bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 89: Parathyroid Hormone-related Protein (PTHrP) is critical for breast tumour metastasis and may constitute a novel target for therapeutic intervention.
Authors: Li Jiarong , Karaplis Andrew C. , Huang Dao C. , Siegel Peter M. , Camirand Anne , Yang1 Xian Fang , Muller William J. , Kremer Richard 
Published: August 2014

Abstract
An increase in PTHrP circulating levels is associated with breast cancer recurrence and reduced survival. Despite the frequent association of PTHrP dysregulation with many tumor types, a precise and direct role for PTHrP in cancer development and progression has been difficult to prove, and its involvement in tumor initiation in vivo and in critical steps of malignant conversion is not clear. In this study, mice carrying a conditional PTHrP allele were crossed with the PyVMT transgenic mouse mammary tumor model and then with a separate transgenic strain expressing Cre in the mammary epithelium (MMTV/Cre). Circulating tumor cells (CTCs) were detectable in animals with PyVMT-PTHrPflox/flox-Cre−phenotype but not in animals with PyVMT-PTHrPflox/flox-Cre+ phenotype. The invasive ability in vitro of PyVMT-PTHrPflox/flox-Cre+cells was reduced by over 80% (P&lt;0.001) as compared to control cells (PyVMT-PTHrP flox/flox-Cre−). Metastatic spread to lungs was seen in 100% of animals with PyVMT-PTHrP flox/flox-Cre− phenotype but none of the animals with PyVMT-PTHrP flox/flox-Cre+ phenotype. AKT1 and CXCR4 expression by Western blot and confocal microscope in both isolated cells and tumors from both genotypes. Akt 1 and CXCR4 expression by Western blot and immunofluorescence were markedly reduced (over 80% P&lt;0.001) in PyVMT-PTHrPflox/flox-Cre+cells and tumors as compared to PyVMT-PTHrPflox/flox-Cre− cells and tumors. Anti-PTHrP neutralizing mAbs significantly inhibited matrigel invasion by human MDA-MB-435 breast cancer and their growth in vivo when injected into the MFPs of BALB/c nu/nu mice. After 6 weeks, approximately 100% of control animals presented lung metastases in contrast with 33% for mAb-treated mice the mAbs antibody reduced the expression of CXCR4 and AKT1 in mammary tumours by over 80% these results suggest that anti-PTHrP antibodies can be considered for therapeutic use against human breast cancer progression. Overall,our study demonstrates that PTHrP plays a crucial role in metastatic spread possibly by altering critical checkpoint of cancer progression and suggest its potential usefulness to prevent progression and recurrence of breast cancer. These results also suggest that anti-PTHrP antibodies can be considered for therapeutic use against human breast cancer progression.
Citation Format: Jiarong Li, Andrew C. Karaplis, Dao C. Huang, Peter M. Siegel, Anne Camirand, Xian Fang Yang1, William J. Muller, Richard Kremer. Parathyroid Hormone-related Protein (PTHrP) is critical for breast tumour metastasis and may constitute a novel target for therapeutic intervention. [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 89. doi:10.1158/1538-7445.AM2013-89
Abstract 902: Role of ABCC10 in taxane mediated resistance in non-small cell lung carcinoma.
Authors: Wangari-Talbot Janet , Zhang Bruce , Hopper-Borge Elizabeth 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer deaths worldwide with non-small cell lung cancer (NSCLC) accounting for ∼85% of diagnosed cases. The 5 year survival rate for NSCLC is ∼15% with less than 7% of the patients alive 10 years after initial diagnosis. The taxanes, docetaxel and paclitaxel are potent chemotherapeutic drugs which result in cell cycle arrest and apoptosis through inhibition of microtubule depolymerization and are fundamental in cancer treatment regimens and are used as first line agents in NSCLC. Chemoresistance is a major obstacle in the treatment of NSCLC, an observation attributed in part to the drug efflux activity of the ATP Binding Cassette (ABC) transporter family proteins. ABCC10, a member of the ABC transporter family has been shown to confer resistance to various anti-neoplastic agents including docetaxel and paclitaxel in vitro. More importantly, Abcc10 null mice have been shown to exhibit increased tissue sensitivity to paclitaxel in vivo. Thus, ABCC10 may be an ideal target for investigation as a factor involved in reducing taxane efficacy. Here, we investigate whether ABCC10 has a role in taxane resistance in non-small cell lung carcinoma.
Human NSCLC cell lines were examined for ABCC10 expression by western immunoblots ABCC10 expression was then targeted for suppression using short-hairpin RNAs in the NSCLC cell lines A549 and H1299. Our results show that ABCC10 is expressed at varying levels in human NSCLC cell lines. Furthermore, suppression of ABCC10 in NSCLC cell lines resulted in increased cellular accumulation of docetaxel as well as a reduction in the efflux of the drug out of the cells. Further studies are needed to assess effects of ABCC10 in vivo on docetaxel sensitivity as well as the mechanisms involved in regulating ABCC10 activity.
Citation Format: Janet Wangari-Talbot, Bruce Zhang, Elizabeth Hopper-Borge. Role of ABCC10 in taxane mediated resistance in non-small cell lung 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 902. doi:10.1158/1538-7445.AM2013-902
Abstract 905: Design and synthesis of regorafenib analogues against signal transducers and activators of transcription 3 in hepatocellular carcinoma cells.
Authors: Su Jung-Chen , Chen Kuen-Feng , Tai Wen-Tien , Huang Jui-Wen , Shiau Chung-Wai 
Published: August 2014

Abstract
Background: Regorafenib has been approved for the treatment of metastatic colorectal cancer (m-RCC) by FDA. The major targets of regorafenib are membrane-bound and intracellular kinases including RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl pathways. In HCC, signal transducers and activators of transcription 3 (STAT3) is a key transcription factor involving in cell proliferation and survival in hepatocellular carcinoma cells, Targeting STAT3 by small molecule is a promising strategy in HCC therapy. Methods: We have designed and synthesized a series of regorafenib analogues without kinase inhibitory activity. These compounds are treated with and analyzed in terms of STAT3 activity in HCC cell lines. Also, Effects of regorafenib analogues induced cell death are evaluated. Results: We demonstrate that regorafenib and its analogues repress STAT3 phosphorylation, subsequently abrogate STAT3-regulated protein, Mcl-1 and cyclin D1 and further induce apoptosis in HCC cells. Overexpression of STAT3 in PLC-5 cells attenuates apoptotic effect with regorafenib and its analogues treatment, suggesting STAT3, at least, is a major target. Interestingly, the new analugues of regorafenib are devoid of kinase inhibitory activity which implies the involvement of other regulation factors. The activity of negative regulator of STAT3, such as protein tyrosine phosphatases, is under investigation. In summary, the new analogues provide a lead for the design of a new class of agents that inhibit STAT3 along and synergize with clinical drugs in HCC.(Supported by NSC 100-2325-B-010-007)
Citation Format: Jung-Chen Su, Kuen-Feng Chen, Wen-Tien Tai, Jui-Wen Huang, Chung-Wai Shiau. Design and synthesis of regorafenib analogues against signal transducers and activators of transcription 3 in hepatocellular carcinoma cells. [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 905. doi:10.1158/1538-7445.AM2013-905
Abstract 914: CIP2A mediates the effect of tamoxifen-induced apoptosis in estrogen receptor negative breast cancer cells.
Authors: Tseng Ling-Min , Liu Chun-Yu , Chang Kung-Chi , Wang Duen-Shian , Shiau Chung-Wai , Chen Kuen-Feng 
Published: August 2014

Abstract
Background: Tamoxifen is an antagonist of the estrogen receptor (ER) in breast tissue and has been a standard anti-estrogen agent in hormone receptor-positive breast cancers. Previous studies have indicated that tamoxifen also induces estrogen receptor-independent cell death in ER-negative breast cancer cells. Our previous study has shown that CIP2A, cancerous inhibitor of PP2A, may be a novel target in breast cancer cells (Breast Cancer Research 2012). Here, we tested efficacy of tamoxifen in a panel of ER-negative breast cancer cells and examined the drug mechanism. Methods: ER-negative breast cancer cell lines (HCC-1937, SK-BR3, MDA-MB-468, MDA-MB-453, MDA-MB-231) were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). In vivo efficacy of tamoxifen was tested in nude mice with breast cancer xenografts. Results: Tamoxifen showed differential effects on apoptosis in human ER-negative breast cancer cell lines. Tamoxifen induced significant apoptosis in SK-BR3, MDA-MB-468, MDA-MB-453, MDA-MB-231 cell lines; however, HCC-1937 cells were resistance to tamoxifen-induced apoptosis. Tamoxifen inhibited CIP2A in a dose-dependent manner in all sensitive ER-negative breast cancer cells, but not in resistant cells (HCC-1937). Overexpression of CIP2A protected MDA-MB-231 cells from tamoxifen-induced apoptosis. In addition, silencing CIP2A by siRNA sensitized HCC-1937 cells to tamoxifen-induced apoptosis. Moreover, in vivo xenograft data showed that tamoxifen inhibited the growth of MDA-MB-468 tumors but had no effect on HCC-1937 tumors. Furthermore, tamoxifen downregulated CIP2A in sensitive MDA-MB-468 xenograft tumors, but not in HCC-1937 tumors. Conclusions: Inhibition of CIP2A determines the effects of tamoxifen-induced apoptosis in ER-negative breast cancer cells. (Supported by Yen Tjing Ling Medical Foundation; NSC 101-2325-B-075-006 and NSC 100-2325-B-010-007; and V100-D-005-4)
Citation Format: Ling-Min Tseng, Chun-Yu Liu, Kung-Chi Chang, Duen-Shian Wang, Chung-Wai Shiau, Kuen-Feng Chen. CIP2A mediates the effect of tamoxifen-induced apoptosis in estrogen receptor negative breast cancer cells. [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 914. doi:10.1158/1538-7445.AM2013-914
Abstract 915: Melanomas with rare BRAF mutations and their responses to MAPK pathway blocking drugs.
Authors: Atefi Mohammad S. , Ng Charles P. , Wong Deborah J. , Robert Lidia , Escuin-Ordinas Helena , Lassen Amanda , Foulad David , Comin-Anduix Begonya , Samatar Ahmad A. , Ribas Antoni 
Published: August 2014

Abstract
The BRAF V600E driver mutation is found in more than 50% of melanomas. Less common BRAF mutations of V600K, V600R, L597S, and G466K have also been identified. In these rare BRAF mutants, the effects of vemurafenib (Vem) and other MAPK pathway inhibitors on signaling, growth rate and clinical course are not well understood. In cell lines with rare BRAF mutations, we investigated the effect of Vem, inhibitors of Pan-RAF (Amgen 2112819), MEK (trametinib), ERK (MERK SCH772984), Pan-RAFi+ MEKi and ERKi+Vem on growth and signaling. These results were compared to the clinical responses to BRAF and MEK inhibitors in patients with the original tumors. Regardless of the mutation, no paradoxical activation of MAPK pathway by Vem was observed and the Pan-Rafi decreased levels of pMEK in all the cell lines. A heterozygous V600K mutated cell line was sensitive to Vem and more sensitive to the other drugs. Clinically, the duration of response to Vem in the patient the cell line was derived from was 7 months, and an additional 3 months to the combination of Vem and MEKi upon progression on Vem. In contrast, a homozygous V600K mutated cell line was resistant to Vem but sensitive to other MAPK inhibitors. The patient the cell line was derived from had a 5 month response to Vem followed by a 2 month response to the addition of a MEKi. BRAF L597S cell line was only sensitive to ERKi and G466K and V600R mutated cell lines were resistant to all the drugs. In general, Vem was the least effective followed by Pan-RAFi with ERKi stronger than both in most cell lines. The combination of Vem and ERKi showed similar or slightly higher growth inhibition than ERKi alone. In conclusion, MAPK inhibitors are not as effective in melanoma cell lines with rare BRAF mutations. However, more growth inhibition can be achieved by MEKi-Pan-RAFi combination. These in vitro data seem to be correlated with the clinical outcomes.
*Charles Ng, equal contribution
Citation Format: Mohammad S. Atefi, Charles P. Ng, Deborah J. Wong, Lidia Robert, Helena Escuin-Ordinas, Amanda Lassen, David Foulad, Begonya Comin-Anduix, Ahmad A. Samatar, Antoni Ribas. Melanomas with rare BRAF mutations and their responses to MAPK pathway blocking drugs. [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 915. doi:10.1158/1538-7445.AM2013-915
Abstract 917: High antitumor activity of the ERK inhibitor SCH722984 against BRAF-mutant, NRAS-mutant and wild-type melanoma cell lines.
Authors: Wong Deborah J. , Robert Lidia , Atefi Mohammad S. , Foulad David , Avramis Earl V. , Comin-Anduix Begonya , Samatar Ahmed A. , Ribas Antoni 
Published: August 2014

Abstract
MAPK pathway dysregulation via mutations in proteins such as BRAFV600E and NRASQ61 is a key feature in melanomas, leading to constitutive ERK signaling. Currently, there are no FDA-approved targeted therapies effective in vemurafenib-resistant BRAFV600E mutant, NRAS mutant, or wild-type melanoma. The effect of SCH722984, an allosteric inhibitor of ERK 1/2, was determined in a panel of 53 melanoma cell lines, including wild-type, NRAS-mutant and vemurafenib-sensitive and resistant BRAF-mutant melanoma. 54% (13 of 24) of BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH722984 with an IC50 &lt;1μM. 100% (3 of 3) of BRAF/NRAS double mutants, 71% (10 of 14) of NRAS mutants and 71% (5 of 7) of wild-type melanomas were sensitive. 13% (5 of 24) of BRAF mutants, 14% (2 of 14) of NRAS mutants and 29% (2 of 7) of wild-type melanomas were intermediately sensitive (IC50 1-1.5μM). Among BRAFV600E mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH722984. Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines, resulting in up to 10-fold decrease in the 50% inhibitory concentration (IC50) and with combination indices (CI) below 1. SCH722984 inhibited phosphorylation of RSK, an ERK downstream target. Finally, long term cultures of two BRAFV600E-mutant cell lines sensitive to SCH722984 showed that treatment with SCH722984 alone or in combination with vemurafenib was more potent than vemurafenib alone and resulted in a significant delay in developing acquired resistance. SCH722984 may therefore be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors.
Citation Format: Deborah J. Wong, Lidia Robert, Mohammad S. Atefi, David Foulad, Earl V. Avramis, Begonya Comin-Anduix, Ahmed A. Samatar, Antoni Ribas. High antitumor activity of the ERK inhibitor SCH722984 against BRAF-mutant, NRAS-mutant and wild-type melanoma cell lines. [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 917. doi:10.1158/1538-7445.AM2013-917
Abstract 927: Combined targeting c-Src and c-Met pathways to impair prostate cancer cell growth and invasion.
Authors: Dai Yao , Bae Kyung-Mi , Siemann Dietmar W. 
Published: August 2014

Abstract
Overexpression of tyrosine kinases c-Src and c-Met has been shown to be highly associated with prostate cancer progression and poor clinical outcomes, therefore small molecule Src or Met inhibitors are being extensively evaluated in clinical trials for advanced prostate cancer. However clinical data suggest that single treatment with any of these inhibitors only yield limited effects in patients. One possibility is that redundant signaling pathways in tumor cells exist that allows tumor cell uninterrupted upon blockade of purely one pathway. We hypothesize that c-Src and c-Met are two compensatory pathways that may cooperate to promote prostate cancer progression, hence here we studied treatment effects of combining inhibitors targeting c-Src (dasatinib, saracatinib) and c-Met (ASLAN002, also named BMS-777607) on multiple functional behaviors associated with tumor growth and metastasis in c-Src and c-Met expressing prostate cancer cells (PC-3, DU145). Combination of Src inhibitors and ASLAN002 was found to inhibit cell proliferation and colony formation more strongly than either single agent, as assessed by MTT and clonogenicity, respectively. In a wound-healing assay, compared to either treatment alone, the combinatorial treatment exhibited greater suppression on cell motility induced by hepatocyte growth factor, the only known ligand of c-Met. Similarly, using a Matrigel-based Transwell assay, Src inhibitors plus ASLAN002 resulted in significant reduction of cell invasion in the presence or absence of HGF. Western blot analysis demonstrated that co-targeting Met and Src kinases lead to not only inhibition on c-Met and c-Src autophosphorylation but also greater blockade of multiple downstream kinases such as focal adhesion kinase (FAK), Akt and extracellular signal-regulated kinase (ERK). These data indicate that combined application of small molecule Src and Met inhibitors cause significant impairment on various phenotypes associated with prostate cancer progression in vitro including proliferation, survival, migration and invasion, suggesting that this combination intervention modality may serve as a potential anti-metastatic strategy that could be further tested in metastatic prostate cancer models in vivo.
Citation Format: Yao Dai, Kyung-Mi Bae, Dietmar W. Siemann. Combined targeting c-Src and c-Met pathways to impair prostate cancer cell growth and invasion. [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 927. doi:10.1158/1538-7445.AM2013-927
Abstract 93: CXCR4 expression in VHL-related and sporadic hemangioblastomas.
Authors: Kruizinga Roeliene C. , den Dunnen Wilfred F.A. , de Vries Elisabeth G.E. , Links Thera P. , Walenkamp Annemiek M.E. 
Published: August 2014

Abstract
Background & aim. Central nervous system hemangioblastomas are sporadically as well in patients with von Hippel-Lindau (VHL) disease. In VHL disease a germline mutation in the VHL- gene leads to a defect VHL protein. This results in enhanced transcription of vascular endothelial growth factor (VEGF)-A, chemokine receptor 4 (CXCR4) and its ligand (CXCL12). The aim of this study was to analyze whether VEGF-A, CXCR4, and CXCL12 protein expression differ between VHL-related and sporadic hemangioblastomas.
Methods. Freshly frozen tissue of patients operated in the University Medical Center Groningen the Netherlands, for hemangioblastomas between 1995-2010 was retrieved. Thirtythree samples of 27 patients were available, including 11 patients diagnosed with VHL-disease. Immunohistochemical analysis of 33 hemangioblastoma specimens (4 VHL patients and 1 sporadic patient were included more than once) was performed for hematoxylin & eosin, VEGF-A, CXCR4 and CXCL12 expression and compared with normal surrounding brain tissue. VEGF-A was evaluated describing morphology in relation to positive cells. A semi quantitative evaluation was performed for CXCL12; negative, positive (&gt;1% positive cells) or strongly positive (&gt;50 % positive cells or high intensity). CXCR4 was scored quantitatively by counting percentage of positive cells per specimen.
Results. VEGF-A was equally expressed in all sporadic and VHL-related hemangioblastomas, and present in hemangioblastoma cells and endothelial cells. CXCL12 was strongly expressed in 78% of hemangioblastoma tissues and did not differ between sporadic and VHL-related hemangioblastomas. In all hemangioblastomas CXCR4 was overexpressed as compared to the normal surrounding brain tissue (found in 15 specimens). Interestingly, in sporadic hemangioblastomas the mean percentage of CXCR4 positive cells per specimen (15%) was higher as compared to VHL-related hemangioblastomas (7%, p=0.001).
Conclusions. VEGF-A and CXCL12 protein expression was overexpressed in the majority of VHL-related and sporadic hemangioblastomas. This makes targeting VEGF-A a potential strategy for hemangioblastoma treatment. In addition, targeting CXCR4 could be of additional value as it was overexpressed in all hemangioblastomas, although differences in expression between sporadic and VHL related hemangioblastomas do exist.
Supported by a grant from the Jan Kornelis de Cock Stichting and a UEF-JSM Talent Grant to RC Kruizinga.
Citation Format: Roeliene C. Kruizinga, Wilfred F.A. den Dunnen, Elisabeth G.E. de Vries, Thera P. Links, Annemiek M.E. Walenkamp. CXCR4 expression in VHL-related and sporadic hemangioblastomas. [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 93. doi:10.1158/1538-7445.AM2013-93
Abstract 943: RRM2: a key contributor in tamoxifen resistance in breast cancer.
Authors: Shah Khyati Niral , Peterson David , Evangelista Marie , Faridi Jesika 
Published: August 2014

Abstract
Tamoxifen is primarily used for early and advanced ER positive breast cancer patients. Unfortunately about 58% of the patients fail to respond to tamoxifen and eventually relapse with more aggressive tumors. Therefore, understanding the molecular mechanism of resistance is necessary to design new therapeutic strategies to overcome resistance. In this study, we show that Ribonucleotide Reductase M2 subunit is highly expressed in Akt over-expressing breast cancer cell lines and these breast cancer cell lines are highly resistant to tamoxifen treatment In-vitro. In these breast cancer cell lines, RNA interference mediated by small interfering RNA against RRM2 sensitizes these cells to tamoxifen-induced toxicity and reversed the tamoxifen resistance. Also, Using Oncomine database, we demonstrate that RRM2 is overexpressed in breast cancer. This is the first demonstration that investigate role of RRM2 in tamoxifen resistance and could serve as a potential target to restore tamoxifen sensititivity in breast cancer cells.
Citation Format: Khyati Niral Shah, David Peterson, Marie Evangelista, Jesika Faridi. RRM2: a key contributor in tamoxifen resistance in 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 943. doi:10.1158/1538-7445.AM2013-943