bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3589: Dovitinib (TKI258), a multikinase inhibitor of FGFR, PDGFR, and VEGFR tyrosine kinases, induces growth inhibition in endometrial carcinoma cells
Authors: Konecny Gottfried E. , Winterhoff Boris , Guorong Ellen Yang , Qi Jingwei , Le Julie , Shi Michael , Dugan Margaret , Linnartz Ronald , Finn Richard S. , Slamon Dennis J. 
Published: June 2012

Abstract
Background: Endometrial carcinoma is the most common gynecological malignancy in the western world. Activating mutations of the fibroblast growth factor receptor 2 (FGFR2) have been described in 12-16% of endometrial cancers. Moreover, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their receptors are involved in the neovascularization, invasiveness, and metastatic potential of endometrial cancer. Therefore, suppression of FGFR/VEGFR/PDGFR signaling by TKI258 may represent a novel approach for treatment of endometrial cancer.
Experimental Design: The aims of this study were 1.) to assess the effect of TKI258 on tumor cell growth in two-dimensional (2D) and three-dimensional (3D) culture assays using a panel of 20 human endometrial cancer cell lines, 2.) to identify candidate molecular markers predicting sensitivity using baseline gene expression profiling and mutational analyses, and 3.) to determine the in vivo antineoplastic activity of TKI258 in endometrial cancer xenograft models. In addition, we screened 200 fresh frozen endometrial cancer specimens to comprehensively assess the distribution pattern of PI3K, PTEN, and FGFR mutations in endometrial cancer.
Results: Concentration-dependent anti-proliferative effects of TKI285 using 2D assays were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC50 range: 0.42µM – 3.06 µM). The three most sensitive endometrial cancer cell lines demonstrated activating FGFR2 mutations (MFE296: N549K, IC50 0.42µM; AN3CA: N549K and K310R, IC50 0.50µM; MFE280: S252W, IC50 0.66µM). Assessment of TKI258 responses in 3D assays demonstrated similar results to those observed in 2D culture assays in that the 3 cell lines harboring FGFR2 mutations were the most sensitive to TKI258 achieving 100% growth inhibition at a concentration of 1µM. AN3CA and MFE296 endometrial cancer cells formed xenografts in nude mice and antitumor activity was studied in both models. Inhibition of p-FGFR, p-PDGFR, p-VEGFR-2, pAKT and p-ERK1/2 were observed. Comprehensive data on the pattern of PI3K, PTEN and FGFR mutations in endometrial cancer will be provided.
Conclusion: TKI258 demonstrates significant antitumor activity in endometrial cancer cells with FGFR2 mutations. This study provides a strong rationale for the clinical evaluation of TKI258 in patients with endometrial cancer, specifically in those harboring FGFR2 mutations.
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 3589. doi:10.1158/1538-7445.AM2011-3589
Abstract 3601: CP-868,596, a highly potent and selective PDGFR TKI inhibits growth of PDGFRα-driven lung cancer cells
Authors: Peyton Michael , Chaudhary Preeti , Ramachandran Abhijit , Minna John 
Published: June 2012

Abstract
Background: Platelet-derived growth factor receptor alpha (PDGFRα) has been identified as an oncogenic kinase in lung cancer tumors and cell lines. CP-868,596 is an orally bioavailable, highly potent and selective PDGFR tyrosine kinase inhibitor (TKI). CP-868,596 is a benzimidazole compound that has been designed to block phosphorylation of PDGFRα and PDGFRβ at 1-2 nM concentrations. The 50% inhibition concentration (IC50) of CP-868,596 for PDGFRα and PDGFRβ is 0.9 nM and 1.8 nM, respectively. A phase I trial of CP-868,596 showed good oral bioavailability and a favorable safety profile. Additionally, serum concentrations as high as 2000 nM were achieved. One bronchoalveolar carcinoma patient showed clinical improvement and remained on the trial for more than 170 days. We have tested the activity of CP-868,596 in ∼20 selected NSCLC cell lines, including H1703, which has been identified as a model system to study PDGFRα-driven lung cancer. Each cell line tested was well-characterized with respect to DNA copy number gain, mRNA and protein expression level.
Materials and Methods: Lung cancer cell lines including H1703 (PDGFRA, PDGFC amplification; PDGFRα overexpression), NCI-H1693, NCI-H23 and NCI-H661 (PDGFRA amplification), H1770 (PDGFRA mutation), H1975 (EGFR T790M mutation), EBC1 (MET amplification), H3122 (EML4-ALK translocation), etc. were cultured in HyQ RPMI-1640 medium (HyClone) supplemented with 5% FBS (HyClone) in 96 well plates. Cells were incubated overnight to allow attachment and drug was added ∼24 hours later as a gradient of concentrations to establish the dose-response curves. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays were performed 96 hours after drug addition to determine the IC50 of CP-868,596.
Results: Lung cancer cell lines were clustered into 2 categories based on their degree of sensitivity to CP-868,596: highly sensitive and resistant. H1703, the only example of a highly sensitive cell line, is reported to have amplification of both PDGFRA (4q12) and PDGFC (4q32) genes on chromosome 4. In H1703, CP-868,596 has an IC50 of ∼80 nM which is about 2 fold lower than the IC50 for sorafenib, a VEGFR/RAF TKI also known to inhibit PDGFR. The remaining cell lines, including the PDGFRA-amplified lines had IC50 values between 2-8 µM.
Conclusions: CP-868,596 potently inhibits the growth of the cell line, H1703, suggesting that the drug may have single agent activity in PDGFR-driven NSCLC tumors. We plan to identify biomarkers for sensitivity to CP-868,596 in NSCLC to help enrich patients for a potential clinical trial.
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 3601. doi:10.1158/1538-7445.AM2011-3601
Abstract 3604: Preclinical antitumor study of famitinib, an orally available multi-targeted kinase inhibitor of VEGFR/PDGFR/c-Kit in phase I clinical trials
Authors: Lou Liguang , Mi Yi , Xu Yongping , Xie Chengying , Zhao Hongbing 
Published: June 2012

Abstract
Angiogenesis plays a key role in tumor progression and anti-angiogenic agents including sunitinib and sorafenib that target VEGF/VEGFR signaling pathway have been proved to an effective therapy for cancer in the clinic. However, severe side effects such as hypertension and bone marrow toxicity limit their clinical application. Thus, development of novel anti-angiogenic agents with fewer side effects is still an unmet challenge. In this study, we characterized the in vitro and in vivo antitumor activity of famitinib, an orally active multi-targeted kinase inhibitor. Famitinib inhibited the activity of c-kit, VEGFR-2, PDGFRα and PDGFRβ with IC50 values of 2.3 nM, 4.7 nM and 6.6 nM, respectively. In addition, Famitinib inhibited the VEGF-induced proliferation, migration and tubule formation of human umbilical vein endothelial cells, and micro-vessel spouting from matrigel-embedded rat aortic rings. In vivo, famitinib exhibited broad and potent anti-tumor activity, leading to regression or growth arrest of various established xenografts derived from human tumor cell lines. Moreover, famitinib significantly enhanced the efficacy of oxaliplatin or 5-fluorouracil when they were combined. In summary, famitinib has potent preclinical antitumor activity which supports its further evaluation in clinic. Famitinib is currently in phase I clinical trials in China.
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 3604. doi:10.1158/1538-7445.AM2011-3604
Abstract 3612: A novel and selective c-Met inhibitor against subcutaneous xenograft and othotopic brain tumor models
Authors: Cui Yumin , Dai Guangxiu , Ren Yongxin , Zhou Feng , Fan Shiming , Sai Yang , Gu Yi , Yan James , Li Jia , Qing Weiguo , Su Weiguo 
Published: June 2012

Abstract
HM5016504 is a novel, highly potent and selective c-Met inhibitor under development by HMPL. In preclinical studies, it demonstrated strong in vitro activity against c-Met and its downstream signaling targets, thus blocking the related cellular functions, including proliferation, migration, invasion, scattering and the secretion of VEGF that plays a pivotal role in tumor angiogenesis. The cross-talk between c-Met and EGFR was investigated, and their contribution to downstream signaling cascade was identified in certain tumor cell lines with dysregulation of both c-Met and EGFR. HM5016504 could effectively inhibit the in vivo growth of a number of human tumor xenografts. Particularly, the tumor cells or xengorafts with high fold of c-Met gene amplification showed high sensitivity to HM5016504, such as gastric cancer SNU-5, Hs746T and lung cancer H1993 and EBC-1 cells or their respective xenografts. The compound not only showed activity in subcutaneous xenograft models, but also demonstrated efficacy in an orthotopic brain tumor model induced by U87MG, indicating it could pass blood brain barrier. In vitro and in vivo activities of HM5016504 were found to be closely correlated with the c-Met expression level and activation status. In addition, HM5016504 exhibited a reasonable pharmacokinetic profile and safety window based on the toxicology study results in rats, dogs, and monkeys. The pre-clinical study results suggest that HM5016504 could be a promising c-Met targeting anti-cancer agent.
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 3612. doi:10.1158/1538-7445.AM2011-3612
Abstract 3620: LIV-1 antibody-drug conjugate: A novel therapeutic agent for breast and prostate cancer
Authors: Sussman Django , Nesterova Albina , Westendorf Lori , Duniho Steven , Anderson Martha , Mbow Brianna , Gregoire Ashley , Hunter Joshua H. , Whiting Nancy , Corey Eva , Vessella Robert L. , Benjamin Dennis R. , Smith Leia M. 
Published: June 2012

Abstract
LIV-1, also known as SLC39A6 or ZIP6, is a member of the zinc transporter family and was first identified as an estrogen-inducible gene in breast cancer. LIV-1, as a downstream target of STAT3, promotes the epithelial to mesenchymal transition that is important in the malignant progression to metastasis. Consistent with its role in cancer, we determined by immunohistochemical (IHC) analysis that LIV-1 is expressed by estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites) and ER-/PR-/Her2- (triple-negative) breast cancers. Hormone refractory metastatic prostate tumor samples express Liv-1, with expression confirmed in both bone and soft tissue metastatic sites by IHC. In healthy human tissues, LIV-1 expression is limited to hormonally-regulated organs (prostate, uterus, and breast). The broad expression of LIV-1 in prostate and breast cancer tumors in combination with the limited expression in vital organs makes LIV-1 an excellent target for an antibody-drug conjugate (ADC). We generated an ADC consisting of a humanized anti-LIV-1 mAb conjugated to the antitubulin agent monomethyl auristatin E (MMAE), via a plasma stable, enzyme-cleavable linker (vc). The humanized LIV-1 mAb bound with high affinity to both human and cynomolgous LIV-1. In vitro, anti-LIV-1-vcMMAE ADCs showed specific cytotoxic activity against a breast cancer cell line. In vivo studies also demonstrated antitumor activity of anti-LIV-1-vcMMAE ADCs in preclinical xenograft models with significant delay of tumor growth compared to control groups. These findings demonstrate that further evaluation and development of anti-LIV-1-vcMMAE is warranted as a promising and potential therapeutic agent for the treatment of prostate and ER+ and triple-negative breast cancers.
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 3620. doi:10.1158/1538-7445.AM2011-3620
Abstract 3635: Improved efficacy of HER2 targeted-immunotoxins using photochemical internalization (PCI)
Authors: Berstad Maria Eb , Berg Kristian , Rosenblum Michael , Cao Yu , Marks James D. , Weyergang Anette 
Published: June 2012

Abstract
Human epidermal growth factor receptor 2 (HER2) is overexpressed in several cancers (breast, ovary, stomach, colon and esophagus) and is an attractive target for delivery of cancer therapeutics. However, both primary and acquired resistance to current anti-HER2 therapies is of major clinical concern and calls for more effective HER2 targeted treatment strategies. We here present photochemical internalization (PCI) of HER2 targeted immunotoxins (ITs) as a novel treatment strategy for HER2 positive cancers. PCI has been shown to result in release of macromolecular therapeutics entrapped in endocytic vesicles. The method is based on photosensitizers (PSs) which localize to the membranes of endocytic vesicles, and subsequent membrane rupture upon light exposure so that the drugs can escape into the cytosol. The purpose of this study was to evaluate photochemical internalization (PCI) of HER2 targeted immunotoxins (ITs) with various binding sites and affinities. ITs were constructed by chemically coupling the monoclonal HER2 antibody, trastuzumab, to a type I ribosome inactivating protein (RIP), saporin, through a biotin-streptavidin linkage, or by genetically fusing human single-chain antibodies (scFv) to recombinant gelonin, another type I RIP. The cytotoxic effect of PCI of the ITs was assessed against HER2 positive Zr-75-1 and BT-20 cells and HER2 negative MDA-MB231 cells. The present data confirm synergistic cytotoxicity of PCI of trastuzumab-based and HER2 scFv-based ITs compared to treatment with ITs and photodynamic therapy (PDT) alone (PS+light). At LD50-PDT a subtoxic dose of 100pM of the different ITs was sufficient to kill 75-85% of Zr-75-1 cells. LD95 of PCI of the recombinant fusions was detected between 1 and 10nM of all 4 ITs (subtoxic dosage) at a photodynamic dose reducing the viability of the BT-20 cells to 50%. PCI of the ITs was shown to be much more effective compared to PCI of the respective toxins alone, as no significant increase in toxicity was found by PCI of 0.1nM of the toxins. Animal model studies to assess the ability of PCI to augment the efficacy of immunotoxins are ongoing. These studies suggest that the selectivity of HER2-based ITs may be further improved by the addition of an independent, selective strategy such as PCI which augments efficacy only in tumor cells.
Research Conducted, in part, by the Norwegian Cancer Society and the Clayton Foundation for Research.
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 3635. doi:10.1158/1538-7445.AM2011-3635
Abstract 3646: The role of myeloid-derived suppressor cells in tumor development
Authors: Ortiz Myrna L. , Cheng Pingyan , Luetteke Noreen , Youn Je-In , Gabrilovich Dmitry I. 
Published: June 2012

Abstract
Myeloid-derived suppressor cells (MDSC) play an important role in regulation of immune response in cancer. They also have been implicated into promotion of tumor metastases and angiogenesis. We asked what role if any these myeloid cells can play in tumor formation associated in inflammation. To address this question we used previously described S100A9 deficient and S100A9 transgenic mice. S100A9, also known as calgranulin B or myeloid related protein 14 (MRP14), is a member of the S100 family of Ca2+ binding proteins. Previous studies have established that up-regulation of this protein in hematopoietic progenitor cells results in inhibition of dendritic cell maturation and accumulation of MDSC. We tested the role of MDSC in skin tumor formation using TgAC transgenic mice. These mice have activated k-ras mutation in keratinocytes. Upon topical treatment with 12-O-tetradecanoyl phorbol-13-acetate (TPA) they develop skin papillomas. We generated double transgenic mice and demonstrated that in mice overexpressing S100A9 the frequency and number of papillomas increased dramatically comparing with wild-type TgAC mice. The formation of papillomas was also significantly accelerated. To confirm the critical role of myeloid cells in the observed effect we used bone marrow transfer from wild-type or S100A9 Tg mice into lethally irradiated TgAC mice. Transfer of S100A9 Tg bone marrow cells resulted in significantly more rapid and more extensive formation of papillomas in TPA treated mice than transfer of control bone marrow. To assess effect of TPA treatment on cell infiltrate into skin wild-type or S100A9Tg mice were treated with TPA for 3 weeks. Skin from S100A9Tg mice had significantly higher number of Gr-1+ myeloid cells and CD4+ T cells than skin from wild-type mice. No differences in F4/80 macrophages and CD11c+ dendritic cells were seen. To further evaluate the possible role of MDSC in tumor formation we treat control and S100A9 knockout (KO) mice with combination of carcinogen DMBA and TPA using accelerated skin carcinogenesis protocol. The absence of S100A9 substantially delayed the onset of papilloma and decreased the number of lesions as compared with wild-type mice. These results suggest that MDSC may play an important role in inflammation associated tumoregenesis.
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 3646. doi:10.1158/1538-7445.AM2011-3646
Abstract 3648: S100A9 play a role in MDSC expansion and migration but not in their activation
Authors: Condamine Thomas , Cheng Pingyan , Youn Je-In , Ortiz Myrna L. , Vogl Thomas , Roth Johannes , Gabrilovich Dmitry I. 
Published: June 2012

Abstract
S100A9 is a pro-inflammatory molecule, secreted by myeloid cells, which has been reported to recruit leukocytes to the sites of inflammation or tumors. Up-regulation of S100A9 expression in myeloid progenitor cells was implicated in inhibition of DC differentiation and promotion of expansion of myeloid-derived suppressor cells (MDSC). These cells have been well described as a major component used by the tumor to be protected from the immune system. In order to determine if extracellular and intracellular S100A9 has similar effects on myeloid cell differentiation and function, we evaluated the effect of recombinant S100A9. Our results demonstrated that in contrast to overexpression of S100A9 in hematopoietic progenitor cell (HPC), the treatment of HPC with recombinant S100A9 did not affect their differentiation to mature macrophages, or dendritic cells. The same treatment does not affect the suppressive activity of MDSC purified from naïve or tumor-bearing mice either. However, recombinant S100A9 had strong chemotactic effect on MDSC. Interestingly, its effect on immature myeloid cells isolated from naïve tumor-free mice was substantially lower. Recently, it has been suggested that MDSC need two different signals: one – required for their expansion and inhibited differentiation of mature myeloid cells and the other one – for activation. Our data suggest that S100A9 may mediate first signals but not the second one. Intracellular up-regulation of S100A9 promotes expansion of MDSC and contributes to block of their differentiation, whereas extracellular S100A9 via cell receptors induce MDSC migration. A better understanding of how MDSC migrate into the tumor and how S100A9 is involved in this process could lead to the generation of new treatment aiming to block the migration of MDSC inside the tumor.
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 3648. doi:10.1158/1538-7445.AM2011-3648
Abstract 3673: Expression profile of phosphorylated proteins from the mTOR and Fyn/RSK2 signaling pathways in solar UV-induced skin carcinogenesis
Authors: Bermudez Yira , Stratton Steven P. , Bowden George T. , Dong Zigang , Bode Ann M. , Curiel-Lewandrowski Clara , Warneke James A. , Hurst Craig A. , Lang Julie E. , Alberts David S. , Einspahr Janine G. 
Published: June 2012

Abstract
Chronic sun exposure is considered the main etiologic agent of non-melanoma skin cancer (NMSC). Inactivation of tumor suppressor p53 and activation of key oncogenic signaling pathways important in cell proliferation and transformation are considered crucial steps in the development of NMSC. Therefore, our overall hypothesis is that topically administered small molecule drugs can modulate specific targets in ultraviolet (UV)-induced signaling cascades resulting in attenuation or reversal of carcinogenic events in human skin. In the study herein, we evaluate the modulation of solar light-activated mTOR and Fyn/RSK2 signaling pathways in normal human skin and solar simulated light (SSL)-irradiated human skin to determine the expression profiles of upstream and downstream phosphorylated proteins p38 (Thr180/Tyr182), p44/42 MAPK (Thr202/Tyr204), histone H3 (Ser10), p90RSK (Thr359/Ser363), Akt (Ser473), mTOR (Ser2448), S6 ribosomal protein (Ser235/236), and 4E-BP1 (Thr37/46). The study population consisted of individuals 18 years or older in general good health with skin types II-III. SSL irradiation at various doses ranging from two to four times the minimal erythema dose (MED) was applied to unexposed skin. Punch biopsies were taken at baseline, 5 minutes, 1 h, 5 h, and 24 h post-irradiation and immediately fixed in 10% formalin. Tissues were evaluated by immunohistochemistry for the expression of phospho-proteins. Proliferating cell nuclear antigen (PCNA) and cleaved caspase 3 (Asp175) were evaluated as markers for keratinocyte proliferation and apoptosis, respectively. Marked SSL-induced changes in human epidermis were seen in the expression of phosphorylated histone H3, S6 ribosomal protein, and 4E-BP1 at 1 h, 5 h, and 24 h post-SSL as compared to control. A linear increase in phosphorylated p44/42 MAPK expression was observed at 1 h, 5 h, and 24 h post-SSL as compared to control. Phosphorylated Akt expression increased post-SSL, and appears dependent on duration and intensity of SSL exposure. Ultimately, the expression profile patterns of phosphorylated proteins in the mTOR and Fyn/Rsk2 pathways will be used to determine activity of new and selective chemoprevention agents being developed to target these SSL-induced skin carcinogenesis pathways.
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 3673. doi:10.1158/1538-7445.AM2011-3673