bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 189: miRNAs regulating members of SLC transporter family genes in penile carcinomas
Authors: Muñoz Juan J. , Linde Sandra A. , Barros Mateus C. , Busso Ariane F. , Marchi Fábio , Soares Fernando A. , Rogatto Silvia R. 
Published: August 2012

Abstract
Background: Penile cancer (PeCa) is a rare disease in developed countries, but with high incidence in South America and Africa. Surgery is frequently used for local control of the disease and it can lead to partial or complete amputation of the organ, with subsequent psychosexual morbidity. Integrating data previously obtained using CGH-array and large-scale gene expression in PeCa, we found deregulation of members of solute carriage (SLCs) gene family that was not associated with genomic alterations. These findings suggested that other regulatory mechanisms could be involved, such as miRNAs. Aim: The purpose of this study was to confirm the gene expression pattern of six SLC genes (SLC1A3, SLC8A1, SLC25A4, SLC25A16, SLC25A25 and SLC27A4) and their putative regulatory miRNAs (miR-22, miR223, miR-23b, miR-26b, miR-27b and, miR-133b, respectively) in PeCa and associate the findings with clinical and pathological data. Patients and Methods: RNA was obtained from fresh PeCa (27 training and 13 validation set samples) and 4 normal penile tissues. SLC genes and miRNAs expression were evaluated by RT-qPCR. HPV genotyping was assessed using Linear Array HPV Test Genotyping (Roche). Results: Positive correlation between SLC1A3, SLC8A1, SLC25A4 and SLC27A4 expression levels detected by microarray and RT-qPCR was observed in the training set samples. Downexpression of SLC8A1 (P=0.009) and SLC25A25 (P=0.002) and overexpression of SLC27A4 (P=0.006) were detected in tumors (training and validation set) compared with normal controls, thus validating the previous findings of global gene expression. Significant downexpression of miR-23b, miR-26b, miR-27b and miR-133b and overexpression of miR-223 were detected in tumors compared with normal controls. Interestingly, lower levels of miR-133b were observed in 96% of the tumors (P=0.0007). Significant negative correlation was detected between SLC8A1 transcript levels and its putative regulatory miRNA (miR-223, P=0.015, r = −0.482) and between SLC27A4 e miR-133b (P=0.023, r = –0.454), suggesting that these genes are regulated by these miRNAs. Higher levels of SLC25A16 were found in HPV positive tumors (P=0.012). A significant association was found between lower levels of miR-23b and miR-27b and perineural invasion (P=0,032 and P=0,032; respectively). Conclusions: This study showed the deregulation of members of SLC gene family in PeCa and the involvement of putative regulatory miRNAs. miR-23b and miR-27b were found as putative prognostic markers in PeCa patients and with potential as therapeutic targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 189. doi:1538-7445.AM2012-189
Abstract 1900: HSP 70 may cause EGFR-TKIs-resistance due to inhibit drug binding to EGFR in the cells that expressed mutant EGFR
Authors: Ohmori Tohru , Kadofuku Tsuyoki , Ichihashi Yoko , Yamaoka Toshimitsu , Hirose Takashi , Adachi Mitsuru , Saijo Nagahiro 
Published: August 2012

Abstract
Cancer cells that expressed mutant EGFR are more sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs) than that expressed wild type EGFR. To elucidate difference of the characteristics between wild type and 15 bp deletion mutant EGFR, we explored the difference of EGFR-binding proteins using respective stable transfectants, 293_pEGFR and 293_p≤15. As the result, we detected heat shock protein 70 (HSP70) specifically binds to the mutant EGFR but wild type EGFR. To examine whether HSP70 influenced EGFR-TKI sensitivity, we examined the effect of HSP70 inhibition. [Methods] HSP70 siRNA was exposed to the cells for 2 days. Cytotoxicity of the drugs was measured by MTT assay. The drug binding to EGFR was measured by [14C]gefitinib. [Results] Suppression of HSP70 by siRNA increased gefitinib and erlotinib sensitivities and enhanced gefitinib binding to this receptor, in 293_p≤15 cells. Same phenomena were observed when HSP70 was inhibited by HSP70 specific inhibitor, 2-phenylethynesulfonamide (PES). PES inhibits HSP70 binding to the mutant EGFR. Interestingly, this compound enhanced the EGFR autophosphorylation and c-Cbl binding to the receptor in 293_p≤15 cells. These results suggest that HSP70 may modulate EGFR activity and may cause EGFR-TKIs-resistance due to inhibit drug binding to the mutant EGFR. HSP70 inhibitor may possibly enhance the efficacy of EGFR-TKIs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1900. doi:1538-7445.AM2012-1900
Abstract 1907: Heat shock protein 90 inhibition overcomes hepatocyte growth factor-triggering resistance to EGFR tyrosine kinase inhibitors in EGFR mutant lung cancer by decreasing client protein expression and angiogenesis
Authors: Yamada Tadaaki , Koizumi Hitomi , Takeuchi Shinji , Nakagawa Takayuki , Yano Seiji 
Published: August 2012

Abstract
The three major, clinically relevant mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant lung cancer are a second mutation in the EGFR gene (T790M), Met amplification, and increased expression of hepatocyte growth factor (HGF). Heat shock protein90 (Hsp90) is a 90kDa molecular chaperone for proteins that include EGFR, Met and EML4-ALK. Hsp90 inhibitors have been reported to reverse resistance to EGFR-TKIs caused by EGFR T790M mutation and Met amplification. Here, we determined whether inhibition of Hsp90 could overcome HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer cells. EGFR-TKI erlotinib inhibited the growth of PC-9, HCC827, and Ma-1 cells, with deletions in exon19 of EGFR, but not HGF-gene transfected Ma-1 (Ma-1/HGF) cells and H1975 cells, which contain the EGFR L858R and T790M mutations, respectively. Erlotinib also did not inhibit the growth of PC-9 and Ma-1 cells in the presence of HGF. However, an Hsp90 inhibitor, 17-DMAG, induced apoptosis and markedly inhibited the growth of these cell lines, even in the presence of HGF. This inhibition by 17-DMAG was associated with decreased expression of EGFR and Met, thereby decreasing Akt phosphorylation in tumor cells. In an in vivo model of HGF-triggered erlotinib-resistance, using Ma-1/HGF cells, 17-DMAG markedly suppressed tumor growth by decreasing angiogenesis and increasing apoptosis. These results indicate that Hsp90 inhibitors may overcome HGF-triggered resistance to EGFR-TKIs and that the use of Hsp90 inhibitors may result in more successful treatment of EGFR mutant lung cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1907. doi:1538-7445.AM2012-1907
Abstract 1908: MDR1 gene overexpression confers resistance to C-MET inhibitor in multidrug resistant cancer cell line
Authors: Hung Tsai-Hsien , Li Yu-Hsin , Chong Kowit-Yu 
Published: August 2012

Abstract
c-MET signaling is implicated in a wide variety of human malignancies. Hepatocyte growth factor (HGF) binding to the proto-oncogenic c-MET receptor lead to activate multiple tyrosine kinase signaling pathway. Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Recently, several reports have indicated that inhibition of c-MET signaling induced apoptosis in a variety of cancer cells and recognized as a novel anticancer therapy approach. Previous study from our laboratory also showed that the higher mRNA expression level of HGF, and its downstream genes including HGF receptor (c-Met) and urokinase (uPA) were detected in drug resistant Dx5-C5 cell compared with parental human uterus sarcoma MES-SA cell line. Furthermore, report indicated that the constitutive expression of P-glycoprotein (P-gp) is involved in the HGF/MET related pathway of MDR-positive human hepatocellular carcinoma cell line. Moreover, MDR1 gene overexpressed leukemia cell line also shown more resistance to tyrosine kinase inhibitor imatinib mesylate. These finding suggested that chemoresistant cancer cells may also develop a similar mechanism to against c-MET inhibitor. Our results shown: when treated both cell cancer lines with c-MET inhibitor PHA665752, we found that compared to parental MES-SA cells, the Dx5-C5 cells with highly expressed P-gp was more resistant to PHA665752, the resistance was also reversed by co-treatment of MDR inhibitor verapamil and PHA665752. In addition, when transfection of c-MET shRNA into Dx5-C5 and MES-SA cell line for 48 hrs, we found that the viability was decreased in the c-MET shRNA transfected Dx5-C5 cell line in a dose dependent manner but not in the MES-SA cell line. In conclusion, our study demonstrated that existence of P-glycoprotein in MDR cell line would attenuate c-MET inhibitor induced cell death and may help us to develop a new strategy for treatment of multiple drug resistance cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1908. doi:1538-7445.AM2012-1908
Abstract 1910: Acquired resistance to HER2 targeted therapy: A common mechanism
Authors: Christenson Jessica , Kane Susan E. 
Published: August 2012

Abstract
There are currently two FDA approved targeted therapies being utilized in the clinic to treat Her2+ breast cancer, trastuzumab and lapatinib. Acquired resistance has become a major concern and several mechanisms for resistance have been proposed. The upregulation of a truncated transcriptional variant of Darpp-32, known as t-Darpp, is a characteristic shared by several independently developed trastuzumab-resistant cell lines. Moreover, exogenous t-Darpp overexpression is sufficient for conferring trastuzumab resistance. No consistent mechanism, however, has been identified for lapatinib resistant cells. By inhibiting signaling through Her2+ pathways such as PI3K/Akt and Erk, lapatinib induces a strong apoptotic response by down-regulating survivin and inducing BIM. Darpp-32 and t-Darpp both have been linked to apoptosis, with t-Darpp identified as having anti-apoptotic properties through its regulation of Bcl-2. The purpose of the current study was to determine if t-Darpp or other dysregulated apoptosis proteins play a role in lapatinib resistance. Lapatinib-resistant SKBR3 cells (Her2+, ER-) were selected by continuous exposure to increasing concentrations of lapatinib (0.3-2.0µM) over the course of one year. Using Sulforhodamine B and colony forming assays, we found that individual clones and pools of SK/LapR cells were, on average, 50-fold resistant to lapatinib, relative to parental SKBR3 cells. This resistance phenotype was stable even after cells were maintained for 1 month outside of drug. As observed in trastuzumab resistance and similar to previous reports of lapatinib-resistant cells, we found that SK/LapR cells had sustained PI3K/Akt signaling in the presence of lapatinib, whereas parental cells did not. Additionally, survivin inactivation and BIM induction by lapatinib seemed to be partially impaired in SK/LapR cells. Finally, SK/LapR cells appeared to down-regulate Darpp-32 and up-regulate t-Darpp, similar to what we have reported in BT474 cells selected for resistance to trastuzumab. Although t-Darpp overexpression is sufficient to confer resistance to trastuzumab, this does not appear to be the case for lapatinib resistance – SK.tDp cells transfected with a t-Darpp cDNA are not resistant to lapatinib. Experiments are currently underway to determine if the t-Darpp overexpression that we observe in SK/LapR cells is required for lapatinib resistance. Identifying a shared mechanism of resistance to lapatinib and trastuzumab would provide a novel therapeutic target that could be widely used among Her2+ breast cancer patients to ameliorate acquired drug resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1910. doi:1538-7445.AM2012-1910
Abstract 1914: Potent anticancer activity against both BRAF-mutant and BRAF wild-type melanoma cell lines using a novel CRM1 nuclear export inhibitor
Authors: Fragomeni Roberto A. Salas , Chung Hye-Won , Shacham Sharon , Kauffman Michael , Cusack James C. 
Published: August 2012

Abstract
INTRODUCTION: BRAF and NRAS oncogenic mutations occur in over half of all human melanomas. BRAF-mutant tumors are highly sensitive to small molecule inhibitors directed against the oncogenic BRAF protein. However, in tumors that lack the specific mutation, patients have few effective therapeutic options. To address the need for new therapies for patients with BRAF-wild-type (wt) melanoma, we hypothesized that the inhibition of the major nuclear export receptor CRM1 would result in nuclear accumulation of nuclear proteins, increase apoptosis and induce cell cycle arrest independent of BRAF mutational status. To test our hypothesis, we examined the effects of a novel CRM1 inhibitor on melanoma cell lines with various BRAF and NRAS mutational backgrounds. METHODS: We used human malignant melanoma cell lines with BRAF mutation (Sk-Mel-28, A375, Mel-624, UACC903, MalMe-3M), BRAF-wt (MeWo) and BRAF-wt and NRAS mutation (Hs940T) to assess the effects of CRM1 inhibition, BRAF inhibition (PLX4032) or MEK inhibition (U0126) using both mono- or combination therapy. MTT assays were used to evaluate the effects of treatment on cell proliferation. FACS analysis with annexin/PI staining was performed to assess effects on cell cycle and cell death. The Chou-Talalay method was used to assess synergistic drug combination effects. Treatment effects on cleaved caspase-3, PARP cleavage, P53, and FOXO3 were analyzed by western blot analysis. RESULTS: As mono therapy, CRM1 inhibition led to a significant decrease in cell proliferation, cell cycle arrest and an increase in apoptosis in both BRAF wt and mutant cell lines. The degree of inhibition and cell death achieved by CRM1 inhibition across all melanoma cell lines is comparable to the results achieved by BRAF inhibitor PLX4032 in BRAF mutant cell lines. Furthermore, the combination of CRM1 inhibition and BRAF inhibition results in a strongly synergistic combination against BRAF mutant cell lines with a statistically significant decrease in cell proliferation and increased apoptotic cell death. CONCLUSION: We found that relative to other cancer cell types, both BRAF-mutant and BRAF-wt melanoma cells are exquisitely sensitive to CRM1 inhibition. In addition, CRM1 inhibition significantly enhanced the effect of PLX4032 in BRAF-mutant cell lines, suggesting that the combination of these two drugs may address the emergence of acquired resistance to BRAF monotherapy. Based on these results, CRM1 inhibition warrants further investigation to determine its potential benefit in treating melanoma patients independent of BRAF mutation status.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1914. doi:1538-7445.AM2012-1914
Abstract 1915: Novel sorafenib derivatives (SC-40, SC-43 and SC-60) show better anti-tumor effects than sorafenib in hepatocellular carcinoma through SHP-1/STAT3-mediated signaling pathway
Authors: Tai Wei-Tien , Shiau Chung-Wai , Cheng Ann-Lii , Chen Pei-Jer , Chen Kuen-Feng 
Published: August 2012

Abstract
Recently, we have reported that sorafenib sensitized hepatocellular carcinoma (HCC) cells to TRAIL via SHP-1 dependent inhibition of signaling transducer and activator of transcription 3 (STAT3) (Clinical Cancer Res, 2010). In addition, we identified the effect of sorafenib on STAT3 was independent to kinases and discovered a series of sorafenib derivatives as SHP-1 enhancers (J Hepatol, 2011; Euro J Med Chem, 2011). Here, we report effects of novel sorafenib derivatives (SC-40, SC-43 and SC-60) in HCC. SC-43 induced apoptotic cell death significantly and inhibited the phosphorylation of STAT3 (p-STAT3) at the concentration of 0.5 μM, which was more potent than sorafenib (5 μM). In addition, SC-60 also exhibited similar effects on down-regulating STAT3 transcription activity and subsequently inhibited the expression of STAT3-related proteins, including cyclin D1, survivin, and Mcl-1 in HCC cells. Furthermore, these analogues showed strong induction of SHP-1 activity while incubated with pure recombinant SHP-1 protein or SHP-1-containing cell extract at the concentrations of low nanomolar ranges. In addition, we found that SHP-2, sharing high homology in critical domains with SHP-1, was not affected neither in cultured HCC cells nor recombinant SHP-2 protein. Knockdown of SHP-1, but not SHP-2, by small interference RNA reduced apoptosis and reversed blockage of p-STAT3 induced by SC-43, 40, 60. Finally, three novel compounds, including SC-43, SC-40, and SC-60 all showed significant and better effects than sorafenib on growth inhibition of orthotopic and subcutaneous xenograft HCC tumors. In conclusion, targeting SHP-1 may be feasible for the treatment of HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1915. doi:1538-7445.AM2012-1915
Abstract 1916: Blockade of the fibroblast growth factor receptor (FGFR) system by the novel FGFR inhibitor BGJ398 modulates oncogenic signaling in human gastric cancer cells, endothelial cells and pericytes
Authors: Moser Christian , Hackl Christina , Schlitt Hans J. , Geissler Edward K. , Lang Sven A. 
Published: August 2012

Abstract
Expression of the FGFR system has been associated with poor prognosis in patients suffering from gastric cancer. Moreover, activation of FGFRs has been demonstrated to mediate tumor angiogenesis through regulation of endothelial cell (EC) and pericyte motility and survival. Therefore, in this study we sought to investigate the effects of targeting FGFR on gastric cancer cells as well as on important components of the tumor microenvironment by the novel FGFR inhibitor BGJ398. For the experiments, human gastric cancer cell lines (TMK-1 and KKLS) as well as ECs and pericytes (vascular smooth muscle cells, VSMCs) were used. The FGFR inhibitor BGJ398 was provided by Novartis Oncology (Basel, Switzerland). Effects of BGJ398 on tumor cell growth and chemoresistance were determined by MTT assays. Impact of BGJ398 on motility of cancer cells was evaluated by modified Boyden chambers. Signaling pathways affected by BGJ398 treatment were assessed by Western blot analyses. To determine effects of FGFR blockade on ECs and pericytes conditioned media from gastric cancer cells was used. Results show that targeting FGFR by BGJ398 impaired growth of gastric cancer cells in a dose-dependent manner in vitro. Furthermore, activation of Akt and Erk in cancer cells was effectively inhibited while expression of c-Myc and HIF-1α was substantially reduced. Additionally, therapy with BGJ398 led to significant inhibition of constitutive migratory and invasive properties of gastric cancer cells (P&lt;0.05). Interestingly, interference with FGFR by BGJ398 increased sensitivity for chemotherapy with oxaliplatin and 5-FU in tumor cells. In ECs as well as pericytes blockade of FGFR by BGJ398 significantly inhibited cell growth and motility even upon stimulation with conditioned media (P&lt;0.05). In conclusion, inhibition of the FGFR system by BGJ398 disrupts oncogenic signaling, impairs tumor cell motility and improves chemosensitivity in gastric cancer. Furthermore, antiangiogenic effects might be mediated via direct effects on ECs and pericytes. Hence, targeting the FGFR system may represent a promising approach to improve current therapy strategies for gastric cancer and warrants further preclinical evaluation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1916. doi:1538-7445.AM2012-1916
Abstract 1920: Small molecule inhibitor of polo-like kinase 1 (Plk1) causes significant melanoma growth delay and regression in vivo
Authors: Cholewa Brian D. , Desotelle Joshua A. , Ahmad Nihal 
Published: August 2012

Abstract
Melanoma is an aggressive skin cancer that rapidly metastasizes to become lethal, if not diagnosed early. An analysis of the Surveillance, Epidemiology, and End Results (SEER) program has suggested that the age-adjusted annual incidence of melanoma, both for young men and women, has increased over the past 20 years. In 2011, it is projected that over 70,000 new cases of melanoma will be diagnosed with nearly 9,000 cases resulting in death. Current preventive and treatment approaches have not been able to effectively manage this neoplasm. Therefore, new mechanism- and target- based approaches are urgently needed. Better understanding of the genetic control of cellular proliferation and cell division may provide the basis for the rational design of specific therapeutics for the management of cancers, including melanoma. We have previously demonstrated that the mitotic regulator Polo-like kinase 1 (Plk1) is over-expressed in clinical melanoma and a targeted depletion of Plk1 through lentiviral shRNA or a small-molecule inhibitor causes mitotic catastrophe and induction of apoptosis in human melanoma cells (J Invest Dermatol 129: 2843-53, 2009). In this study, we assessed the effect of BI6727, a second generation Plk1 specific small molecule inhibitor, in vivo in athymic nu/nu nude mice implanted with human melanoma cells. A375 cells (1x106 cells) were implanted in athymic nude by subcutaneous injection on the right flanks. The tumors were allowed to grow and the mice bearing established tumors (&gt;100 mm3) were randomized into 3 groups (containing 12 mice each). The mice were treated with BI6727 at two doses (10 mg/kg or 25 mg/kg) or a vehicle control via tail vein injections twice weekly. Our data demonstrates that in BI6727 treated animals, the rate of tumor growth (to reach to a 1000 mm3 target volume) was significantly delayed. We also found that BI6727 at 25 mg/kg resulted in a near complete tumor regression. The observed tumor regression was stable for several days following discontinuation of treatment, after which, the tumors started growing again. Additionally, we found that BI6727 caused i) a significant inhibition of cell growth and viability, and ii) induction of apoptosis in multiple melanoma cell lines. Based on this study, we suggest that Plk1 is a druggable target for melanoma and pharmacological inhibitors of Plk1 could be clinically useful in melanoma therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1920. doi:1538-7445.AM2012-1920