bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3626: Development of inhibitors of the fibroblast growth factor receptor (FGFR) kinase using a fragment based approach
Authors: Squires Matthew S. , Perera Timothy , Saxty Gordon , Murray Chris , King Peter , Ward George , Feltell Ruth , Rich Sharna , Angibaud Patrik , Lewis Edward J. , Gilissen Ron , Harada Isobel , Fazal Lynsey , Irving Julie A. , Batey Mike A. , Zhao Yan , Newell David R. , Thompson Neil T. 
Published: February 2011

Abstract
Recent data in a number of tumour types has implicated Fibroblast Growth Factor (FGF) and Fibroblast Growth Factor receptor (FGFR) signalling as being key to the molecular pathology of cancer. FGFR is a receptor tyrosine kinase which activates the extracellular signal-regulated kinase / mitogen-activated protein kinase and the protein kinase B / Akt pathways which promote cell growth and survival. Amplification, over-expression or activating mutations of fibroblast growth factor receptors have been associated with bladder tumours, multiple myeloma, hormone-refractory prostate cancer and breast cancer.
Multiple lead series of FGFR inhibitors were developed using Astex's fragment based medicinal chemistry approach, Pyramid™, linked to high throughput X-ray Crystallography. We describe here the characterisation of some examples of these lead molecules. In particular we detail the pharmacological profile of a compound from one of these lead series that demonstrated activity against FGFR 1-4 with an IC50 &lt;100nM in an isolated kinase assay. This compound inhibited FGFR1-4 kinase activity in BaF3 cell lines engineered to express the relevant kinase fusion proteins and proliferation and survival of a panel of FGFR-dependent human tumour cell lines derived from several different tissues. The cytotoxic activity was &gt;10 fold lower in cell lines lacking FGFR expression. We demonstrate inhibition of FGFR 2 and 3 phosphorylation in gastric and multiple myeloma cell lines respectively with associated inhibition of downstream signalling pathways.
This lead molecule has an excellent pharmacokinetic profile and high oral bioavailibility in mice and rats. In xenograft models in mice where aberrant FGF signalling underlies tumour pathology, tumour growth inhibition is observed at doses of 100mg/kg /day orally for 21 days. This xenograft efficacy was observed in several models, with significantly lower activity in models where aberrant FGF signalling is not involved in tumour pathology. This suggests that the mechanism of action is consistent with FGFR inhibition. The pharmacological profile in these models is also distinct from other broader spectrum receptor tyrosine kinase inhibitors.
The pre-clinical data shown here suggests that such compounds warrant further investigation pre-clinically and may benefit patients whose disease is driven by FGFR activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3626.
Abstract 3634: Overcoming drug resistance to EGFR-tyrosine kinase inhibitors by FUS1 or FHIT-gene therapy in human lung cancer
Authors: Sakai Ryo , Xu Kai , Fang Bingliang , Roth Jack A. , Ji Lin 
Published: February 2011

Abstract
Dysregulation of the epidermal growth factor receptor (EGFR) and apoptotic pathways is a hallmark of human lung cancer and regulate tumor cell proliferation, survival, angiogenesis, and metastasis. Inhibition of oncogenic EGFR activity is proving to be an effective therapeutic strategy for lung cancer. Though EGFR-tyrosine kinase inhibitors (TKIs) are promising drugs, resistance occurs frequently. ZD6474 is an orally available small-molecule that inhibits both EGFR and VEGFR2 tyrosine kinases. FUS1 and FHIT are novel tumor suppressor genes identified in the human chromosome 3p21.3 and 3p14.2 regions, respectively and have been shown to suppress tumor cell growth by induction of apoptosis and down-regulation of multiple oncogenic tyrosine kinase activities in human non-small-cell lung cancer (NSCLC) cells in vitro and in vivo. We evaluated the therapeutic effects of EGFR-TKIs at dose levels equivalent to those of steady-state serum levels achieved in the clinic as single agents and in combination with FUS1- or FHIT-nanoparticle-mediated gene therapy in NSCLC cells. We found that expression of wild type FUS1 or FHIT sensitized NSCLC cells to ZD6474 treatment (at 2µM), as shown by significantly enhanced inhibition of tumor cell growth in a cell proliferation assay. A combination treatment with FUS1-nanoparticles and ZD6474 also significantly enhanced inhibition on tumor cell-induced colony formation in H322 cells compared to treatment with either agent alone. Combination treatment with ZD6474 and FUS1 or FHIT-nanoparticles increased down-regulation of the EGFR signaling pathway and up-regulation of the apoptosis pathway as indicated by the reduced expression of the phosphorylated Akt and ERK1/2 and by enhanced expression of cleaved PARP on Western blots. We found that the expression level of p-Met, which is one of acquired resistant factors to EGFR-TKIs, was reduced by FHIT-gene therapy in H1975 cells. We evaluated the antitumor effects of combination therapy using a fluorometric migration assay and found that the migration of H1299-GFP cells were inhibited by co-treated with ZD6474 and FHIT-gene therapy. Our findings imply that a combination treatment with FUS1 or FHIT-gene therapy and ZD6474 may be a useful strategy for enhancing lung cancer therapy. (supported by NIH Lung SPORE P50CA70907 and RO1CA116322)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3634.
Abstract 364: Coat color mutations alter angiogenic responsiveness
Authors: Rogers Michael S. , Birsner Amy E. , D'Amato Robert J. 
Published: February 2011

Abstract
Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations, including humans and mice, harbor genetic variations that alter angiogenesis. Angiogenesis-regulating gene variants can result in increased susceptibility to multiple angiogenesis-dependant diseases in humans. Our efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Using the murine corneal micropocket assay, we have observed more than ten-fold difference in angiogenic responsiveness among various mouse strains. This degree of difference is observed with either bFGF or VEGF induced corneal neovascularization. Ongoing mapping studies have identified multiple loci that control angiogenic responsiveness in several mouse models. We have identified the polymorphism responsible for two of these loci. Using composite interval mapping and multiple interval mapping in crosses involving C57BL/6J, A/J, and SJL/J strains, we have confirmed the existence of multiple angiogenesis-response loci on chromosome 7. One of these (AngVq4) localized to the middle of the chromosome and was centered on tyrosinase. Congenic animals confirmed this locus, but could not demonstrate that the classical tyrosinase albino (c) mutation was causative because of the existence of additional linked loci in the congenic. In 1970, a second tyrosinase albino mutation (c-2J) arose in the C57BL/6J background at Jackson Labs. Testing this strain (C57BL/6J&lt;c-2J&gt;) demonstrated that the albino mutation is sufficient to completely explain the alteration in angiogenic response that we observed in congenic animals. Thus, we conclude that the classical tyrosinase mutation is responsible for AngVq4. Similar methods have identified the classical pink-eyed dilution mutation as the genetic change responsible for AngFq5.
Characterizing novel angiogenesis regulating genes detected by QTL mapping may identify additional therapeutic targets for antiangiogenic agents. These experiments also reveal the important effect of the host genetics on angiogenesis and tumor growth. The identification of “high angiogenic” individuals which are at risk for angiogenesis dependent diseases will allow for increased monitoring and better clinical management. Further, new antiangiogenic therapies with low toxicity may allow for the pretreatment of such individuals rendering them “low angiogenic” and thereby increase survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 364.
Abstract 3641: The DNA repair protein hABH2 mediates temozolomide resistance in human glioblastoma cells
Authors: Johannessen Tor-Christian A. , Prestegarden Lars , Tysnes Berit B. , Bjerkvig Rolf 
Published: February 2011

Abstract
Background and Purpose:
Glioblastoma multiforme is the most malignant and frequent primary brain tumour in adults. Current treatment remains insufficient as these tumours display a diffuse infiltrative growth pattern and tend to recur despite extensive debulking surgery followed by radio- and chemotherapy. The methylating agent temozolomide is at present the cornerstone of glioblastoma chemotherapy. However, several independent DNA repair mechanisms can restore the integrity of methylated DNA bases, and thus contribute to temozolomide resistance and subsequent therapy failure. In this work we examined whether human AlkB homologue 2 (hABH2), an oxidative demethylase capable of reversing methyl lesions in DNA, might provoke temozolomide resistance in human glioblastoma cells.
Materials and Methods:
hABH2 expression was examined in eight established glioma cell lines as well as normal human brain using quantitative real-time PCR. Cells derived from a hABH2 deficient glioblastoma were transfected with a hABH2 plasmid prior to antibiotic selection, and subsequent colonies were screened for hABH2 expression by western blotting. Temozolomide sensitivity was assessed for hABH2 proficient and deficient colonies using a tetrazolium salt assay after 96 hours of drug incubation.
Results:
mRNA levels of hABH2 were generally 2-4 fold higher in the established cell lines compared to normal human brain. Furthermore, hABH2 overexpressing glioblastoma cells were significantly more resistant to temozolomide than hABH2 deficient cells derived from the same patient.
Conclusions:
Our results show that hABH2 is expressed at high levels in glioma cells, and that overexpression of this protein mediates temozolomide resistance in vitro.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3641.
Abstract 365: Autocrine vascular endothelial growth factor signaling mediates survival and chemoresistance of human colorectal cancer cells
Authors: Samuel Shaija , Fan Fan , Dang Long H. , Gaur Puja , Xia Ling , Zhou Yunfei , Liu Jia , Tozzi Federico , Sceusi Eric , Ye Xiang-Cang , Ellis Lee M. 
Published: February 2011

Abstract
Introduction. Although the effects of VEGF on angiogenesis and vascular function are well known, the autocrine effects of VEGF on tumor cell function remain to be elucidated. We studied phenotypic changes in human colorectal cancer (CRC) cells with homologous deletion of VEGF alleles to determine any potential autocrine/intracrine role of VEGF on tumor cell function.
Methods. The human CRC cell lines HCT116 and LS174T with homologous recombination-mediated deletion of VEGF alleles were generated previously (Dang et al, Can Res 2006). To exclude the effect of exogenous VEGF, the cells were grown in low serum condition for all assays. MTT assay was used to detect changes in cell growth. Migration and invasion were determined using modified Boyden chamber assays. Cell death and apoptosis were assessed by FACS analysis following PI and Annexin V/PI staining respectively. Changes in protein levels of VEGF signaling intermediates and mediators of apoptosis were evaluated by Western blotting. Chemosensitivity was determined by FACS analysis following 5-FU treatment and PI staining of cells.
Results. Loss of VEGF expression decreased cell growth and increased spontaneous apoptosis in CRC cells. Cells null for VEGF demonstrated increases in migration and invasion. Loss of VEGF expression also increased the sensitivity of cells to the cytotoxic effects of the chemotherapeutic drug, 5-FU, as shown by increased cell death and apoptosis. These effects are mediated via upregulation of the pro-apoptotic mediators cleaved caspase-3 and PARP and, downregulation of the anti-apoptotic mediator survivin. In addition, loss of VEGF led to increased levels of PlGF, SDF-1 and phosphorylated VEGFR-1 in CRC cells.
Conclusion. Loss of autocrine/intracrine VEGF signaling leads to an increase in spontaneous apoptosis and chemosensitivity of colon cancer cells. In addition, loss of VEGF signaling led to increases in PlGF and SDF-1, suggesting that loss of VEGF signaling can lead to induction of compensatory pathways that may be mediated by numerous cell types in the tumor microenvironment. These findings have implications for a better understanding of mechanisms of action for VEGF targeted therapies when combined with chemotherapy in patients with metastatic CRC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 365.
Abstract 3658: 5F 203 modulates oxidative stress, induces single-strand break formation and promotes mitochondrial membrane potential loss in sensitive breast cancer cells
Authors: Brantley Eileen J. , Watkins Cheri , McLean Lancelot , Amis Louisa , Davis Willie 
Published: February 2011

Abstract
Targeted pharmacotherapeutic agents have been successful in treating women with breast cancer that either over-expresses human epidermal growth factor receptor 2 (Her2/neu) or is dependent upon estrogen receptor signaling. However, patients with Her2/neu-negative or hormone-independent breast cancer do not benefit from these targeted agents. A candidate anticancer agent 2-(4-amino-3-methylphenyl)-5-benzothiazole (5F 203) targets the aryl hydrocarbon receptor signaling pathway and potently inhibits the growth of breast cancer cells irrespective of either estrogen receptor or Her2/neu status. 5F 203 may represent a promising agent for women who lack targeted therapeutic options. We have previously assessed the role reactive oxygen species (ROS) play in mediating the anticancer activity of 5F 203. In our current studies, we pretreated 5F 203-sensitive breast cancer cells with rotenone prior to treatment with 5F 203. This pretreatment diminished 5F 203-mediated ROS formation as measured by DCF-DA staining followed by flow cytometry. This suggests 5F 203-induced ROS production is partially derived from the mitochondria. Using the comet assay and a JC1 dye-based fluorometry assay respectively, we found 5F 203 induced single-strand break formation and mitochondrial membrane potential loss in sensitive breast cancer cells. Pretreatment with the antioxidant N-acetyl-L-cysteine partially diminished apoptosis as assessed by relief contrast microscopy and the Annexin V/PI assay. This implies that 5F 203-induced apoptosis depends at least in part on ROS derived from mitochondria. We also analyzed 84 oxidative stress-responsive genes using PCR-array and determined that 5F 203 significantly increased the expression of cytoglobin, a novel tumor suppressor, in sensitive breast cancer cells. These data imply ROS and cytoglobin contribute to the anticancer activity of 5F 203.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3658.
Abstract 3663: Effects of chemotherapy on cell survival, cell cycle biology and apoptosis in the SK-N-FI neuroblastoma cell line
Authors: Blanco Idoia , Lazcoz Paula , Celay Jon , Fan Xing , Castresana Javier S. , Encio Ignacio J. 
Published: February 2011

Abstract
Neuroblastoma is a malignant embryonal childhood tumor of the peripheral nervous system, which often shows poor clinical prognosis. p53 mutations are rare at diagnosis of neuroblastoma but may be acquired at relapse, as well as chemoresistance.
We have previously detected a mutation in exon 5 of the p53 gene (codon 135; Cys to Phe) in the SK-N-FI neuroblastoma cell line. To test whether this mutation affects p53 function driving the cells to a higher chemoresistant phenotype, we analyzed the action of doxorubicin, etoposide, cisplatin, melphalan and retinoic acid on cell survival, apoptosis induction and cell cycle distribution in these cells.
SK-N-FI cells were incubated in the presence of doxorubicin, etoposide, cisplatin, melphalan and 9-cis or all-trans retinoic acid at five different concentrations ranging from 10-4 to 10-8 M. After 72 h of treatment, cell survival was estimated by the MTT method. Quantification of apoptosis and cell cycle analysis were carried out by flow cytometry. With this purpose, fixation of SK-N-FI cells was conducted after 12, 24, 72 h and 5 days of treatment with the previously mentioned drugs.
All tested compounds were toxic at the micromolar range except for the retinoic acid isomers which were active at higher doses. The smaller GI50 values were found with doxorubicin, followed by melphalan, etoposide and cisplatin.
A statistically significant rise in apoptosis was observed in all cases at day 5. This increase was even noticeable at 72 h for doxorubicin, 9-cis retinoic acid and cisplatin.
With regard to the cell cycle distribution, a decrease of the G0/G1 cell population at day 5, accompanied by a time course increase in the Sub-G1 phase, was detected for every tested drug but the retinoic acid isomers. Melphalan also decreased S phase cells. Moreover, while for doxorubicin treatment reduction of the G0/G1 cell population was preceded by an increase in S and G2/M cells at shorter periods, for etoposide and cisplatin only the reduction in the G0/G1 cells in the long term was observed. Finally, 9-cis retinoic acid but not all-trans retinoic acid treatment provoked an initial accumulation of G0/G1 cells that was followed by an increment in the Sub-G1 phase.
Despite bearing a mutation of the p53 gene, SK-N-FI cells respond to doxorubicin, cisplatin, etoposide, melphalan, 9-cis and all-trans retinoic acid. All mentioned drugs were able to induce apoptosis, affected to the cell cycle distribution of the cells in a drug specific manner and, except for the retinoic acid isomers, displayed cytotoxic activity at the micromolar range.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3663.
Abstract 3675: Farnesyltransferase inhibitor (FTI) disruption of Rheb/FKBP38 association leads to FKBP38-mediated inactivation of mTOR
Authors: Yang Hua , Wang De-An , Hamilton Andrew D. , Sebti Said M. 
Published: February 2011

Abstract
The activation of the Rheb (Ras homologue enriched in brain) / mTOR (mammalian target of rapamycin) pathway plays a central role in integrating growth factor, nutrient and energy signals and regulates cell growth (cell mass and size) and proliferation (cell number). Recently Rheb was found to activate mTOR by binding and antagonizing its endogenous inhibitor, FKBP38. However, it is not known whether inhibition of Rheb farnesylation by farnesyltransferase Inhibitors (FTIs) is sufficient to disrupt Rheb/FKBP38 interaction and leads to inactivation of mTOR. Here we demonstrate that FTI-2153 disrupts Rheb binding to FKBP38 allowing FKBP38 to bind and to inactivate mTOR. Furthermore, in human cancer cells, FTI-2153 also blocks IGF-1-stimulated Rheb/FKBP38 binding and promotes mTOR/FKBP38 binding. We further show that FTI-2153 inhibits Rheb-mediated activation of mTOR to phosphorylate S6 kinase, and that a geranylgeranylated mutant variant of Rheb that is as efficient as wild-type farnesylated Rheb at activating mTOR rescues cancer cells from FTI-induced inactivation of mTOR signaling, inhibition of anchorage-dependent and -independent tumor cell growth and induction of apoptosis. These results demonstrate that FTI-mediated disruption of the Rheb/FKBP38 interaction leads to inactivation of mTOR and is an effective approach to inhibiting tumor proliferation and survival and that inhibition of Rheb farnesylation mediates, at least in part, the anti-tumor effects of FTIs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3675.