bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A227: Positron emission tomographic (PET) imaging of activated matriptase, a marker for cancer progression
Authors: Choi Julia C. , Hausner Sven H. , Gagnon M. Karen J. , Kukis David L. , Holland Jason P. , Lewis Jason S. , Lin Chen-Yong , Johnson Michael D. , Sutcliffe Julie L. 
Published: June 2012

Abstract
The serine protease matriptase has been implicated in epithelial cancers, has been found in ∼45% of node-negative breast cancers at high levels, and is indicated as a biomarker for survival independent of HER-2/neu. While in vitro methods are invaluable, few breast cancer cell-lines express matriptase, though 83% of breast cancer patients are positive for matriptase—this suggests that imaging the in vivo behavior of matriptase may aid in understanding its role in the context of the tumor system. Specifically, activated matriptase is associated with cancer progression. We have developed radiotracers against activated matriptase for in vivo imaging using PET.
M69, an antibody against activated matriptase, was functionalized to capture [64Cu]copper or [89Zr]zirconium: 64Cu-TETA-M69 and 89Zr-DF-M69 were evaluated in a mouse model of human breast cancer. A dox-regulable pair of PyVmT cell-lines was bilaterally introduced into nude female mice to generate matriptase-positive and control tumors. Mice were fed dox chow ad libitum, administered radiotracer, imaged using microPET at 1–4d p.i.; and through 336h for 89Zr; corresponding biodistribution was performed.
PET images indicated specific tumor retention. Biodistribution at 4d revealed both 64Cu-TETA-M69 and 89Zr-DF-M69 retained two-fold uptake ratios for the positive tumor over control; this was also observed at 336h for 89Zr-DF-M69. Immunohistochemistry on FFPE tissues confirmed human matriptase expression in the positive tumor.
In summary, we have developed two novel radiotracers and performed the first in vivo imaging of activated matriptase. This approach has the potential for imaging metastasis, the primary cause of mortality in breast cancer patients.
Table 1 Tumor-to-liver ratios from biodistribution at 96h for activated matriptase. Radiotracer Matriptase-positive tumor Control tumor 64Cu-TETA-M69 2.55 ± 0.41 1.54 ± 0.33 89Zr-DF-M69 3.79 ± 0.25 1.88 ± 0.33
Table 2 Tumor-to-blood ratios from biodistribution at 96h for activated matriptase. Radiotracer Matriptase-positive tumor Control tumor 64Cu-TETA-M69 1.67 ± 0.39 1.01 ± 0.30 89Zr-DF-M69 1.97 ± 0.40 0.98 ± 0.45
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A227.
Abstract A233: Generation of in vitro and in vivo tumor models driven by insulin-like growth factor receptor (IGF1R) and their use in the development of OSI-906, a selective IGF1R inhibitor
Authors: Liu Qing , Lorena Lerner , Tao Nianjun , Huang Lu , Yang John , Krieger Brian , Buck Elizabeth , Wang Ruojie , Kannan Karuppiah , Chiu M. Isabel , Robinson Murray O. 
Published: June 2012

Abstract
The emergence of insulin-like growth factor-1 receptor IGF1R as an important cancer target is evidenced by the growing number of clinical trials currently underway for both small molecule inhibitors and antibody therapeutics developed against it. In preclinical studies, perturbation in IGF1R signaling has been associated with tumor growth inhibition, blockade of metastasis, and enhanced sensitivity to therapeutic agents, including cytotoxic chemotherapeutics and molecular targeted agents. Currently agents directed against IGF1R are being evaluated in clinical trials for their therapeutic utility.
Given the differential dependence on IGF1R exhibited by human tumors and xenograft lines, there is a need for additional preclinical models in which the relationship between genetic context and drug response in solid tumors can be better understood in an in vivo setting. To this end, we utilized our HER2 driven inducible breast cancer model to create a panel of genetically-engineered mouse tumors, each driven by the human IGF1R. Some of the models were also engineered to express a cognate ligand IGF2. In these models, tumors initially driven by human HER2 expression are re-programmed by the addition of the human IGF1R cDNA upon withdrawal of the original HER2 expression. Thus, the newly introduced IGF1R- IGF2 cDNA functionally maintains tumor survival by re-directing downstream signalling effectors in a process referred to as ‘Directed Complementation’ (DC). Using this approach, introduction of IGF1R strongly complemented tumor formation across the panel, whereas introduction of the ligands, either IGF1 or IGF2, alone or in combination did not. We recently showed that treatment of IGF1R/IGF2 DC tumors with OSI-906, a potent, selective orally active inhibitor of IGF1R, resulted in tumor regression within a week of treatment, with corresponding loss of phospho-IGF1R signaling (AACR 2009: Abstract # 2902, Lerner, et al). These results demonstrate the singular dependence of these tumors on IGF1R signaling, as well as the in vivo efficacy of the compound.
Next, we sought to extend the utility of these validated tumor models to drug discovery by establishing IGF1R-dependent cell lines for high-throughput screening.
Here we describe detailed molecular characterization of these cell lines derived from the IGF1R/IGF2 DC tumor models as well as their drug sensitivities. Importantly, we show that the IGF1R/IGF2 DC cell lines, like their parent tumors, retain activation of the pathway as well as sensitivity to OSI-906. Therefore, these tumor models and derived cell lines provide an effective preclinical tool for the development of targeted anti-IGF1R therapies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A233.
Abstract A254: A phase 1 safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor, XL765 (SAR245409), in combination with erlotinib in patients (pts) with advanced solid tumors
Authors: Janne Pasi A. , Felip Enriqueta , Cedrés Susana , Cohen Steven J. , Engelman Jeffrey A. , Lucca Joan , Martínez Pablo , von Mehren Margaret , Gendreau Steven B. , Lara Katherine K. , Martini Jean-Francois , Cohen Roger B. 
Published: June 2012

Abstract
Background: XL765 is an oral, selective inhibitor of Class I PI3Ks, as well as TORC1 and TORC2. The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mediator of resistance to EGFR inhibitors. In preclinical studies, XL765 has demonstrated dose-dependent target modulation in tumor xenograft models. In an ongoing Phase 1 single agent clinical study, XL765 has exhibited robust pharmacodynamic activity in diverse solid tumors.
Methods: Pts with advanced solid tumors are enrolled in successive cohorts of 3 to receive escalating doses of XL765 in combination with erlotinib. Cycles consist of 28 days of XL765 and erlotinib, each given qd. During the ongoing dose-escalation phase of the study there is a 14-day run-in period of erlotinib monotherapy. Cycle 1 safety data determine dose limiting toxicities (DLTs). Tumor response is evaluated every 8 weeks.
Results: As of 24Aug2009, 14 pts with advanced solid tumors have been enrolled: NSCLC (11), CRC (1), liposarcoma (1), and endometrial adenocarcinoma (1). Most of the NSCLC pts have been previously treated with erlotinib before entering the study. Pts have been treated at 2 dose levels of XL765 (30 and 50 mg) administered once-daily in combination with 100 mg erlotinib. No DLTs or study treatment-related SAEs have been reported. As of 03Aug2009, AEs have been reported for 7 pts. Grade 3 adverse events of nausea, vomiting, and anorexia considered related to study treatment were observed in one pt dosed at 30 mg qd. The PK of XL765 given in combination with erlotinib is consistent with that observed for XL765 given alone (Exelixis study XL765-001). Likewise, XL765 does not appear to alter the PK of erlotinib. In skin biopsies, substantial post-dose reductions were evident in phosphorylation of AKT, the mTOR substrate 4EBP1, and EGFR. For example, progressive pharmacodynamic effects were evident in serial skin biopsies from a pt with EGFR-mutant NSCLC previously treated with erlotinib who has remained on study through 26 weeks, culminating in decreases in pAKT-T308 (72%), p4EBP1 (57%), pERK (73%), and pEGFR (50%) at Day 85 post-start of combination dosing (50 mg XL765/100 mg erlotinib). Pharmacodynamic analyses of paired tumor biopsies are in progress. Of the first 9 patients enrolled, five have remained on study for at least 12 weeks.
Conclusions: XL765 in combination with erlotinib is generally well tolerated at doses up to 50 mg XL765/100 mg erlotinib, with no apparent drug-drug PK interaction, and results in robust simultaneous inhibition of PI3K and EGFR signaling.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A254.
Abstract A257: Antitumor activity of E-3810, a new, potent and selective dual inhibitor of VEGF and FGF receptors
Authors: Damia Giovanna , Bello Ezia , Colella Gennaro , Scarlato Valentina , Giavazzi Raffaella , D'Incalci Maurizio , Cereda Roberta , Cavalletti Ennio , Spinelli Silvano , Camboni Gabriella 
Published: June 2012

Abstract
E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N-methyl-naphthalene-1-carboxamide, is a novel small molecule that potently and selectively inhibits VEGFR1-3 and FGFR-1 tyrosine kinases (TKs) with IC50 in the 10-20 nM range. Concentrations at least 1-order higher were required to inhibit FGFR-2 and 3, PDGFRα and β and c-Kit receptors and no relevant activity was seen against different cancer-related TKs. E-3810 1-10 nM inhibited the ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 and the downstream phosphorylation of Erk in HUVEC cells; inhibition of PDGFR- auto-phosphorylation in NIH-3T3 cells was detected at concentrations higher than 100 nM. E-3810 inhibited the VEGF- and FGF-driven growth of HUVEC cells (IC50 40-50 nM), while anti-proliferative activity on different human cancer cell lines was shown at 10-30 M concentrations. E-3810 was tested in different human tumor xenografts in nude mice, including colon HT-29, ovarian A-2780, renal A498, RXF393 and SKN12I carcinomas. A dose dependent antitumor effect was observed in a range from 10 to 40 mg/kg given orally for 30 consecutive days. The optimal dose schedule, 20 mg/kg for 30 days, was well tolerated and caused up to 90% suppression of tumor growth. Sustained growth inhibition was also seen when treatment was repeated after a 2-week dosing interval or when dosing was initiated at a larger tumor volume (average 400 mm3). Tumor regression was observed in the RXF393 xenograft. E-3810 showed antitumor activity equal or better than Sunitinib and Brivanib at their respective optimal doses. Pharmacokinetic studies in mice demonstrated high oral bioavailability, high volume of distribution and terminal half life of 4 hrs. After single and repeated administration E-3810 systemic exposure was proportional to the dose, without any accumulation after repeated doses. The good bioavailability and the remarkable antitumor activity of E-3810 in several tumor xenografts make this compound an interesting candidate for clinical development.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A257.
Abstract A26: Aromatase over-expression results in the development of ductal growth abnormalities in the mammary gland of a conditional transgenic mouse model
Authors: Diaz-Cruz Edgar S. , Nakles Rebecca E. , Sugimoto Yasuro , Brueggemeier Robert W. , Furth Priscilla A. 
Published: June 2012

Abstract
Estrogens are required for the development of the normal mammary gland; however, studies suggest that estrogen and its metabolites may have mutagenic and carcinogenic potential in the mammary gland. Aromatase is key to estrogen biosynthesis, but its over-expression may play a role in the development of breast cancer by increasing mitotic activity in breast epithelial cells. Therefore, it is highly valuable to have mouse models with increased local estrogen production to use to develop optimal therapeutic and chemopreventive strategies to treat these lesions. The purpose of this study was to evaluate if increased local estrogen production led to the development of mammary gland preneoplasia. To test our hypothesis we developed a conditional transgenic mouse model to control the spatial and temporal aromatase expression in the mammary gland. Mammary glands were collected at 4 and 12 months of age for morphological, histological, gene and protein expression studies in both MMTV-rtTA/tet-op-Aromatase and wild-type mice. RT-PCR analysis of aromatase mRNA confirmed that the gene was conditionally expressed in the mammary gland as compared to control mice. Aromatase activity assays confirmed a significantly higher enzyme activity in the mammary glands of MMTV-rtTA/tet-op-Aromatase compared to wild-type. Mammary glands were evaluated for morphological changes using confocal microscopy, whole-mount and hematoxylin and eosin staining. Aromatase over-expression resulted in a higher incidence of morphological and histological abnormalities such as hyperplastic alveolar nodules, ductal dysplasia, ductal carcinoma in situ, and the unexpected persistence of terminal end buds at 12 months of age. These changes were associated with ERK1/2 and AKT activation. In summary, we generated a novel transgenic mouse system to investigate the role of aromatase over-expression in mammary epithelial cells during mammary gland development. Increased aromatase activity resulted in the development of ductal growth abnormalities and increased ductal density. This model represents a valuable tool to investigate the effect of estrogen over-production in the mammary gland microenvironment at specific times during development.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A26.
Abstract A261: In vitro characterization of AMG 900, an orally active small molecule inhibitor of aurora kinases in phase 1 clinical trials
Authors: Chung Grace , Kendall Richard , Geuns-Meyer Stephanie , Payton Marc 
Published: June 2012

Abstract
Background: The aurora family of serine-threonine kinases (Aurora-A, -B, -C) regulate cell-cycle progression in mammalian cells. Aurora kinases A and B are essential for proper chromosome congression, segregation, and cytokinesis during mitosis, whereas aurora kinase C function appears restricted to male meiosis. Aurora kinase B is responsible for the direct phosphorylation of histone H3 on serine-10 (p-histone H3). Aurora kinase A and B expression is elevated in a variety of human cancers and is associated with advanced clinical staging and poor prognosis. The emergence of aurora kinases as key mitotic regulators and their potential role in tumorigenesis has focused substantial interest in developing selective small molecule inhibitors for the treatment of human cancers.
Objective: The aim of this study was to characterize the in vitro effects of AMG 900 in tumor cell lines, including cell lines resistant to paclitaxel and three well-characterized aurora kinase inhibitors.
Results: AMG 900 is a novel ATP competitive small molecule inhibitor that is highly potent and selective for aurora kinases A, B, and C. In cells, AMG 900 inhibits autophosphorylation of aurora kinases A and B as well as the phosphorylation of histone H3. The predominant cellular response of tumor cells to AMG 900 treatment is aborted cell division without a mitotic arrest, which leads to endoreduplication and cell death. The effect of AMG 900 was tested in a panel of 26 tumor cell lines to evaluate its potential to inhibit cell proliferation across multiple tumor types. AMG 900 inhibited the proliferation of tumor cell lines at low nanomolar concentrations (EC50 values 1–6 nM). Importantly, AMG 900 was equally potent against multidrugresistant (MDR) cell lines expressing ATP-binding cassette transporters (P-gp and BCRP1), whereas paclitaxel and three aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358) showed a loss of potency in these MDR-positive cell lines compared with matched parental cell lines. To further investigate potential mechanisms of resistance, an HCT116 cell line was adapted to grow in the presence of AZD1152, a selective inhibitor of aurora kinase B. The resulting AZD1152-resistant HCT116 subline harbors a mutation in one allele of the aurora kinase B gene (W221L substitution) and was negative for P-gp and BCRP1 expression. AMG 900 induced an accumulation of cells with ≥4N DNA content (EC50 value 5 nM) and inhibited colony formation in this AZD1152-resistant HCT116 subline.
Conclusion: To our knowledge, AMG 900 is the first described inhibitor of aurora kinases A, B, and C that has uniform in vitro potency in MDR-positive tumor cell lines. AMG 900 is currently undergoing phase 1 clinical evaluation in patients with advanced solid tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A261.
Abstract A262: Antiangiogenic proprieties of E-3810, a new dual inhibitor of VEGF and FGF receptors
Authors: Giavazzi Raffaella , Oliva Paolo , Taraboletti Giulia , Berndt Alexander , Colombo Sonia , Valbusa Giovanni , Cavalletti Ennio , Cereda Roberta , Damia Giovanna , Camboni Gabriella 
Published: June 2012

Abstract
E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N-methyl-naphthalene-1-carboxamide, is a novel small molecule that potently and selectively inhibits VEGFR1-3 and FGFR-1 tyrosine kinases. E-3810 has shown antitumor activity against various types of cancer xenografts with good tolerability. The anti-angiogenic proprieties of E-3810 were investigated in vitro on endothelial cells and in vivo in angiogenesis-induced models and human tumor xenografts.
E-3810 inhibited VEGF- and FGF-2-induced HUVEC (human umbilical vein endothelial cells) proliferation with an IC50 of 40–50 nM. The ability of E-3810 to inhibit angiogenesis in vivo was assessed in the Matrigel plug assay, where angiogenesis is induced by FGF-2 embedded in Matrigel pellets, implanted subcutaneously in mice. Treatment with E-3810 (20 mg/kg p.o., daily for 6 days) completely inhibited the angiogenic response measured by hemoglobin content.
The effect on tumor angiogenesis was investigated in the human A498 renal carcinoma xenografted subcutaneously in nude mice. Oral treatment with E-3810 for up 30 days at the optimal antitumor dose of 20 mg/kg led to significant tumor growth delay (Treated -Controls = 24 days). E-3810 significantly decreased blood vessel density and increased vessel maturation index (assessed by immunostaining with anti CD31 and CD31/ SMA antibodies); this was accompanied by decreased expression of stroma collagen IV and increased tumor necrosis.
A498 xenografts growing in nude mice were also analyzed by DCE-MRI (dynamic contrast-enhanced magnetic resonance imaging) before and after 5 and 12 days of oral treatments with 20 mg/kg E- 3810. The kinetic analysis of the distribution of the contrast agent (Gadocoletic Acid Trisodium Salt, B22956/1, Bracco S.p.a., Italy) showed significant reduction in perfusion, calculated applying the IAUC method over the first 30 minutes post contrast injection, in E-3810 treated tumors compared with both baseline values and untreated controls already after 5 days of treatment. These results show a significant antiangiogenic activity of E-3810, which is likely to contribute to its potent antitumor activity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A262.
Abstract A29: Development of liposomal curcumin as a new potential anticancer agent
Authors: Smith Judith A. , Mathew Lata , Mach Claire M. , Santiago Katherine , Helson Larry 
Published: June 2012

Abstract
Previously, pre-clinical dose finding tolerance study in a human xenograft pancreatic cancer model of intravenous liposomal curcumin determined 20 mg/kg TIW was to be the optimum dose and schedule for anticancer activity. Follow up pharmacokinetic and dose finding studies in a health rat model evaluated doses up to 40 mg/kg was not associated with weight loss, hematological, serologic, or dose-limiting toxicity. In canine model, a single-dose finding tolerance study ranging from 2 mg/kg up to 40 mg/kg revealed the maximum tolerated dose (MTD) of liposomal curcumin to be 20 mg/kg or 540 uMol/L of curcumin maximal blood concentration. Toxicity observed at this dose level was characterized by a brief single episode of reversible hematuria. The dose limiting toxicity was observed at a single dose of 40 mg/kg of liposomal curcumin. Following dose on day 1, life threatening toxicity followed within 48 hours with the dogs exhibiting irreversible acute hemolysis with hematuria, over 60% blood loss, and associated serologic abnormalities. A control cohort of dogs infused with the same quantity of liposome contained in the 40/mg/kg dose was without ensuing toxicity. These changes suggest the mechanism of hemolysis following 40mg/kg curcumin is due to an oxidant effect. Following acute hemolysis, the iron chelation activity of curcumin could contribute to unremitting anemia by blocking iron reutilization. In conclusion, at concentrations below the canine MTD of 20 mg/kg, curcumin acts as an anti-oxidant, and acts as a pro-oxidant at higher concentrations. The disparity between rodent and canine sensitivity to liposomal curcumin may be due to species differences in pharmacokinetics and/or curcumin metabolism. Ongoing study will define liposomal curcumin pharmacokinetic parameters at the MTD in canine mode as well define tolerability of multiple dosing in dogs. In addition hematological studies are being conducted to determine the mechanism of hemolysis that was observed at higher dose levels and identify potential biomarkers for predicting toxicity. Preliminary data suggests liposomal curcumin will have promising anticancer activity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A29.
Abstract A30: Integrated analysis of genomic data and annotations in cancer research
Authors: Ustach Carolyn V. , Han Haiyong , Kim Seungchan , Hostetter Galen , Diep Caroline H. , Hidalgo Manuel , Barret Michael , Keats Johnathan J. , Von Hoff Daniel , Kingsley Christopher 
Published: June 2012

Abstract
Many cancer researchers are currently generating heterogeneous genomic data sets containing mRNA expression, array based comparative genomic hybridization (aCGH), and other information from multiple patients. In the near future, data sets will likely include proteomics, methylomics, and high throughput sequencing data. Analytical tools that integrate these different data types to prioritize genes for further study have lagged, however. With this in mind, we have implemented a standalone software application that integrates CGH and mRNA expression profiling data. This application implements several different methods to generate ranked lists of genes and genomic regions based on breakpoint frequency, aberration frequency, and the impact of copy number changes on mRNA expression. The software is Java GUI based, with abstracted object models that can be extended as new genomic data types and annotations become available. We used this application to analyze aCGH datasets generated from 22 primary pancreatic tumor xenografts and mRNA expression datasets from 16 of the 22 samples. Genes which were located near a putative breakpoint and whose expression levels were high in a majority of the xenografts samples were considered putative targets. Preliminary IHC analysis of pancreas primary tumor tissue microarrays confirms one of these putative targets, Chemokine (CXC motif) Ligand 5 (CXCL5). By allowing cancer researchers to correlate genomic aberrations with expression data, we believe that this application will generate more meaningful targets for further biomarker identification and/or drug target discovery.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A30.