bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1643: AZD4547, a potent and selective inhibitor of FGF-receptor tyrosine kinases 1, 2 and 3, inhibits the growth of FGF-receptor 2 driven gastric cancer models in vitro and in vivo
Authors: Xie Liang , Su Xinying , Zhang David , Tang Lily , Xu Jessie , Wang Maggie , Yin Lucy , Zhang Jingchuan , Ye Katherine , Wang Zengquan , Kilgour Elaine , Ji Qunsheng 
Published: June 2012

Abstract
Gastric cancer is the second most lethal cancer worldwide. We and others have shown that the FGFR2 gene is amplified in a subset of gastric cancers. To validate FGFR2 as a potential therapeutic target for gastric cancer, we employed an inducible shRNA system to specifically block expression of individual FGFRs, both in vitro and in vivo. When FGFR2 was specifically down regulated in an FGFR2-amplified gastric cancer cell line Snu-16, the activation of pFGFR2 and its downstream signaling effectors were blocked and there was significant inhibition of the cell growth and survival that further translated into tumor growth regression in vivo, demonstrating that in this model tumor growth/survival is dependent on the FGFR2 pathway. To further confirm this, AZD4547, a selective inhibitor of FGFR 1, 2 and 3 receptor tyrosine kinases was tested in a panel of gastric cancer cell lines for its anti-proliferative effect. In this panel the cell-lines that were most sensitive to AZD4547 were the Snu-16 and KATOIII, both of which are gene amplified for FGFR2. Exposure of the Snu-16 cells to AZD4547 resulted in cell-death and once daily oral dosing of AZD4547 resulted in tumor growth inhibition of the Snu-16 xenografts in a dose-dependent fashion, with significant tumor regression observed when AZD4547 was dosed once daily at 12.5 mg/kg. The anti-tumor efficacy of AZD4547 correlated with inhibition of pFGFR2 and modulation of other downstream markers of FGFR pathway activation, including pErk, pS6 protein and pPLCγ and efficacious doses of AZD4547 induced elevations of levels of plasma FGF23, a known marker of FGFR inhibition. In addition to the single-agent efficacy, combining of AZD4547 with cytotoxic agents, currently used for the treatment of gastric cancer patients, revealed enhanced growth inhibition of Snu-16 xenografts. Taken together, these data support clinical testing of AZD4547 in gastric cancer patients harboring FGFR2 gene amplification.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2011-1643
Abstract 2823: TAK-441, a novel investigational small molecule hedgehog pathway inhibitor for use in cancer therapy
Authors: Tojo Hideaki , Shibata Sachio , Satoh Yoshihiko , Kawamura Mihoko , Inazuka Masakazu , Yamakawa Hiroko , Kashiwagi Masahide , Miyamoto Maki , Kondo Shigeru , Oohashi Tomohiro , Oguro Yuya , Sasaki Satoshi 
Published: June 2012

Abstract
Dysregulation of hedgehog (Hh) signal, which is caused by Hh-ligand overexpression or patched1 (Ptch1) mutation, has been found to play an important role in tumorigenesis. TAK-441 is a potent and selective smoothened (Smo) antagonist that blocks Hh signaling. In the Gli-responsive promoter-luciferase (Gli-luc) reporter assay in NIH3T3/Gli-luc cells, TAK-441 inhibited Gli transcriptional activity with an IC50 of 4.4 nM. TAK-441 also inhibited expression of human Gli1 messenger mRNA with an IC50 of 1.9 nM in MRC5 human embryonic fibroblasts. In addition, TAK-441 inhibited binding of cyclopamine, a plant-derived well-known Smo inhibitor, to human Smo on 293T cells overexpressing human Smo with an IC50 of 8.6 nM. These data suggest that TAK-441 inhibits the Hh signaling pathway through its binding to Smo.
Oral administration of TAK-441 (0.5, 1, 5, 25 mg/kg QD) in mice bearing a Ptch1 (+/-), p53(−/-) medulloblastoma allograft resulted in dose-dependent antitumor activity with concomitant reduction of Gli1 mRNA expression in the tumors. Complete remissions were observed in the 25 mg/kg QD dose cohort after two consecutive weeks of treatment. Significant (p≤0.025 by one-tailed Williams test) antitumor activity was also detected in sonic hedgehog expressing human primary pancreatic and ovarian cancer xenografts when dosed at 10 and 25 mg/kg QD for two weeks, and in a colon cancer xenograft when dosed at 6.25 and 25 mg/kg BID for three weeks. In these models, the expression of tumor-associated mouse stromal Gli1 mRNA was markedly decreased following TAK-441 treatment, suggesting that Hh signaling in these tumors was driven in a paracrine mode of action. The combination of TAK-441 and rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), demonstrated significantly better antitumor activity than either agent alone in human primary pancreatic cancer xenograft models (p≤0.05 by Students’ t-test). In addition, delayed tumor re-growth was observed in the TAK-441/rapamycin combination treatment group compared with the rapamycin single-agent treatment group after terminating treatment. As a result of these preclinical studies, TAK-441 has recently entered Phase I clinical studies in cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2823. doi:10.1158/1538-7445.AM2011-2823
Abstract 3270: Combination strategy to circumvent the acquired resistance to VEGF receptor tyrosine kinase inhibitor in M24met melanoma in mice
Authors: Zhang Lianglin , Lira Maruja E. , Ching Keith A. , Chen Enhong , Lu Tina , Christensen James G. , Hu-Lowe Dana D. 
Published: June 2012

Abstract
Anti-angiogenic therapy targeting the tumor vasculature has demonstrated clinical benefits in certain types of tumors. However, many patients develop resistance and eventually progress on anti-angiogenic therapy. The mechanism of resistance is largely unknown and warrants extensively investigation. We developed a human xenograft tumor model (M24met/R) in mice that has acquired resistance to VEGF receptor tyrosine kinase inhibitors (VEGFR TKI), by chronically treating the parental M24met tumors (M24met/P) with PF-0337210 (20-40 mg/kg, QD, PO) and serially passaging resistant tumor fragments in nude mice. M24met/R tumors were also resistant to axitinib, a selective VEGFR TKI in late stage clinical development. Immunohistochemical (IHC) staining revealed higher degree of hypoxia and lower microvessel density in M24met/R tumors compared to parental tumors. Compared with those in M24met/P, vessels in M24met/R tumors appeared to be larger in diameter and more mature as shown by high incidence of co-localization between endothelial cells and perivascular cells (CD31+Desmin+). Microarray analysis of tumor lysates (human UA133 2.0, mouse 430 2.0 chip) revealed distinct gene expression profiles between M24met/R tumors and size-matched M24met/P tumors. Of note, several angiogenesis-related genes, including human VEGF, bFGF, integrin α5β1, IL-8, PDGF,CSF and murine VEGF, integrin α5β1, ALK1 (activin receptor-like kinase 1), IL-8, c-Met, IL-6 were up-regulated in M24met/R tumors, whereas murine VEGFR1 and 2, PROX1, PDGFR and endogenous angiogenic inhibitor TSP-1 were down-regulated in the resistant tumors. The above observations were verified with ELISA and/or IHC. Next, targeted combination approaches were applied in an attempt to circumvent M24met/R resistance to axitinib. Concurrent administration of axitinib plus either anti-IL-8 monoclonal antibody (mAb), c-Met inhibitor, anti-integrin α5 mAb or anti-ALK1 mAb significantly improved anti-tumor efficacy compared to single agents alone. IHC analyses showed that combinatorial therapy of anti-ALK1 plus axitinib reduced the amount of CD31+Desmin+ vessels compared to axitinib alone, suggesting that targeting ALK1 destroyed VEGFR TKI-resistant vessels. Together, our results suggested that multiple alternative angiogenic factors contributed to the acquired resistance of M24met/R melanoma to VEGFR TKI. Combination treatment using inhibitor of IL-8, c-Met, integrin α5β1 or ALK1 with VEGFR TKI may represent a new strategy to mitigate resistance to VEGFR TKI in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3270. doi:10.1158/1538-7445.AM2011-3270
Abstract 332: B-Raf mutations are associated with a worse outcome in ovarian cancer
Authors: Libra Massimo , Russo Alessia E. , Pellizzari Ilenia , Bagnoli Marina , Raspagliesi Francesco , Sorio Roberto , Baldassarre Gustavo , Canevari Silvana ,   M.I.T.O. Group
Published: June 2012

Abstract
Epithelial ovarian cancer is the leading cause of death from gynecologic malignancies and its frequency has increased dramatically in the last decade. Most women present with advanced disease at diagnosis due to the insidious onset of this disease and the lack of effective early detection methods. Current treatments, consisting of debulking surgery and subsequent platinum-based chemotherapy, yield a response rate of over 80%, but almost all patients relapse or develop resistance to therapy and ultimately succumb to their cancer. Therefore, there is a need for understanding the molecular pathways involved in ovarian cancer progression and chemoresistance in order to control/reverse them and develop more tailored therapies.
Disregulation of Ras/Raf/MEK/ERK pathway plays a key role in pathogenesis of several human cancers. Mutations at membrane receptors, upstream signalling transducers, as Ras and B-Raf, as well as in genes regulating Raf activity (e.g., PI3K, PTEN, Akt), promote constitutive ERK signaling, stimulating proliferation and survival and providing essential tumour growth and maintenance functions. Conflicting data have been generated about B-Raf mutational status in ovarian cancer. Furthermore, no previous investigations have explored the association of this gene alteration with clinical response.
To this aim, in the present study, tumor samples from 48 advanced ovarian cancer patients, with clinical follow-up of at least 5 years, were analyzed for B-Raf mutations within exon 15. All patients were treated with standard therapy containing paclitaxel and carboplatin chemotherapeutic agents and clinical response was obtained in 58% of them. B-Raf mutation (V600E) was detected in 18 out of 48 (37.5%) patients. Interestingly, this mutation occurs mostly among non responders patients (75% vs 11%; p&lt;0.0001).
These preliminary data indicate that V600E B-Raf mutation may correlate with a loss of clinical response to therapy. To explore this possibility, functional experiments have been also performed by analyzing several ovarian cell lines transfected with mutated B-Raf (V600E). In agreement with our clinical observations, transfected clones showed a higher chemo-resistance, supporting the notion that alteration of Ras/Raf/MEK/ERK pathway may be associated with resistance to chemotherapy. Overall, our data indicate that in ovarian cancer the Ras/Raf/MEK/ERK pathway may represent a promising therapeutic target to reverse chemoresistance.
This work was partially supported by AIRC grants and Italian League against Cancer
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 332. doi:10.1158/1538-7445.AM2011-332
Abstract 3535: Diindolylmethane potentiates the effect of cisplatin in ovarian cancer cells by inhibiting STAT-3 and VEGF
Authors: Kandala Prabodh K. , Wright Stephen E. , Srivastava Sanjay K. 
Published: June 2012

Abstract
Ovarian cancer remains the second leading gynecological cancer in United States. It is usually detected in late stages with poor prognosis. Cisplatin is a chemotherapeutic drug currently used to treat patients with ovarian cancer. However, ovarian tumors develop resistance and cisplatin is associated with systemic toxicity. We previously reported that Diindolylmethane (DIM), a natural compound present in cruciferous vegetables inhibits the proliferation of ovarian cancer cells [Kandala and Srivastava, Mol. Pharmacol. 2010, 78, 297-309]. In this study, we evaluated the effect of DIM with cisplatin in ovarian cancer cells. Exposure of SKOV-3 cells to 50μM DIM for 24 hours followed by treatment with 10µM cisplatin resulted in about 70% reduction in the survival of cells as compared to 30% by cisplatin treatment alone. Western blot analyses indicate that combination (DIM + cisplatin) treatment block the activation of STAT-3 by inhibiting the phosphorylation at Tyr 705 and Ser 727 as compared to cisplatin or DIM treatment alone. The STAT-3 protein level was reduced by 90% by combination treatment. Mcl-1and survivin, which are regulated by STAT-3 were also down-regulated by combination treatment. Interestingly, survivin was up-regulated by cisplatin treatment but completely blocked by combination treatment. Increased apoptosis by combination treatment was evident by caspase-3 and PARP cleavage. In addition, we tested the effects of this combination treatment on ovarian tumor angiogenesis and metastatsis. The results of aortic ring assay suggested that the combination treatment completely suppressed the formation of microvessel sprouts. Furthermore, combination treatment blocked invasion of cells by approximately 50% as evaluated by Boyden's chamber. Combination of DIM and cisplatin suppressed VEGF secretion by 50% as compared to 20% by cisplatin treatment in SKOV-3 cells. Taken together, our results suggest that DIM potentiates the effect of cisplatin by blocking the activation of STAT-3 and inhibiting angiogenesis and metastasis. Further mechanistic and in vivo testing of this combination treatment is under progress. [Supported in part by R01 grants CA106953 and CA 129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3535. doi:10.1158/1538-7445.AM2011-3535
Abstract 3592: Preclinical combination strategies for development of JI-101, a selective inhibitor of Ephrin B4, VEGF R2 and PDGF-Rβ
Authors: Gilcrease Glynn W. , Wade Mark , Mullangi Ramesh , Srinivasa Sreesha , Northrup Jonathan , Govindarajan Raman , Sharma Sunil 
Published: June 2012

Abstract
Background: JI-101 is a novel, highly selective and potent angiogenesis inhibitor with unique EphB4 activity along with VEGFR2 and PDGFRβ inhibitor activity. JI-101 shows a good pre-clinical profile and is well tolerated to date in phase 1 and early phase 2 clinical trials. In order to investigate combination partners, in vitro and in vivo studies were undertaken to combine JI-101 with chemotherapies and various targeted agents.
Materials and Methods: Cancer cell lines from different tissue types were seeded on 96 well plates at a density of 2,000 cell per well and allowed to adhere overnight. To determine if JI101 could enhance the toxic effects of traditional chemotherapy, cells were incubated with 10-0.003 μM Gemcitabine, Oxaliplatin and 5-Fluorouricil in the presence or absence of 1 μM JI101. To determine the effect of JI101 with other targeted therapies, cells were incubated with 10-0.03 μM JI101, Axitininb, and Imantinib and 1-0.003 μM BEZ235. In addition, cells incubated with BEZ235 were combined with 1 μM of JI101, Axitininb or Imatinib. Cells were incubated with the drugs for 96 hours at 37oC in a cell culture incubator. After incubation cell viability was tested with the MTS Assay.
Results: Toxicity profiles of traditional chemotherapies were not significantly altered when combined with JI101. Incubation of BEZ235 with multiple cancer cell lines resulted in dose dependent toxicity to the cells whereas JI101, Axitinib and Imatinib showed little to no toxicity in the cancer cell lines tested. Coincubation of the PI3 kinase/mTOR inhibitor BEZ235 with JI101, an EphB4, VEGFR2, and PDGF-Rβ or Axitinib a specific VEGF-R2 inhibitor enhanced the cellular toxicity of BEZ235 in a cell line specific manner.
Conclusions: JI-101 is highly synergistic with mTOR inhibitors and PI 3 kinase inhibitors in vitro and in vivo. The molecular mechanism will be presented for this synergy. A combination trial of JI101 and PI3 kinase inhibitor or JI101 and mTOR inhibitor is indicated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3592. doi:10.1158/1538-7445.AM2011-3592
Abstract 3680: Comparison of risk of advanced cervical lesions among women with first detection of atypical squamous cells, atypical glandular cells, and low-grade squamous intraepithelial lesions by Pap smear
Authors: Chen Yun-Yuan , You San-Lin , Koong Shin-Lan , Chen Chi-An , Chen Chien-Jen ,   Taiwan Cervical Cancer Screening Task Force
Published: June 2012

Abstract
The study aimed to examine the incidence of invasive cervical cancer (ICC), cervical carcinoma in situ (CIS), and cytologic high-grade squamous intraepithelial lesions (HSIL) or more severe cytologic lesions among women detected their first atypical squamous cell undetermined of significance (ASC), atypical glandular cells (AGC), and low-grade squamous epithelial lesions (LSIL), and to estimate the associations between the subsequent follow-up attending and risks of developing cervical cancer.
National cervical cancer screening program in Taiwan has been implemented since 1995, all screening records are mandatory to report, and a centralized screening database has been established as well. The first cytologic abnormalities, included 110,561 ASC cases, 8,339 AGC cases, and 45,671 LSIL cases, and cytologic HSIL or above lesions were identified from Taiwan cervical cancer screening registry. Women received Pap smear or biopsy in one year after their first cytologic abnormalities were considered have attended subsequent follow-up. Cervical cancers were ascertained from national cancer registry in Taiwan until Dec, 31st, 2007. Hazard ratios were estimated by Cox's proportional hazards model, and cumulative incidences were estimated by Nelson-Aalen method.
There was at least 14% reduction of CIS and 23% reduction of ICC if women attended screening two years before their first abnormalities, and at least 32% reduction of CIS and 58% reduction of ICC if they attended screening within two years. Follow-up attending for the first abnormality significantly reduced 13% to 53% of cytologic HSIL occurrence, 40% to 49% of CIS occurrence, and 52% to 71% of ICC occurrence. AGC is the most clinical significant lesion compared with ASC and LSIL, and is suggestive to include in the positivity follow-up system. Compared to LSIL, ASC is less risky to develop cytologic HSIL, similar risk to develop CIS, and possesses more risk to develop ICC. Subsequent follow-up attendance for their first abnormality and previous negative smear detection were inversely associated with cervical cancer occurrence.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3680. doi:10.1158/1538-7445.AM2011-3680
Abstract 3790: Loss of BRCA1 regulates autophagy as a cellular stress response in breast and ovarian cancer cells
Authors: Tang Maggie Kei Shuen , Wong Alice Sze Tsai 
Published: June 2012

Abstract
Inactivation of cell death is a major step in tumor development. The BRCA1 tumor suppressor, which is frequently mutated in human breast and ovarian cancers, is a critical mediator of cell death. Although the role of BRCA1 gene loss for inhibiting apoptosis is well established, little is known regarding its involvement in other cell survival pathways. Increasing evidence strongly supports that autophagy is a key strategy for cell survival in response to stress. Endoplasmic reticulum (ER) stress and nutrient deprivation are common environmental stresses governing the survival and adaptation of tumor cells in vivo. Here we show that BRCA1 is an important regulator of autophagy, particularly under stress conditions. We found that autophagy could be induced by chemicals that cause ER stress and nutrient deprivation in T47D breast cancer cells and OVCAR-3 ovarian cancer cells with targeted inhibition of endogenous BRCA1 using small interfering RNA. This was characterized by conversion of microtubule-associated protein 1 light chain 3 (LC3) I into LC3 II, punctate green fluorescent protein-labeled LC3 fluorescence, and autophagosomes formation. Treatment of cells with the lysosomal inhibitors, Pepstatin A and E-64d, augmented autophagy, suggesting that autophagosomes were actively produced. In contrast, BRCA1-mediated autophagy that was induced under stress conditions was inhibited by treatment with autophagy inhibitor 3-methyladenine. Similar results were obtained in cells with decreased beclin 1 level by RNA interference. These results reveal a novel link between BRCA1 and autophagy, which may contribute to the survival of BRCA1-deficient cancer cells in their microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3790. doi:10.1158/1538-7445.AM2011-3790