bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A163: Development of Grb2 SH3 domain antagonists
Authors: Giubellino Alessio , Liu Fa , Burke Terrence , Bottaro Donald P. 
Published: June 2012

Abstract
Src-homology 3 (SH3) domains are small modules of about 60 amino acids residues found in proteins that participate in many signaling pathways. As such, SH3 domains are involved in the regulation of several important cellular processes, including cell growth and differentiation, cell movement, protein trafficking and degradation, and immune responses. The adaptor protein Grb2 contains two SH3 domains. The canonical model of Grb2 function relies on the widely confirmed observation that Grb2 SH3 domains are constitutively associated with Sos1, a guanine-nucleotide exchange factor that promotes GDP-GTP exchange on Ras. Upon growth factor receptor activation and tyrosyl phosphorylation, Grb2 brings Sos1 into close proximity of membrane-bound Ras, thereby activating Ras and the downstream MAPK cascade, a well-know oncogenic signaling convergence point. Thus, antagonism of Grb2-Sos interaction is a logical strategy for inhibiting tumor cell growth. Using a short synthetic peptide corresponding to the SH3 domain recognition motif of Sos1 as a starting point, and systematically introducing bridging carbonyl sequences and other modifications, novel antagonists of Sos1-SH3 domain interaction were developed.
The performance of these antagonists was systematically evaluated using a solid phase Grb2-Sos1 binding assay and cell lysates prepared from the pheochromocytoma cell line PC12, which has robust expression of both Grb2 and Sos1 proteins. Refinement of candidates identified in initial screens yielded a set of peptidomimetic antagonists with nanomolar IC50 values that were selected for further study. The potency and target selectivity of these compounds suggest that they may have utility as anti-cancer therapeutics for tumors where Grb2-Sos1 interactions are critical for oncogenesis and disease progression.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A163.
Abstract A17: The dual angiogenesis/heparanase inhibitor PG545 inhibits solid tumor progression in models of breast, prostate and liver cancer: A comparative assessment of once versus twice weekly administration schedules
Authors: Hammond Edward , Bytheway Ian , Handley Paul , Kappler Michelle , McGirr Crystal , Gonda Thomas J. , Smith Maree , Dredge Keith 
Published: June 2012

Abstract
PG545 is Progen's lead oncology candidate currently undergoing formal preclinical development. PG545 is a synthetic heparan sulfate (HS) mimetic that prevents neovascularization by inhibiting growth-factor heparan sulfate binding and metastasis through the inhibition of heparan sulfate cleavage by heparanase. PG545 was assessed for efficacy in a number of xenograft models, namely the MDA-MB-231 (breast), PC3 (prostate), HepG2 (liver) and the orthotopic model Hep3B (liver). In the Hep3B liver cancer model, a concurrent study dosed tumor-bearing mice with radiolabeled PG545 every 96 h for three doses in order to generate a pharmacokinetic (PK) profile of the compound in blood and tumor tissue. In the efficacy studies, once or twice weekly treatment was initiated once the tumors reached 100–200cm3 (depending on the study). Although not significantly different to twice weekly dosing, PG545 exhibited maximal antitumor efficacy when dosed once weekly in each of the four independent studies. Moreover, in the Hep3B liver cancer study, PG545 exhibited antitumor activity to a similar extent as the tyrosine kinase inhibitor sorafenib which is approved by the FDA for inoperable hepatocellular carcinoma. A preliminary pharmacokinetic profile using radiolabeled compound [3H]-PG545 was also obtained. Data generated using both compartmental and non-compartmental modeling indicate a favourable pharmacokinetic profile and significant uptake of [3H]-PG545 into the tumor from the bloodstream. Taken together, the tumor efficacy and pharmacokinetic data support the ongoing preclinical development of PG545 as a once weekly, subcutaneously administered injection for the treatment of cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A17.
Abstract A175: Isolation and identification of compounds from the fruits of Kigelia pinnata with anti-proliferative activity towards human cancer cells
Authors: Higgins Catherine A. , McGrath Owen , Delbederi Zoicha , McGarel Kelly , Feutren-Burton Stephanie , Watters William , Armstrong Paul , Waugh David , van den Berg Hendrik 
Published: June 2012

Abstract
Kigelia pinnata DC. (Bignoniaceae also referred to as K. Africana or sausage tree), is a tree which is found widely in Africa and the tropics in general. Traditionally hot aqueous extracts of fruit pods from Kigelia pinnata have been claimed to have widespread ethnomedicinal importance. A preliminary study of the components of the aqueous extracts from the fruits of Kigelia pinnata was undertaken to identify fractions with potential anti-cancer activity. A bioactivity guided fractionation process of extracts from fruits of the tree was carried out yielding a number of crude fractions, which demonstrated cytotoxicity in vitro against human melanoma cells. A number of compounds were isolated and identified within purified fractions of several fruit extracts including the dihydroisocoumarins, demethylkigelin and kigelin, a number of fatty acids, and a furonaphthoquinone, as compounds at least in part responsible for the anti-proliferative activity observed in extracted material from the fruits. We tested a number of structurally related dihydroisocoumarins for their anti-proliferative activity in order to conduct a preliminary structure-activity relationship (SAR) study. The preliminary medicinal chemistry programme clearly identified structures with enhanced anti-proliferative activity relative to the isolated compounds. In conclusion, using a bioassay fractionation approach, we have isolated and characterized several classes of compounds that exhibit biological activity against human cancer cell lines. Structurally-related derivatives of these compounds have been synthesized to develop knowledge of the structure-activity relationship for these classes of compounds. Our data to date suggest that this class of molecule has structural features that appear to be of importance in determining its activity against human cancer cells.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A175.
Abstract A182: PI3K inhibitors overcome resistance to HER2-targeted agents caused by PIK3CA mutations in HER2-amplified breast cancer cell lines
Authors: Kataoka Yu , Minami Hironobu , Shimada Hiroyuki , Saijo Nagahiro , Hirai Midori , Mukohara Toru 
Published: June 2012

Abstract
Background: The mechanisms of resistance to HER2-targeted agents and the means to overcome them have not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to HER2-targeted agents in naturally derived breast cancer cells. We also tested potential usefulness of various inhibitors against molecules on PI3K signaling pathway.
Materials and Methods: We examined the effects of CL-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab, humanized anti-HER2 monocloncal antibody, on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR). We also examined different PI3K pathway inhibitors that were PI3K inhibitor, m-TOR inhibitor, and PI3K/m-TOR dual inhibitor, on the same panel of cell lines.
Results: Four cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 mg/ml trastuzumab: 58% versus 92%; p = 0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1 M CL-387,785: 21% versus 77%; P = 0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. All HER2-amplified cells showed detectable level of phosphorylated-Akt on serum-starved condition, while cell lines without PI3K pathway enhancement or HER2-amplification did not. Growth of all HER2-amplified cells was inhibited by PI3K pathway inhibitors regardless of PIK3CA genotype. PI3K/m-TOR dual inhibitor had much lower IC50 than the other PI3K pathway inhibitors, suggesting that complete blockade of phosphorylation of Akt and S6K may be required for maximal growth inhibition.
Conclusions: PIK3CA mutations are associated with resistance to HER2-targeted agents. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy. PI3K inhibitors, especially PI3K/m-TOR dual inhibitor, are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A182.
Abstract A190: In vivo activity of SGI-110, a novel hypomethylating agent for treatment in hematology and solid malignancies
Authors: Scholl Jason , Vollmer David , Bearss Jared , Jones Carissa , McCarthy Virgil , Severson Paul , Redkar Sanjeev , Joshi-Hangal Rajashree , Inloes Roger , Shi Chongtie , Bearss David 
Published: June 2012

Abstract
SGI-110 is a second generation hypomethylating agent being developed for treatment in myelodysplastic syndrome (MDS) and solid tumor malignancies. In previous work, SGI-110 has demonstrated potent in vivo activity in a number of tumor types, including non-hematological cell lines. Current efforts are underway to optimize formulation and delivery of SGI-110 for first-in-human (FIH) studies.
In animals, SGI-110 is well-tolerated across multiple species utilizing multiple routes of drug delivery. Tolerability studies have been performed in mouse, rat, and rabbit models with multiple dose routes and schedules. Myelosuppression is an observed toxicity endpoint for hypomethylating agents. Hence, myelotoxic effects were investigated by comparing RBCs and bone marrow cellularity of mice treated with and without SGI-110. Mice dosed with SGI-110 for five consecutive days showed a significant decrease in RBCs at the end of the dosing period and a continued decrease one week after dosing. Bone marrow cellularity also showed a decrease at the end of dosing, but recovered to near normal levels one week later. Interestingly, RBCs from SGI-110 treated mice were elevated in the bone marrow after the dosing period. Pyrosequencing methylation analysis of colon samples was also evaluated in this study. A significant decrease in B1 methylation was observed in colon samples of treated mice, indicating global DNA methylation is being inhibited. Decreased levels in several hematology parameters and decreases in bone marrow cellularity were also observed in rat and rabbit studies after five consecutive days of SGI-110 dosing. Increased dosing frequency, while maintaining the same total dose per week, appears to result in increased toxicity.
Previous pharmacokinetic studies have shown that SGI-110 rapidly metabolizes to decitabine, an FDA-approved drug for MDS. Multiple formulations and different routes of delivery were examined to determine the optimal dose form to be used in FIH studies. Subcutaneous dosing results in bioavailability that is similar to that of intravenous dosing. Subcutaneous dosing appears to reduce the Cmax while maintaining similar AUC values when compared to intravenous dosing. Similar results in pharmacokinetic parameters are observed when the delivery vehicle is changed from an aqueous to non-aqueous formulation.
SGI-110 is a novel hypomethylating agent that is well-tolerated in rodent models, provides excellent PK exposure, and demonstrates inhibition of DNA methylation in a mouse model.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A190.
Abstract A194: Epigenetic modification of RXRα in human colon carcinomas by the green tea polyphenol, EGCG
Authors: Morris Jay , Brown Vondina R. , Coleman Kathleen V. , Wargovich Michal J. 
Published: June 2012

Abstract
Silencing of regulatory genes through hypermethylation of CpG islands is an important mechanism in tumorigenesis of numerous cancers. In colon cancer, one such gene which undergoes this type of silencing is Retinoid X Receptor alpha (RXRα) an important dimerization partner with other nuclear transcription factors. Previous studies have shown that ApcMin/+ mice treated with the carcinogen azoxymethane (AOM) will develop colonic tumors and when treated with green tea a reduction in tumor numbers was found. AOM treated mice also have reduced RXRα protein levels which is restored by treatment with green tea, reducing the amount of promoter methylation. We examined human colonic tumor microarrays by immunohistochemcial staining and found a marked decrease in RXRα a expression in tumor tissue compared to normal matched tissues, inversely β-Catenin levels increased. To determine how RXRα loss is reversed in human cancers by green tea, we treated HT-29 (methylation insensitive) and HCT116 (methylation sensitive) human colon cancer cell lines with Epigallocatechin gallate (EGCG - major polyphenolic compound in green tea for 48, 72 & 96 hr; 2, 3 & 4 doubling times). We found EGCG to restore RXRα activity levels in HCT116 cells treated with EGCG, in a dose dependant manner. We also found that EGCG treatments reduce the amount of promoter methlyation in 2 CpG island in the RXR promoter in HCT116 cells in a dose dependant manner. Numerous epidemiological reports have shown the benefits of green tea consumption in reducing colon cancer risks but to date no known studies have shown direct genetic effects of green tea on human colon cancer cells. Our results here show that EGCG, a common dietary compound, can modulate the reversal of gene-silencing involved colon carcinogenesis and maybe a possible avenue for colon cancer treatment.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A194.
Abstract A200: Differential kinase requirements of human cell lines pertaining to metastasis and c-Met signaling
Authors: Li Wenliang , Bhattacharya Nandita , Boyce Frederick M. , Gupta Piyush , Watnick Randolph S. , Harlow Edward E. 
Published: June 2012

Abstract
Metastasis accounts for over 90% of cancer death, but its mechanisms are still poorly understood. One valuable approach that has been commonly used to study metastasis was to compare paired poorly and highly metastatic cell lines, either for roles of a few genes of interest or global gene expression differences. Our work involved in using shRNA screen to identify global key functional differences between these matched cell lines. We postulated that the distinct in vivo phenotypes of these paired cell lines are a consequence of alterations in their cellular signaling networks during tumor progression. To characterize these functional differences, we performed arrayed shRNA screens against the human kinome to examine kinase requirements for survival and proliferation on several pairs of melanoma, colon or prostate cancer cell lines. From these screens, we have identified a set of kinases that become essential for multiple highly metastatic cells, some of which have been linked to metastasis (such as c-Met) but more have not. Several of these genes were shown to be amplified or mutated in human cancers. In vivo metastatic experiments are underway to prioritize these kinases by evaluating which kinases can promote metastasis when ectopically expressed. Since inhibition of these kinases phenocopied c-Met inhibition, we also sought to test if any of these kinases are functionally linked to c-Met signaling. Indeed, several of the identified kinases became essential when immortalized melanocytes were made tumorigenic and metastatic by introduction of activated c-Met. Biochemical and genetic rescue experiments are currently ongoing to further examine the links between these genes and c-Met. These studies offer new insights into the cellular signaling pathways operating in metastatic cancer cells and also suggest potential targets to treat metastatic cancers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A200.
Abstract A21: Preclinical bioanalytical development to optimize drug treatment regimens using orthotopic models of human gastric cancer
Authors: Wick Michael J. , Cooper Joshua D. , Kelly Scott G. , Nieves Francis E. , Patnaik Amita , Tolcher Anthony W. , Kuhn John G. , Papadopoulos Kyriakos P. 
Published: June 2012

Abstract
Gastric cancer remains the second leading cause of cancer deaths worldwide and while gains have been made its treatment including neo- and post- adjuvant chemotherapy response rates are variable with limited survival benefit. Recent identification of molecular markers important in the pathogenesis of gastric cancer has spurred development of standard and targeted therapies to treat gastric cancer; however, lack of validated models has hindered this effort.
Preclinical development of anticancer agents can be accelerated with better tools to optimize a treatment regimen for in vivo studies. Identifying a useful drug concentration, route of administration and treatment schedule is costly and time consuming and often the decided regimen is suboptimal for efficacy experiments.
To address these issues, we have developed and characterized two cell-based orthotopic gastric tumor xenograft models (MKN-45 and 23132-87) in nude mice and rats. Using the mouse models we compared efficacy of several relevant anticancer agents including cisplatin, trastuzumab, docetaxel, ixabepilone, capecitabine and lapatinib. Bioanalytical methods using a UPLC-MS/MS system were developed for the latter four agents. Drug plasma concentrations were analyzed using blood collected at multiple in study timepoints from each animal (&lt;30 l plasma per timepoint) and at study completion. In the capecitabine and lapatinib groups, tumors were also collected and analyzed. Docetaxel was active towards both models with tumor growth inhibition (%TGI) values &gt;85% versus control. However, 23132-87 was insensitive to cisplatin and ixabepilone as well as trastuzumab and lapatinib but not capecitabine (TGI=79%) which was ineffective towards the MKN-45 model (T/C=19%). Bioanalytical analysis yielded Cmax values for each agent and steady state concentrations and plasma to tumor concentration ratios determined for capecitabine and lapatinib.
Results from these studies confirm two useful orthotopic models of gastric cancer with variable drug sensitivity. We have developed a platform for testing new drugs which can be tailored to optimize treatment regimen parameters and correlate with efficacy in a single study.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A21.
Abstract A215: Hsp90 inhibitor IPI-504 demonstrates antitumor activity against a panel of neuroendocrine/carcinoid cell lines in vitro and in vivo
Authors: Lim Alice R. , Slocum Kelly , Denyeko Igor , West Kip A. , Palombella Vito J. , Fritz Christian C. , Vosburgh Evan , Normant Emmanuel Y. 
Published: June 2012

Abstract
Heat shock protein 90 (Hsp90), an emerging target in cancer, is a chaperone protein that contributes to tumorigenesis by maintaining the stability and activity of multiple oncogenic proteins. Infinity Pharmaceuticals is currently developing two Hsp90 inhibitors: IPI-504 (retaspimycin hydrochloride), an intravenous agent that has entered several phase II clinical trials, and IPI-493, an orally administered compound that is currently being tested in a phase I dose-escalation trial. In pre-clinical animal models, IPI-504 and IPI-493 have demonstrated anti-tumor activity against a wide variety of tumor types.
Neuroendocrine tumors form a heterogeneous group of malignancies, which differ from each other in their biology, prognosis, and genetics. They mainly occur in the gastrointestinal tract and bronchopulmonary system. Conventional cytotoxic therapy has failed to demonstrate effective treatment of neuroendocrine/carcinoid cancers over the past 4 decades, resulting in an unmet need for improved pharmacological treatment of these tumors. To date, no data have been reported on the activity of Hsp90 inhibitors against carcinoid cancer cells.
Herein we describe the activity of the Hsp90 inhibitors IPI-504 and IPI-493 against a panel of neuroendocrine tumors including: BON-1, a cell line derived from a metastasis of a primary pancreatic neuroendocrine tumor, NCI-H720, a lung carcinoid, QGP-1, a pancreatic carcinoma of islet cells and HC-45, an ileal carcinoid. In vitro, most of the carcinoid cell lines are sensitive to the Hsp90 inhibitors with EC50 values between 10 and 189 nM for IPI-493 and 49 and 930 nM for IPI-504. In vivo, IPI-504 dosed twice weekly inhibits the tumor growth of BON-1 cells in mice.
To identify the potential mechanism of action of IPI-504 in BON-1 cells we have determined that IGF-1R, a tyrosine kinase receptor and an Hsp90 client protein, is constitutively activated in these cells suggesting that it could participate in the unregulated growth of these tumor cells. Upon treatment of BON-1 cells with IPI-504, phospho-IGF-1R is degraded in a dose-dependent manner. The EC50 of the protein degradation and the in vitro growth inhibitory activity of IPI-504 are similar (∼50 nM), suggesting that the anti-tumor activity of IPI-504 could be due, in part, to the inactivation of this growth factor receptor.
In conclusion, we demonstrated that the Hsp90 inhibitors IPI-504 and IPI-493 potently inhibit the growth of neuroendocrine tumor cell lines both in vitro and in vivo and identified IGF-1R as a potential client protein. These data suggest further exploring IPI-504 for the possible treatment of neuroendocrine tumors in the clinic.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A215.