bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C250: The pericyte as a novel stromal element and therapeutic target in sarcoma
Authors: Morozov Alexei , Downey Robert , Healey John , Moreira Andre L. , Lou Emil , Maki Robert , Moore Malcolm A.S. 
Published: June 2012

Abstract
Background: Mesenchymal Stem Cells (MSCs) have been proposed as the cell of origin of sarcoma. In soft tissues, the microvascular pericyte has been recently shown to have MSC properties (Crisan et al, Cell Stem Cell 3:301). We have previously reported the isolation of benign mesenchymal cultures from sarcoma surgical samples. These cells have the immunophenotype (CD45-CD31- CD73+CD105+CD90+) and in vitro differentiation potential characteristic of MSCs. We hypothesized that these sarcoma-associated MSCs (SA-MSCs) are derived from pericytes associated with the sarcoma vasculature.
Methods: We examined whether benign SA-MSCs have surface markers characteristic of pericytes and cooperate with endothelial cells in tube formation assays. We also examined expression of CD146, a pericyte marker, and CD105, an MSC marker, in sarcoma archived tissue by IHC.
Results: Benign SA-MSCs indeed demonstrated properties of pericytes, such as characteristic cytoplasmic projections at low density, surface expression of pericyte markers (CD146, PDGFR-beta, NG2 and endosialin) and cooperation with endothelial cells in tube formation assays in matrigel. To demonstrate the existence of pericytes in sarcoma archived tissue, we used CD146 that has been shown to be restricted to the vasculature in sarcoma, but thought to be an endothelial marker (Shih et al, CCR 2:569). We demonstrate for the first time the existence of CD146+ pericytes in diverse sarcoma subtypes. In addition, we examined sarcoma archived material for expression of CD105 (endoglin), an MSC marker and a known tumor-specific endothelial marker in carcinoma. We found that CD105 was expressed in sarcoma endothelium similarly to its expression on carcinoma endothelium. In addition, by three-color immunofluorescence, CD105 was expressed in a subset of sarcoma pericytes. It was not expressed in normal surrounding tissues.
Conclusion: We show that SA-MSC cultures have properties of pericytes. Using a novel combination of markers we demonstrate that pericytes are abundant in sarcoma. Being in contact with both the endothelial cells and the malignant sarcoma cells, pericytes represent a novel stromal element in sarcoma and a potential therapeutic target. Based on these findings we are evaluating endosialin (CD248) and CD105 antibodies, both of which are in clinical development, for effectiveness in preclinical models of sarcoma.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C250.
Abstract C251: Heparanase mechanistically links chronic colitis and tumorigenesis
Authors: Lerner Immanuel , Zcharia Eyal , Bensoussan Esther , Sherman Yoav , Vlodavsky ISrael , Elkin Michael 
Published: June 2012

Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely associated with colon cancer. Here we report that heparanase enzyme acts as an important mediator of colitis-associated tumorigenesis. Heparanase is an only known mammalian enzyme that cleaves heparan sulfate, the major polysaccharide of the extracellular matrix, and plays multiple roles in inflammation and cancer progression. Applying histological specimens from UC patients and a mouse model of dextran sulfate sodium (DSS)-induced colitis, we found that heparanase is constantly overexpressed and activated during the course of the disease, both in the active and inactive phases of inflammation. Employing heparanase-overexpressing transgenic mice in the model of colitis-associated cancer, induced by carcinogen azoxymethane followed by repeated DSS administration, we demonstrated that heparanase overexpression markedly increased the incidence and severity of colitis-associated colonic tumors, enabling faster tumor take, angiogenic switch and enhanced tumor progression. Notably, DSS-induced colitis alone (without azoxymethane pretreatment) lead to formation of colonic tumors in heparanase-transgenic, but not wild type mice, positioning heparanase as important physiological determinant in inflammation-driven colon carcinoma, replacing the need for carcinogen. Investigating molecular mechanisms underlying heparanase induction in colitis, we found that TNF-alpha is responsible for continuous overexpression of heparanase by chronically-inflamed colonic epithelium. Moreover, our results suggest the occurrence of heparanase-driven vicious cycle that powers colitis and associated tumorigenesis: heparanase activity in inflamed colon, acting synergistically with the local cytokine milieu, stimulates macrophage activation, and the activated macrophages secrete TNF-alpha which stimulate further production of heparanase by colonic epithelium. In addition, activated macrophages secrete cathepsin L - a cysteine protease responsible for proteolytic activation of latent heparanase enzyme. Altogether, our results identify heparanase as a key factor in pathogenesis of colitis-associated cancer and attest the inhibition of heparanase as a promising mean to disrupt the vicious cycle that fuels chronic colitis and the associated tumorigenesis.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C251.
Abstract C254: Suppression of E-cadherin function leads to deregulation of FAK and Src to direct squamous cell carcinoma progression
Authors: Alt-Holland Addy , Sowalsky Adam G. , Szwec-Levin Yonit , Shamis Yulia , Feig Larry A. , Garlick Jonathan A. 
Published: June 2012

Abstract
Advanced stages of epithelial carcinogenesis are linked to loss of intercellular adhesion, but it remains unclear how alterations in cell-cell and cell-matrix adhesions are coordinated to promote the early stages of cancer development. To address this, we used 3D tissue models that mimic human premalignant disease, and studied the impact of E-cadherin suppression in early stage, epithelial tumor cells (HaCaT-II-4) on the expression and activity of Focal Adhesion Kinase (FAK) and Src kinase and on tumor cell motility and invasiveness. Suppression of E-cadherin function triggered elevated expression of FAK, increased tyrosine phosphorylation of FAK and Src, and redirected these protein tyrosine kinases to a perinuclear distribution. Pharmacological inhibition of FAK or Src, by either Tyrphostin AG1007 or PP2, reduced their phosphorylation, and reversibly inhibited tumor cell motility in 2D, monolayer cultures. Decreased FAK or Src expression by lentivirus-mediated shRNA restored E-cadherin expression and cell-cell adhesion and inhibited cell migration. 3D, bioengineered tissues harboring E-cadherin-deficient-II-4 cells in which FAK or Src were depleted, demonstrated increased membrane localization of E-cadherin, normalization of tissue phenotype and suppression of tumor cell invasion into the underlying matrix. When these 3D tissues were grafted to the dorsum of immunocompromised mice, down-regulation of FAK or Src resulted in suppression of tumor growth in vivo. Specifically, decreased Src expression reversed the tumor phenotype from high-grade, aggressive and infiltrative SCC to low-grade, well-differentiated and demarcated tumor islands. Collectively, our findings demonstrate that E-cadherin suppression directs the biological behavior of early stage, E-cadherin-deficient tumor cells in vitro and SCC progression in vivo, through modulation of FAK and Src expression and/or activity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C254.
Abstract C26: Nuclear factor I/B regulates cell proliferation of ER negative breast cancer
Authors: Kim Jeong-Ah , Han Wonshik , Jung Eun-Mi , Hwang Ki-Tae , Noh Dong-Young 
Published: June 2012

Abstract
Previously, we reported that DNA copy number of NFIB is amplified in triple negative breast cancer (TNBC; estrogen(−)/progesterone(−)/HER2(−)). The transcriptional activator NFIB plays wide roles in regulation of gene transcription, cell proliferation, viral DNA replication and development. But the functional role of NFIB in breast cancer cell has not been elucidated. In order to understand the role of upregulated NFIB in breast cancers, we examined mRNA and protein level of NFIB in 20 breast cancer tissues. In ER negative breast cancer subtype, expression of NFIB is up-regulated and correlated with Ki67 expression. And intracellular localization of NFIB is restricted in nucleus. In ER negative cell line, knock-down of NFIB leads to reduced cell proliferation by cell cycle arrest. Cell cycle arrest is accompanied by S phase arrest and alteration of S phase regulating protein expression. Take together, transcription activator of NFIB regulates cancer cell proliferation in ER negative breast cancer and it may act as a therapeutic marker.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C26.
Abstract C33: A two-arm phase 1 clinical trial with NPI-0052, a novel proteasome inhibitor
Authors: Price Timothy , Millward Michael , Mainwaring Paul , Harrison Simon , Catley Laurence , Townsend Amanda , Sukumaran Shawgi , Longenecker Angie , Palladino Michael A. , Lloyd G. Kenneth , Neuteboom Saskia , Padrik Peeter , Spear Matthew A. , Spencer Andrew 
Published: June 2012

Abstract
Background: The bi-cyclic structure of NPI-0052 differentiates it from other proteasome inhibitors which are structurally polypeptide based, leading to its differential properties of rapid, broad and prolonged inhibition of all 3 proteolytic sites, and unique proteasome inhibition, toxicology and efficacy profiles. Preclinical studies indicated an increased therapeutic ratio with activity in hematologic and solid tumor malignancies leading to the initiation of Phase 1 clinical trials. These biologic differences also led to the question of whether twice weekly administration schedule, as is typical for other proteasome inhibitors, or more convenient once weekly schedule would be preferable.
Materials and Methods: Patients with solid tumor, lymphoma, leukemia or myeloma diagnoses failing after standard therapies were given NPI-0052 intravenously on a weekly or twice weekly arm in the dose escalation portion of this study. Subsequently 10 patient Recommended Phase 2 dose Cohorts of patients with lymphomas, CLL and myeloma are enrolled. Proteasome inhibition and pharmacokinetics are also assayed in whole blood, and/or peripheral blood mononuclear cells (PBMC) on Day 1 and multiple subsequent time points.
Results: 44 patients have been enrolled into this study. Notable adverse events have been fatigue, parosmia/dysgeusia, transient peri-infusion site pain, lymphopenia, headaches, dizziness / unsteady gait, closed-eye visuals, cognitive changes. Peripheral neuropathy, neutropenia and thrombocytopenia do not appear to be induced. Pharmacokinetic data indicate a short T1/2 and large Vss. Proteasome inhibition assays demonstrated inhibition of chymotrypsin-like activity of up to 88% Day 1 and 100% Day 15. Inhibition accumulates initially in whole blood presumably secondary to the inability of RBC to synthesize new proteasomes, whereas inhibition recovers over several days in PBMC further leading the question as to an optimal dosing regimen. Stable disease, regression or response, have been reported in mantle cell lymphoma, myeloma, Hodgkin's lymphoma, cutaneous marginal zone lymphoma, follicular lymphoma, sarcoma, prostate carcinoma and melanoma.
Conclusions: NPI-0052 produces expected or greater levels of proteasome inhibition in patient blood samples, with a toxicity profile that is dissimilar to what is reported with other proteasome inhibitors. The profile of the proteasome inhibition, toxicity and efficacy profiles that have been revealed during this clinical trial and correlative studies reveals further basis and hypothesis as to what an optimal dosing regimen might be, which is being assessed in this study.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C33.
Abstract C37: A Phase 1 open-label study evaluating pharmacokinetics, safety, and tolerability of linifanib in Japanese patients with solid tumors
Authors: Tamura Tomohide , Yamamoto Noboru , Nokihara Hiroshi , Yamada Yasuhide , Asahina Hajime , Shibata Takashi , Goto Yasushi , Tanioka Maki , Tamura Yosuke , Seki Yoshitaka , Chiu Yi-Lin , Gupta Neeraj , Carlson Dawn 
Published: June 2012

Abstract
Background: Linifanib (ABT-869) is a novel orally active and selective inhibitor of vascular endothelial growth factor and platelet derived growth factor families of receptor tyrosine kinases. Linifanib demonstrated antitumor activity in a variety of advanced solid tumor pts enrolled in early-phase clinical trials. Preliminary data from an international phase 1 multicenter study (M04-710) showed specific single-agent antitumor activity with a recommended tolerated dose of 0.25 mg/kg and a maximum tolerated dose of 0.30 mg/kg. Efficacy was observed in 3 phase 2 studies in pts with hepatocellular carcinoma, non-small cell lung cancer and renal cell carcinoma.
Methods: This is a phase 1, open-label, dose-escalating study evaluating the PK, safety/tolerability of linifanib in Japanese pts with solid tumors. Pts were assigned to 4 dosing cohorts (0.05, 0.10, 0.20 and 0.25 mg/kg) of linifanib given orally once daily (QD) on Cycle (C) 1 Day (D) 1 under fasting conditions for 21 days. PK samples were collected at various time points after single dose on C1D1 and multiple doses on C1D15. CT scans were performed at baseline and at D1 of every second cycle; efficacy was evaluated using RECIST criteria. Adverse events (AEs) were graded by NCI CTCAE V3.0.
Results: As of August 2009, 15 pts have received linifanib in this study: 3 at 0.05 mg/kg; 6 at 0.10 mg/kg; 3 at 0.20 mg/kg and 3 at 0.25 mg/kg. Pts had NSCLC (5), lung carcinoid (1) sarcoma (4), breast cancer (3), thymic carcinoma (1) and angioendothelioma (1). Partial response was noted in 1 breast cancer pt in the 0.20 mg/kg cohort (32% reduction from baseline). 15 pts had ≥ Grade 2 AEs; hypertension (12); neutropenia (4), thrombocytopenia (3) and hand foot syndrome (2). Among all pts, 2 experienced a dose limiting toxicity; 1 each at 0.10 mg/kg (Grade 3 ALT increase) and at 0.25 mg/kg (ECG T wave inversion). 4 pts had AEs leading to dose interruptions (3 pts at C3 and 1pt at C1) and 1 pt had an AE leading to dose reduction in C5. 5 pts have discontinued study at the time of this analysis; 2 due to radiographic progressive disease (PD), 1 due to clinical PD and 2 due to AEs. At 0.25 mg/kg dose, the exposures (AUC24) after single and multiple doses were 6.2±1.2 µg*hr/mL (mean±SD) and 10.7±3.1 µg*hr/mL, respectively. These multiple dose exposures are approximately 2-fold higher than efficacious exposures predicted based on observed results in preclinical animal models. The estimation of effective half-life based on observed accumulation was approximately 1 day.
Conclusion: Preliminary ongoing results show that linifanib is tolerated in Japanese pts at ≤ 0.25 mg/kg and has antitumor activity as a single-agent in 1 pt with breast cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C37.
Abstract C4: TLN-4601 is a novel tumor selective pro-apoptotic agent acting independently of Bax, Bak or Bcl-2 expression
Authors: Bertomeu Thierry , Gourdeau Henriette 
Published: June 2012

Abstract
Background: TLN-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through Thallion's proprietary DECIPHER® technology platform. The compound has demonstrated broad in vitro cytotoxicity and in vivo tumor growth inhibition. Phase I clinical testing has shown the compound to be safe and well tolerated, with early signs of anti-tumor activity. Although considerable research efforts have focused on the ability of TLN-4601 to inhibit the Ras/MAPK signalling pathway, the compound has also been shown to induce apoptosis through caspase activation. The objectives of the present work were to further elucidate the molecular events, pathways and temporal patterns associated with TLN-4601-induced apoptosis.
Material and Methods: Protein extracts from Jurkat cells (a human T cell lymphoblast-like cell line), Jurkat cells with caspase 8 knocked-down, Jurkat cells over-expressing Bcl-2, mouse embryonic fibroblasts isolated from Bax/Bak double knock-out mice, and both quiescent and PHA-L stimulated human peripheral blood lymphocytes (PBLs) treated with TLN-4601 over different exposure times were analyzed by Western blot to evaluate the induction of apoptotic markers, including cytochrome c release, caspase activation and PARP cleavage. Apoptosis was assessed by DNA laddering and sub-G1 DNA content. The effect of TLN-4601 on cell viability were measured using commercial Caspase-3/7 activity and ATP assays.
Results: TLN-4601 caused rapid apoptotic cell death in Jurkat cells as characterized by mitochondrial cytochrome c release, caspase activation, loss of cellular ATP and DNA laddering. Equal sensitivity of the wild-type and caspase 8 knocked-down Jurkat cells to TLN-4601 suggests that the extrinsic apoptotic pathway was not involved in mediating this activity. Interestingly, TLN-4601 exposure resulted in cytochrome c release independently of the apoptosis-inducing proteins Bax and Bak. Furthermore, the over-expression of the anti-apoptotic protein Bcl-2 did not affect the ability of TLN-4601 to induce cell death. Finally, a short exposure of TLN-4601 exhibited a preferential selectivity for triggering apoptosis in Jurkat cells as compared to either quiescent and PHA-L stimulated PBLs.
Conclusions: TLN-4601 mediates rapid cell death via the intrinsic apoptotic pathway independent of Bax, Bak or Bcl-2 expression. Moreover, the differential sensitivity to TLN-4601 observed between Jurkat cells and PBLs highlights the potential for a usable therapeutic margin between cancer and normal cells. Taken together, these properties represent a very promising profile for an anti-cancer agent and suggest that further investigation of TLN-4601 in hematological malignancies is warranted.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C4.
Abstract C42: QBI-139, a human RNase variant in a phase I trial, has broad in vivo efficacy
Authors: Strong Laura E. , Kink John A. , Mei Baigen , Shahan Mark N. , Pensinger Dan , Raines Ronald T. 
Published: June 2012

Abstract
The RNA in cancer cells is the target of a new class of anti-cancer drugs: the EVade™ Ribonucleases (RNases). The EVade™ RNases are variants of native RNases that have been modified to diminish their binding to their natural inhibitor, allowing the EVade™ RNases to kill cancer cells. These RNase variants are broadly efficacious, competitive with approved drugs. A lead candidate, called QBI-139, has been selected for clinical devleopment and is currently in a Phase I clinical trial in patients with solid tumors. The next stage of development requires selection of a specific indication for a Phase II trial of QBI-139. In addition to the Phase I trial, mouse models of cancer will be used to select the tumor type for future development. The efficacy of QBI-139 in in vivo models of human cancer (e.g. lung, colon and prostate) has been examined relative to FDA approved cancer therapies. QBI-139 was tested at different doses in nude mouse xenograft models using a variety of tumor types and multiple cell lines within the different tumor types (e.g. prostate cancer cell lines DU145 and PC3). Each model compared the efficacy of QBI-139 with control groups which included: vehicle, and an effective commercial chemotherapeutic specific for each tumor type (e.g. docetaxel, 5-fluorouracil and cisplatin). The human cancer cells were grown in culture and approximately 5 ×106 cells were implanted subcutaneously into the flanks of (nu/nu) nude mice. The tumors are allowed to grow to ∼75 mm3 prior to treatment and all drugs were administered intraperitoneally (ip) once weekly. Calculated tumor volumes in mm3 and animal body weights (g) were recorded twice weekly. The percent tumor growth inhibition (TGI) used as a measure of efficacy was determined by comparing final and starting tumor volumes of groups treated with drug relative to the vehicle.
A favorable response was seen for QBI-139 against prostate cancer (DU145) compared to docetaxel. The TGI of QBI-139 was 83% compared to 84% for docetaxel. Treatment with QBI-139 did not lead to observable toxicity and the mice all gained body during the course of treatment. In contrast, docetaxel treatment resulted in death for one mouse after 4 treatments (day 42) and another after 6 treatments (day 52). In colon cancer (HT-29), the efficacy of QBI-139 was 58%, similar to the results for 5-fluorouracil (54%). Additional results will be provided, including for multiple cell lines of human non-small cell lung cancer.
QBI-139 is a broadly efficacious agent that provides a new way to attack the RNA in cancer cells and an innovative new tool for oncologists. The results above will be considered with the results of the Phase I trial to select an indication for a Phase II clinical trial.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C42.
Abstract C47: Dual kinase inhibition of EGFR and HER2 can overcome resistance to an EGFR-targeting agent
Authors: Quesnelle Kelly M. , Joyce Sonali C. , Grandis Jennifer R. 
Published: June 2012

Abstract
EGFR and HER2 expression are correlated with poor prognosis in several cancers including bladder cancer. The EGFR-targeting agent cetuximab is currently in phase II clinical trials for the treatment of bladder cancer, but has only been modestly effective as a single agent in most solid tumor types. In colon cancer, lack of cetuximab efficacy has been attributed to compensatory activating mutations in Kras. The incidence of Kras mutations is rare in bladder carcinomas. There is a need for preclinical models with which to study resistance to EGFR-targeting agents. Here, we generated four cetuximab-resistant clones of a cetuximab-sensitive transitional bladder cancer cell line in vivo by exposing cetuximab-sensitive bladder cancer cell line xenografts to slowly increasing concentrations of cetuximab. We verified this resistance in vivo by demonstrating growth of cetuximab-resistant xenografts in the presence of high doses of cetuximab, as well as establishing differential sensitivity to cetuximab between sensitive and resistant xenografts in vivo. We validated the cetuximab-resistant phenotype of these cells in vitro by showing decreased response to cetuximab in an invasion assay. We examined the levels of total and phosphorylated EGFR, HER2, HER3, AKT, MAPK, and the total protein levels of epithelial-to-mesenchymal transition markers E-cadherin and Vimentin in the isogenic cetuximab-sensitive and cetuximab-resistant cells. Increased phosphorylation of the ERBB family members HER2 and HER3 was detected in cetuximab-resistant clones compared with their cetuximab-sensitive parental cell lines. Treatment of the cetuximab-resistant cells with an irreversible dual kinase inhibitor targeting EGFR and HER2 (BIBW2992), successfully inhibited their growth. These data suggest that activation of HER2 and HER3 may contribute to cetuximab resistance where targeting these other HER family members may enhance the efficacy of EGFR blockade.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C47.