular switch for promoting drug resistance in breast cancer therapy.
Citation Format: Mossa Gardaneh, Sahar Shojaei. The anti-apoptotic impact of neurotrophic factor GDNF on breast cancer cells pre-treated with trastuzumab. [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 969. doi:10.1158/1538-7445.AM2013-969
Abstract 999: Epidermal growth factor protects squamous cell carcinoma against cisplatin-induced cytotoxicity through increased interleukin-1β expression.
Authors: Huang Chi-Ruei , Yang Jhen-Hong , Chang Wen-Chang , Chen Ben-Kuen 
Published: August 2014

Abstract
The expression of cytokines, such as IL-1β, and the activation of the epidermal growth factor receptor (EGFR) are crucial regulators in the process of carcinogenesis. The correlation between growth factor and activated cytokine signals in the control of tumor development is a critical issue to be clarified. In our study, we found that the IL-1β gene and protein expression were induced by EGF in squamous cell carcinoma. To clarify the mechanism involved in EGF-regulated
IL-1β expression, we examined the transcriptional activity and mRNA stability of IL-1β in EGF-treated cells. We found that EGF induced the expression of IL-1β, and was mediated through transcriptional activation, but not through mRNA stability. The involvement of Akt and NF-κB signaling pathways in the EGF-induced IL-1β gene expression and promoter activity was confirmed by treating cells with Akt and NF-κB inhibitors, LY294002 and parthenolide, respectively. Using immunofluorescence staining assay, the EGF-stimulated nuclear translocation of NF-κB (p65) was inhibited by pre-treating cells with
LY294002 and parthenolide. Furthermore, EGF increased the binding of NF-κB to the NF-κB binding site of the IL-1β promoter through the activation of the Akt/NF-κB pathway, which resulted in activating IL-1β promoter activity. The expression and secretion of IL-1β induced by EGF considerably reduced chemotherapeutic drug cisplatin-induced cell death. These results showed that EGF enhanced the expression of IL-1β, which was mediated by the Akt/NF-κB pathway. The activation of EGF signaling and increase of IL-1β contributed to chemotherapeutic resistance of cancer cells, suggesting that the expression of IL-1β may be used as a biomarker to evaluate successful cancer treatment.
Citation Format: Chi-Ruei Huang, Jhen-Hong Yang, Wen-Chang Chang, Ben-Kuen Chen. Epidermal growth factor protects squamous cell carcinoma against cisplatin-induced cytotoxicity through increased interleukin-1β expression. [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 999. doi:10.1158/1538-7445.AM2013-999