bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1778: Antitumor effect of PM01183 in a patient-derived Cisplatin-sensitive and -resistant serous epithelial ovarian orthotopic tumor model
Authors: Villanueva Alberto , Vidal August , Guillén M José , Salazar Ramón , Cuevas Carmen , Aviles Pablo M. 
Published: August 2012

Abstract
Background: Epithelial ovarian cancer (EOC) is the leading cause of deaths in women diagnosed with gynecologic malignancies. The low survival rate is due to its advanced-stage diagnosis and either intrinsic or acquired resistance to standard platinum-based chemotherapy. As such, the development of effective innovative therapeutic strategies to overcoming cisplatin resistance remains a high priority. PM01183 is a new alkaloid that binds to the minor groove of DNA and induces delayed progression of S phase and cycle arrest in G2/M. Currently, PM01183 clinical development includes Phase II single agent trials (pancreas, breast and platinum-resistant/refractory ovarian) as well as Phase I trials in combination (with doxorubicin and gemcitabine) and in advanced acute leukemia. Here, we report that PM01183 is effective in the treatment of new developed orthotopic subject-derived epithelial serous ovarian tumor grafts Cisplatin-sensitive and-resitan models. Material and Methods: Athymic nude female mice were orthotopically engrafted with derived-fragments of OVAX1 (Cisplatin-Sensitive) or OVAX1R (Cisplatin-Resistant) tumors, and when tumors reached homogeneous palpable size were randomly allocated into the treatment groups (N = 8-12/group): i) Placebo; ii) PM01183 (0.18 mg/kg); iii) Cisplatin (3.5 mg/kg); and, iv) PM01183 plus Cisplatin (0.18+3.5 mg/kg). Drugs were intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14) and seven days after the last dose (Day 21), animals were sacrificed, their ovaries dissected-free and weighed. Statistical differences between groups were determined using two-tailed Mann-Whitney U test. Results: On day 21, OVA1X tumors experienced reductions of 95.3, 88.3 and 87.2% following the treatment with Cisplatin, PM01183 and PM01183+Cisplatin, respectively. The results obtained for OVA1XR tumor demonstrated tumor weight reductions of 48.2, 93.6 and 96.7% for Cisplatin, PM01183 and PM01183+Cisplatin treatments, respectively. Single therapy with PM01183 induced a statistically significant better response than Cisplatin (P=0.003). Also, PM01183+Cisplatin treatment increased the activity following Cisplatin (P=0.002) or PM01183 (P=0.022) administration as single agents, suggesting thus a synergistic effect of both compounds. Conclusions: PM01183 demonstrated strong in vivo antitumor activity in pure patient-derived Cisplatin-sensitive and Cisplatin-resistant serous epithelial ovarian orthotopic tumor models.
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 1778. doi:1538-7445.AM2012-1778
Abstract 178: A novel mechanism of hypoxia mediated cell cycle dysregulation: miR-134 targets CDKN2A
Authors: Rupaimoole Rajesha , Pecot Chad V. , Wu Sherry Y. , Bottsford-Miller Justin , Ivan Cristina , Coleman Robert L. , Zhang Wei , Sood Anil K. 
Published: August 2012

Abstract
Background: Among the various factors in the tumor microenvironment influencing tumor growth and progression, hypoxia plays a key role in promoting tumor growth and resistance to therapeutics. However, a mechanistic understanding of the complicated biological interplay between the stromal framework (hypoxia context) and malignant regions of the same tumor remains an unmet need. In this study, we examined the molecular networks of interplay between hypoxia and miRNA deregulation. Study methods and results: In this study, we profiled the expression of miRNAs in ovarian cancer cells upon exposure to hypoxia (1% O2) using microRNA microarray (Agilent v14). We found that significant numbers of miRNAs are dysregulated. In A2780 and Skov3 ovarian cancer cells, using a statistical cutoff (p&lt;0.05 and fold change &gt;1.5), normoxia v/s short term (48hrs) and long term (6 days) hypoxia exposure, we found that 23 MicroRNAs were down regulated whereas 11 were upregulated. Among these, miR-134 validated to be overexpressed under hypoxia by 3 - 4 fold in A2780 and SKOV3 ovarian cancer cells consistently across the short and long term time points. Upon bioinformatics analyses for target sites of commonly up regulated miRNAs, we found that miR-134 was predicted to target CDKN2A (Miranda, microT, PITA, RNA22, TargetScan). CDKN2A is a protein involved in cell cycle control, precisely regulating cell cycle G1 control through complexing with CDK4. Considering the fact that CDKN2A expression is lost in several cancer types and its correlation with the aggressive tumor growth, we checked expression of CDKN2A under hypoxic conditions. CDKN2A was down-regulated under hypoxia by 55% and was inversely correlated with miR-134 expression in cell lines tested. Upon transfection of A2780 ovarian cancer cells with miR-134 microRNA mimics, we observed consistent down regulation of CDKN2A by &gt;40%, compared to scrambled control transfected cells. This further proves the role of miR-134 in deregulating CDKN2A expression in ovarian cancer. Discussion: This study provides new insights into miRNA-134's role in regulating cell cycle in the context of hypoxia mediated signaling. These findings may have implications for new approaches targeted at curbing the deleterious effects of hypoxia on tumor growth.
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 178. doi:1538-7445.AM2012-178
Abstract 1781: LGI147, a novel small-molecule inhibitor of the mitotic kinesin Eg5, shows anticancer effects in human hepatocellular carcinoma
Authors: Lin Zhong-Zhe , Huang Chi-Ying F. , Pan Hung-Wei , Sun Nai-Yun , Hsiao Li-Pin , Hsu Hey-Chi , Cheng Ann-Lii 
Published: August 2012

Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, for which novel therapies are urgently needed. Recently, the inhibitors of mitotic kinesin Eg5 emerge as potential anticancer therapeutics. The aim of this study was to investigate the anticancer activity of a potent Eg5 inhibitor, LGI147, as targeted therapy of HCC. Method: Antiproliferative effect of LGI147 (kindly provided by Novartis), a highly selective inhibitor of mitotic kinesin Eg5, was tested in three liver cancer cell lines (Hep3B, HepG2, PLC/PRF/5). Cell viability was measured by trypan blue exclusion assay. Mitotic perturbation was visualized by immunofluorescence staining and confocal microscopy. Cell cycle profiles were assessed by flow cytometry. Apoptosis was estimated by analysis of sub-G1 fraction, Annexin V expression and immunoblotting of apoptotic proteins. Results: LGI147 induced a dose-dependent growth inhibition with IC50s ranging from 43.47 pM to 53.59 pM in the tested HCC cell lines. LGI147 treatment for 24 hours led to inhibition of Eg5 activity and induction of abnormal mitosis in a dose-dependent manner. Polypolar spindle defects in mitosis, disturbed cell cycle progression, and induction of apoptosis were observed in the HCC cells treated with LGI147. Conclusions: These findings show that LGI147 has potent anticancer effects in human HCC. Inhibitors of mitotic kinesin Eg5 may deserve further exploration as molecular targeted agents against 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 1781. doi:1538-7445.AM2012-1781
Abstract 1786: Characterization of the inhibitory capacity of EMD1214063, a novel small molecule inhibitor of the MET hepatocyte growth factor receptor on a panel of MET mutated variants
Authors: Zimmer Yitzhak , Pochon Benoît , Stroka Deborah M. , Aebersold Daniel M. , Blaukat Andree , Bladt Friedhelm , Medová Michaela 
Published: August 2012

Abstract
The receptor tyrosine kinase MET is a prime target in clinical oncology because of its aberrant activation in a broad spectrum of malignancies. Here, we tested the anti tumor activity of a novel MET inhibitor, EMD1214063, on cancer cells overexpressing MET and in eight transfected NIH3T3 cell lines expressing different activating mutants of the MET kinase. Our results demonstrate a dose-dependent decrease in MET autophosphorylation in both MET overexpressing cell lines (IC50 of 20nM and 30nM for GTL-16 and H1993, respectively) and in six of the eight cell lines transfected with MET activating mutants (IC50 5-18nM). Blockade of MET by EMD1214063 resulted in reduced downstream activation of AKT, ERK and PLCγ. In contrast, lack of MET inhibition by EMD1214063 in the resistant Y1248H and L1213V MET mutants was associated with high levels of AKT, ERK and PLCγ activation. In all sensitive mutants, EMD1214063 attenuated MET-dependent cellular proliferation and significantly altered cell cycle distribution profiles (increase in G1 and concomitant decrease of S phase). Furthermore, EMD1214063 strongly affected MET-driven biological functions, such as cellular morphology, motility and anchorage-independent growth. To assess the in vivo efficacy of EMD1214063, we established tumor transplantation models exploiting NIH3T3 cells expressing the H1112L or L1213V MET mutants, respectively sensitive and resistant, to in vitro treatment with EMD1214063. Animals bearing H1112L or L1213V tumors were randomized for the treatment with EMD1214063 (50mg/kg/day) or vehicle only. Remarkably, 5 days of treatment with EMD1214063 induced complete regression of sensitive H1112L tumors, while tumor growth remained unaffected in mice injected with resistant L1213V tumor cells and in vehicle-treated mice. Taken together, these results underscore the concordance between in vitro and in vivo effects of EMD1214063 and strongly support its efficacy in inhibiting MET-driven tumor cell growth.
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 1786. doi:1538-7445.AM2012-1786
Abstract 1793: Imatinib treatment for gefitinib-resistant lung cancer harboring epidermal growth factor receptor mutation
Authors: Fukuhara Tatsuro , Treda Cezary Jan , Sakakibara Tomohiro , Inoue Akira , Ebina Masahito , Nukiwa Toshihiro 
Published: August 2012

Abstract
Background: Epidermal growth factor receptor (EGFR) mutant-lung cancer showed significant response to EGFR-tyrosine kinase inhibitor (TKI) treatment, however, treatment failure due to acquired resistance to EGFR-TKI become important clinical problem for long-term survivors. Our purpose is to develop the new treatment for EGFR-TKI resistance. Methods: We used PC9 human lung cancer cell line harboring EGFR exon 19 deletion (E746-A750). When PC9 cells were cultured with 2 μM gefitinib solved in dimethylsulfoxide (DMSO), most of cells died and surviving cells proliferated slowly. By 90 days-culture with 2 μM gefitinib, PC9 gefitinib resistant cells (PC9GR90) were established and confirmed that EGFR-T790M resistance-related mutation was negative. In PC9GR90, an immunoblot assay revealed MET (hepatocyte growth factor receptor) amplification and alternative EGFR3 tyrosine phosphorylation, which is known as one of the major resistant mechanisms. Results: When PC9GR90 were cultured with 2 μM gefitinib and one inhibitor (histone deacetylase inhibitor, insulin-like growth factor receptor inhibitor, gamma secretase inhibitor, or imatinib known as bcr-abl, c-kit and platelet derived growth factor receptor inhibitor), 10 μM imatinib treatment with gefitinib showed significant suppression of cell growth. The ratio of cell count of 2 μM gefitinib/DMSO and 10 μM imatinib with 2 μM gefitinib/DMSO were 91.7% and 6.0%, respectively. When imatinib concentration was decreased to 1 μM known as appropriate concentration for chronic myeloid leukemia treatment, there was no effect. The imatinib effect was not shown for NCI-H1975 lung cancer cells harboring both EGFR-L858R and -T790M. By immunoblot, we found EGFR3 phosphorylation was inhibited by imatinib treatment. Conclusion: It is the first report that imatinib inhibits EGFR3 phophorylation and induce cell death in the EGFR-TKI resistant lung cancer with MET amplification and EGFR3 phophorylation. Although further studies are required to apply this strategy to a clinical setting, we demonstrate a hopeful data to conquer one important resistant mechanism.
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 1793. doi:1538-7445.AM2012-1793
Abstract 1798: Identification of pan-Trk inhibitors for the treatment of Trk-driven cancers
Authors: Bouhana Karyn S. , Gomez Anna M. , Alford Taylor J. , Woessner Richard , von Carlowitz Ira , Lee Patrice A. , Andrews Steven D. , Winski Shannon L. 
Published: August 2012

Abstract
The Trk family of genes, which includes trkA/NTRK1, trkB/NTRK2 and trkC/NTRK3, encode the tyrosine kinase receptors for the neurotrophin family of nerve growth factors. Deregulated kinase activity of trk family members is associated with human cancer. Oncogenic translocations involving trkC kinase domain have been identified in AML, salivary gland carcinoma, adult secretory breast cancer, congenital fibrosarcoma, and pediatric nephroma. Oncogenic trkA translocations have been reported in papillary thyroid and colorectal cancers. We have identified orally bioavailable, potent and selective ATP-competitive inhibitors of the trk family of receptor tyrosine kinases and are developing these for the treatment of Trk-driven cancers. AR523 is a pan-Trk inhibitor which demonstrates similar activity against TrkA, TrkB and TrkC receptors in a cell based assay (IC50 ∼10 nM). In a screen at 1 µM against a panel of 230 kinases, AR523 inhibited only three additional kinases more than 50% (TNK2, Bmx and Txk). In cell culture AR523 was found to exhibit selective anti-proliferative activity toward the cell line KM12, which harbors the oncogenic TPM-TrkA translocation, while exhibiting no activity toward HT29, a cell line with no trk gene rearrangements. Studies in mice engrafted with KM12 tumors revealed significant anti-tumor and pharmacodynamic activity of AR523. Administration of a single oral dose of AR523 reduced tyrosine phosphorylation of TrkA by nearly 80% at twelve hours after dosing. Parallel analysis of Akt and Erk revealed reduced phosphorylation of these downstream effectors. Administration of 100 mg AR523 daily for two weeks to mice with KM12 xenografts produced mean tumor growth inhibition of 86% and a mean of 42% tumor regression. AR523 exhibits dose dependent inhibition of tumor growth at 10 and 30 mg/kg in KM12 xenografts with 54 and 72% TGI respectively. AR523 was well-tolerated, causing no weight loss or deaths compared with vehicle control. Increasingly Trk mutations have been shown to be activating and the use of Trk inhibitors may provide a new therapeutic strategy for targeted treatment.
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 1798. doi:1538-7445.AM2012-1798
Abstract 1801: Lyn and Fyn inhibition as a potential novel treatment for glioblastoma multiforme
Authors: Prakash Om , Wilk Anna , Vashistha Himanshu , Lin Shih-Chao , Aregbezola Rita , Levitt Daniel , Reiss Krzysztof 
Published: August 2012

Abstract
Background: Glioblastoma multiforme (GBM) is the most malignant and most aggressive of the adult brain tumors. The current therapies including surgical resection, radiation therapy and chemotherapy remain palliative with median survival of 14 months. Two of the Src family kinases, Lyn and Fyn, have been reported to be involved in the pathogenesis and aggressiveness of GBM in clinical and laboratory research studies. Specific Aims: We evaluated the effect of Lyn and Fyn kinase inhibition on GBM cell motility and survival by utilizing a clinically relevant Lyn and Fyn kinase inhibitor, bafetinib or formerly INNO-406 (CytRx Corporation, Los Angeles, CA). Bafetinib, a dual Bcr-Abl and Lyn tyrosine kinase inhibitor has been shown to inhibit 4 of the 79 tyrosine kinases, namely Abl, Abl-related gene (Arg), and two of the Src family kinases Lyn and Fyn but not Src. Methodology: We used Lyn- expressing T98G and Fyn-expressing U87MG human GBM cell lines. The effect of bafetinib on the motile activity was evaluated by the wound healing, single cell trajectory, and the trans-well assays. The cell survival and mitochondrial membrane potential were evaluated by Guava Easycyte *HT flowcytometer (Millipore) in cells treated with bafetinib for 24 h. Further, we examined the effect of bafetinib on cell survival in combination with temozolomide (TMZ), a widely used chemotherapy agent for the management of GBM, in U87MG cells using microplate MTT assay. Results: At 16 h post-wounding, bafetinib at 5 µM concentration inhibited the motility of T98G and U87MG cells by 33% (P &lt; 0.01) and 24% (P &lt; 0.01), respectively. This significant inhibition in the wound healing was accompanied by the inhibition of total length of cell trajectory, total length of the final cell displacement and average speed of cell locomotion. Bafetinib induced 62% mitochondrial membrane depolarization in U87MG cells and 20% depolarization in T98G cells. Higher depolarization levels in U87MG cells correlated with higher apoptosis (49.4%). Treatment of U87MG cells for 4 days with a combination of bafetinib and TMZ reduced the IC50 values as much as 60% and 80%, respectively, compared to the values obtained with each of the drugs, suggesting that bafetinib has the potential to improve the therapeutic effect of TMZ in GBM cells. Conclusion: Our preliminary findings suggest that targeting Lyn and Fyn kinase pathways with bafetinib may have a therapeutic potential for GBM. Our in vivo studies in mouse models with bafetinib will further establish the feasibility of targeting Lyn and Fyn kinases as possible therapeutic targets in GBM.
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 1801. doi:1538-7445.AM2012-1801
Abstract 1802: IGF-1R inhibition as a novel therapeutic strategy for small cell lung cancer
Authors: Zinn Rebekah L. , Rudin Charles M. 
Published: August 2012

Abstract
Small cell lung cancer (SCLC), which makes up approximately 15% of all lung cancer cases, is characterized by short responses to standard chemotherapy and a median survival duration of less than one year. New therapies are critically needed to improve the outcome for patients with this disease. Signaling through the insulin-like growth factor 1 receptor (IGF-1R) leads to activation of the PI3K-AKT and MAP kinase pathways, resulting in inhibition of apoptosis and stimulation of proliferation. The IGF-1R pathway is commonly upregulated in SCLC. Recent evidence suggests that inhibition of IGF-1R may be a potential treatment strategy for many types of cancer, including SCLC. We sought to characterize the relative sensitivity of SCLC cell lines to a novel IGF-1R tyrosine kinase inhibitor, OSI-906, identify predictive biomarkers of sensitivity, and evaluate the efficacy of OSI-906 in vivo on SCLC cell line xenografts and primary patient xenografts as a single agent and in combination with etoposide. We assessed the sensitivity of a panel of 16 SCLC cell lines to OSI-906. Approximately one third of these cell lines were highly sensitive to OSI-906, with an IC50 &lt; 1 μM, as measured by the MTS cell proliferation assay. Treatment with increasing doses of OSI-906 resulted in dose dependent inhibition of phosphorylated IGF-1R and phosphorylated AKT in both sensitive and resistant cell lines, suggesting that while the IGF-1R signaling pathway is intact in resistant cell lines, they rely on other signaling pathways for survival. Expression profiling of our panel of cell lines for components of the IGF-1R pathway including IGF-1R, insulin receptor (IR), and receptor ligands (IGF-1 & IGF-II) did not suggest a simple correlation between receptor/ligand expression and sensitivity to OSI-906. Interestingly, OSI-906 sensitive cell lines appear to express lower levels of phosphorylated ERK at baseline compared to resistant cell lines. In addition, phospho-ERK is not inhibited by OSI-906 and is upregulated in response to treatment in some resistant cell lines. We tested the efficacy of OSI-906 alone and in combination with etoposide in vivo using an H187 cell line xenograft model and two primary patient xenograft models. OSI-906 alone resulted in approximately 50% tumor growth inhibition in H187 xenografts and 30% inhibition in the primary patient xenograft models compared to mock treated animals. There was no evident synergy with etoposide in any of these models. Our preliminary data support that IGF-1R inhibition may be a viable treatment strategy for a subset of SCLC. Identification of the subset that will respond to this therapy may be more complex than screening for expression IGF-1R pathway components.
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 1802. doi:1538-7445.AM2012-1802
Abstract 1806: The indolocarbazole derivative Go6976 suppresses the growth of leukemia cells with FLT3 mutations
Authors: Yoshida Akira , Zokumasu Kouichi , Ueda Takanori 
Published: August 2012

Abstract
The FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in hematopoietic progenitor cell development. Mutations of FLT3 have been reported in about a third of patients with acute myeloid leukemia (AML), and inhibitors of FLT3 are of clinical interest. Go6976 is an indolocarbazole inhibitor of the calcium-dependent isozymes of protein kinase C (PKC). In the present study, we demonstrated that Go6976 possesses a potent inhibitory activity against recombinant FLT3 using in vitro kinase assay. We also showed that Go6976 is a potent inhibitor of Aurora-B kinase. Go6976 significantly inhibited proliferation of leukemia MV4-11 cells having FLT3-internal tandem duplication (ITD). Cell growth inhibition by Go6976 occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways such as extracellular signal-regulated kinase1/2, STAT-5 and p38. The FLT3-independent myeloid leukemia HL-60 and U937 showed strong resistance to Go6976 treatment. Induction of massive apoptosis were observed upon treatment with Go6976 in MV4-11 cells associated with significant down-regulation with Survivin and Mcl-1 protein. Interestingly, Go6976 treatment also inhibited Survivin phosphorylation on Thr34, which is critical for its anti-apoptotic activity. This inhibition of Survivin phosphorylation occurred due to the direct suppression of Aurora-B by Go6976 treatment. These data indicate that Go6976 may have a unique therapeutic potential for patients with FLT3-driven leukemias.
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 1806. doi:1538-7445.AM2012-1806