bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C191: Preclinical investigation of the antitumor efficacy in lung cancer of Y15, a novel focal adhesion kinase inhibitor.
Authors: Dy Grace K. , Shao Huanjie , Ho Baotran , Yemma Michael , Adjei Alex , Golubovskaya Vita , Cance William 
Published: June 2012

Abstract
Introduction: Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that associates with a number of cell adhesion components, such as integrins, paxillin and talin, as well as with various signaling proteins such as phosphatidylinositol 3-kinase (PI3K) and the Src family of protein kinases. It thus plays an important role in cell motility, invasion, growth and cell survival. Y15 (1,2,4,5-benzentetraamine tetra hydrochloride) is a small molecule that inhibits FAK autophosphorylation by selectively targeting the Y397 phosphorylation site of FAK. It has shown activity against breast, colon and pancreatic cancers. We herein present data in lung cancer.
Methods: Various lung cancer cell lines as well as minimally passaged patient-derived tumor (containing PIK3CA mutation E545K) propagated in vitro were treated with escalating doses of Y15 or DMSO for 72 hours to evaluate single-agent activity. Cell lines were also treated with cytotoxic agents (cisplatin, gemcitabine, pemetrexed, paclitaxel) in combination with escalating doses of Y15. Cellular viability was assessed by trypan blue exclusion assay and colony formation assay. For in vivo experiments, selected cell lines were implanted into nude mice and vehicle versus Y15 treatment, via either intraperitoneal or oral gavage administration, once daily was started when tumors reached a mean volume of 50–60 mm3. Western blot will be performed to investigate alterations in the activity of various signaling proteins.
Results: Y15 exhibited time and dose-dependent cell death in 6 out of 9 lung cancer cell lines tested. Activity was demonstrated beginning at 4 uM dose, with almost 100% cell kill demonstrated at 10 uM dose. There was also corresponding dose-dependent loss of clonogenic ability starting at 1 uM dose in sensitive cell lines. In addition, Y15 enhanced paclitaxel-induced cell death. Mice treated with Y15 at 100 mg/kg oral gavage administration showed reduced tumor growth compared to control mice.
Conclusion: Y15 demonstrates promising antitumor efficacy against various non-small cell lung cancer cell lines. Further development of this agent in lung cancer is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C191.
Abstract C195: Inhibition of polo-like kinase 1 (PLK1) by BI 2536: Effects on mitotic index, clonogenic capacity, and proliferation in medulloblastoma cell lines.
Authors: Pezuk Julia Alejandra , Brassesco Maria Sol , Morales Andressa Gois , de Oliveira Jaqueline Carvalho , Scrideli Carlos Alberto , Bobola Michael S. , Tone Luiz Gonzaga 
Published: June 2012

Abstract
Medulloblastoma is the most common central nervous system tumor in childhood. Despite high survival rates (over 50% for most protocols) the treatment for this tumor usually results in severe sequels. Still, in patients younger than 3 years-old radiotherapy cannot be used turning the prognosis even worse. Polo-like kinase 1 (PLK1), a serine-threonine kinase that regulates mitosis progression, has been repeatedly associated with increased cell proliferation and poorer prognosis in several types of cancer. The aim of this study was to evaluate the effects of the inhibition of PLK1 with BI 2536 on mitotic index clonogenic capacity and cell proliferation, on the UW402 and UW473 pediatric medulloblastoma cell lines. Equal numbers of cells were treated with 50, 100 and 150 nM of BI 2536 for 24, 48 and 72 hours. To calculate the mitotic index cells after treatment dropped onto glass slides, allowed to air dry and stained with Giemsa, 1000 cells were counted. To calculated the clonogenic capacity cells were treated, let to grow for 7 days and then the colonies were fixed with methanol and stained with Giemsa. Only colonies with &gt; 50 cells were counted. To analyze the proliferation cells after treatment were let with culture medium containing 10 μL of XTT dye (XTT II; Roche Molecular Biochemicals, Indianapolis, IN), plates were incubated for 2 hours at 37°C and the formazan product was measured at 450 nm by using an iMark microplate reader (Bio-Rad Laboratories). Each experiment was performed in triplicate wells and repeated in three sets of tests. The tests were analyzed by oneway ANOVA followed by Home-Sidak test. Values of p≤0.05 were considered statistically significant. The Inhibition of PLK1 by this drug showed an efficient decrease (p&lt;0.05) on cell proliferation in dose- and time-dependent manner. The clonogenic assay also demonstrated that BI 2536 causes a significant reduction in colony formation at concentrations as low as 5nM (p&lt;0.05). The mitotic index analysis showed a significant accumulation of dividing cells (p&lt;0.05) with a more evident effect after 24h of treatment. Although further studies are needed, our results point to PLK1 as a potential target to improve medulloblastoma treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C195.
Abstract C201: The combination of the small molecule TGFβR1 inhibitor LY2157299 monohydrate with CCNU substantially blocks SMAD phosphorylation and significantly suppresses human glioblastoma xenograft growth.
Authors: Parsons Stephen , Sawyer Scott , Yan Lei , Foreman Robert , Weir Spring , Lahn Michael , Yingling Jonathan , Graff Jeremy R. 
Published: June 2012

Abstract
TGF-β signals through the type I and type II TGF-β receptors (TGFβRI and TGFβRII) to phosphorylate the SMAD proteins. In normal tissues, this signaling axis provides a growth inhibitory signal. However, in some cancers, TGF-β is often secreted at high levels and has been implicated in tumor invasion, angiogenesis and decreased immune surveillance. Recent work in GBM indicates that TGFβ may promote aggressive proliferation if the tumor cells are able to express Platelet Derived Growth Factor in response to TGFβ. Indeed, in glioblastoma patient samples, high pSmad2 levels are related to increased proliferation as well as reduced progression-free and overall patient survival. These data strongly implicate aberrant TGFβ signaling in human glioblastoma (GBM) and provide strong rationale to target this pathway for therapeutic intervention. Indeed, phase 1 and 2 clinical trials in GBM patients have begun using the recently developed small molecule inhibitor of TGFβR1 (LY2157299 monohydrate) alone and in combination with lomustine (CCNU). Herein, we show, in GBM cell lines, that LY2157299 monohydrate blocks signaling through the heteromeric TGFβ receptor complex to reduce levels of active, phosphorylated SMAD. Similarly, CCNU treatment of these same GBM cell lines also blocks Smad phosphorylation. In combination, CCNU and LY2157299 monohydrate more effectively block Smad phosphorylation than either agent alone. Furthermore, in U87MG and CRL-2611 human glioblastoma xenografts, oral dosing of LY2157299 monohydrate significantly enhanced the efficacy of CCNU (lomustine). Taken together, these preclinical data support the exploration of LY2157299 monohydrate in combination with CCNU for glioblastoma therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C201.
Abstract C234: Decreasing ovarian tumor stromal signaling via SFRP2 mitigates ovarian cancer progression.
Authors: Thompson Melissa S. , Albitar Lina , Wong Kwong K. , Zaid Tarrik M. , Birrer Michael J. , Mok Samuel C. 
Published: June 2012

Abstract
The tumor microenvironment has been definitively shown to be a key player in tumor progression and metastasis in a variety of cancers, including ovarian cancer and provides a plethora of potentially significant therapeutic targets. As ovarian cancer is the deadliest gynecological disease due to a lack of reliable diagnostic testing and efficacious treatments, our objective was to determine how the ovarian cancer-associated fibroblasts (CAFs) are contributing to the propagation of ovarian cancer. Our lab has identified a distinct gene signature for the ovarian stromal component of high-grade late-stage (HGLS) serous ovarian cancer as compared to normal stroma, human ovarian surface epithelium, and ovarian tumor, and many of these genes are secreted proteins suggesting a paracrine role for the tumor microenvironment. Secreted frizzled related protein 2 (SFRP2), a protein integral to stemness and proliferation, is overexpressed in ovarian CAFs by over 10-fold. Quantitative RT-PCR and immunohistochemical staining validated the overexpression of SFRP2 in ovarian CAFs and also showed a clinical correlation for stromal SFRP2 overexpression with poorer overall survival and chemoresistance in patients with HGLS serous ovarian cancer. Furthermore, increased SFRP2 expression correlated with significantly higher microvessel density suggesting an angiogenic effect. In vitro functional studies illustrated increased ovarian cancer cell proliferation in response to recombinant SFRP2 that was dose and time dependent. Ovarian cancer cells overexpressing SFRP2 (autocrine signaling) also illustrated increased cell proliferation. Additionally, ovarian cancer cell co-cultured with ovarian CAFs induced increased SFRP2 expression in the CAFs. Using an allogenic mouse model, we determined that silencing stromal SFRP2 using a SFRP2 knockout mouse significantly decreased ovarian cancer cell growth, suggesting that eliminating tumor stromal signaling cues may mitigate ovarian cancer progression. Together, these results illustrate a direct and specific signaling linkage between ovarian tumor cells and their associated microenvironment, specifically CAFs, suggesting that elimination of this signaling linkage may slow ovarian cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C234.
Abstract C237: Merkel cell polyomavirus infection-related Merkel cell carcinomas have intratumoral lymphocyte infiltrates and favorable survival.
Authors: Sihto Harri , Kukko Heli , Koljonen Virve , Sankila Risto , Salmi Marko , Jalkanen Sirpa , Bohling Tom , Joensuu Heikki 
Published: June 2012

Abstract
Introduction: Merkel cell carcinoma (MCC) is rare and often aggressive skin cancer that manifests mainly in elderly white people. The majority of MCCs contain Merkel cell polyomavirus (MCPyV) DNA. Patients with MCPyV-positive MCC have favorable survival as compared to those with MCPyV-negative tumor. The reasons for this remain speculative, but host immune defence might influence outcome of patients with MCPyV infection.
Material and Methods: Tumor infiltrating T-lymphocytes (CD3+ cells) and macrophages (CD68+ cells) were stained using immunohistochemistry from 116 MCCs. The numbers of stained cells were counted at 400× magnification of the microscope. Presence of MCPyV infection was assessed by detecting MCPyV DNA using quantitative PCR and the viral large T antigen using immunohistochemistry. The associations between the tumor immune cell counts, presence of MCPyV DNA, clinicopatholocial factors and patient survival were examined using the Mann-Whitney test and the Kaplan-Meyer survival analysis.
Results: MCPyV-positive tumors contained more CD3+ and CD68+ cells as compared to MCPyV-negative cancers (5.3 vs. 3.3 cells/high-power field [HPF], p=0.014; and 5.3 vs. 4.0 cells/HPF, p=0.028, respectively). Similar results were obtained when presence of MCPyV infection was efined by expression of the viral large T-antigen (5.9 vs. 2.7 cells/HPF, p&lt;0.001; and 5.6 vs. 3.9 cells/HPF, p=0.003, respectively). Patients with regional nodal metastases had fewer CD3+ cells in the primary tumor as compared to those without metastases (2.3 vs. 5.3 cells/HPF, p=0.006). Patients who had MCC with a higher than the median number of CD3+ cells had better MCC-specific survival (55.2% vs. 82.1%, log-rank test p=0.003) and overall survival (22.4% vs. 50.0%, p=0.002) as compared to those with a smaller than the median tumor CD3+ cell count. Tumor CD3+ count was an independent prognostic factor for overall survival in a Cox multivariable analysis that included the presence of regional nodal etastases, gender and MCPyV large T-antigen expression as covariates (HR=0.55, 95% CI, 0.35 to 0.88, p=0.012). Conclusions: MCCs with evidence of MCPyV infection harbor high numbers of tumor infiltrating T-lymphocytes. A high number of CD3+ cells in the tumor is associated with generally favorable survival. Host immune response to MCPyV might explain in part the favorable survival associated with MCCs with MCPyV infection.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C237.
Abstract C241: Phase I trial of EUS-guided intratumoral vaccination with recombinant Panvac-F and systemic Panvac-V in patients with locally advanced pancreatic cancer.
Authors: Poplin Elizabeth A. , August David A. , Ben-Menachem Tamir , Michael Hazar , Artymyshyn Renee , Gulley James L. , Schlom Jeffrey , DiPaola Robert S. , Lattime Edmund C. 
Published: June 2012

Abstract
Preclinical studies in our laboratory were the first to demonstrate the superiority of intratumoral poxvirus vaccines in overcoming immune escape and effectively treating murine solid tumor models. We present here the translation of these findings to a Phase I trial in six patients with locally advanced inoperable adenocarcinoma of the pancreas (NCT00669734). The first dose cohort of patients were treated using a combination of EUS (Endoscopic Ultrasound)-guided intrapancreatic tumor injection of recombinant Panvac-F (Fowlpox encoding MUC-1, CEA, TRICOM, 108 PFU) in addition to systemic Panvac-V (vaccinia, 2 × 108 PFU) and Panvac-F (109 PFU) boosts (accompanied by subcutaneous rH-GM-CSF, 100 mcg × 4 days). Patients received a total of 2 intrapancreatic injections of Panvac-F (2 weeks apart) with systemic Panvac-V and Panvac-F boosts given with GMCSF extending to day 71 (total of 2 intrapancreatic Panvac-F, 1 sc Panvac-V, 4 sc Panvac-F). Patients were allowed to transition to standard care at day 31. Patients were evaluated for toxicity, tumor progression, and serum CA 19–9 and CEA levels. Two of six patients were removed from study after approximately two weeks due to rapid disease progression and died one and six months after trial initiation. Of the remaining four, one had received prior treatment with gemcitabine followed by capecitabine and radiation and received no further treatment after vaccination; three received post-vaccination standard treatment with gemcitabine. Of the 4 patients with followup of greater than 6 mos, all have clinically stable disease (15 mos, 13 mos, 12 mos, 9 mos). One pt had a DLT (pancreatitis) that resolved allowing completion of protocol therapy. Results demonstrate that the “first in human” intrapancreatic administration of the full recombinant poxvirus regimen was well tolerated with encouraging stable disease duration. The trial is currently accruing patients at intrapancreatic dose level 2 (109 PFU).
This study is supported by the NCI Cancer Therapy Evaluation Program (CTEP) and by NCI U01-CA07031 and P30-CA72720.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C241.
Abstract C27: Targeting ErbB3 and EGFR in lung cancer patients: A phase I trial of MM-121 in combination with erlotinib in patients with non-small cell lung cancer (NSCLC).
Authors: Sequist Lecia V. , Modiano Manuel , Rixe Olivier , Natarajan Chandra , Onsum Matthew , Kubasek William , Andreas Karen , Nering Rachel , Moyo Victor , Harb Wael A. 
Published: June 2012

Abstract
Background: The benefit of EGFR tyrosine kinase inhibitors (TKIs) is largely restricted to EGFR mutation-positive cancers and resistance invariably develops. A central theme of acquired resistance is persistent ErbB3 signaling, resulting in activation of the PI3K/AKT survival pathway. MM-121 is a fully human IgG1 monoclonal antibody (mAb) to ErbB3 with pre-clinical activity as a single agent and in combination with erlotinib in NSCLC, particularly in cancers with ligand-dependent activation of EGFR. This phase 1 study evaluated the safety and tolerability of MM-121 and erlotinib in NSCLC, as well as PK, immunogenicity, efficacy endpoints and exploratory biomarker evaluation.
Methods: Patients with advanced NSCLC, good performance status and adequate organ function were enrolled. Patients were EGFR TKI-naïve, unless they were EGFR mutant, in which case acquired resistance was allowed. MM-121 was administered weekly and erlotinib was administered daily. Seven cohorts were enrolled, evaluating varying dose levels of the combination, as well as alternate MM-121 infusion schedules. Dose levels were determined by safety and pharmacokinetic (PK) data.
Results: Between February 2010 and July 2011, 33 patients were enrolled. Median age was 64 years and there were 19 (57.5%) women. Twenty-four patients were erlotinib-naïve and 1 patient was an EGFR mutant. The most frequent adverse events were rash, diarrhea, nausea and fatigue. As of 31 July 2001, 16 patients remain on study. Full results will be presented at the meeting.
Conclusions: In this phase 1 dose escalation study, MM-121 plus erlotinib was well tolerated by the majority of patients. A phase 2 study is planned.
Reference: NCT00994123
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C27.
Abstract C37: Thromboxane synthase and COX-1 as drug targets to prevent systemic chemoresistance.
Authors: Voest Emile E. , Roodhart Jeanine , Daenen Laura M.G. , Houthuijzen Julia M. 
Published: June 2012

Abstract
Background: Chemotherapy remains the primary treatment for most disseminated cancers. However, the response to chemotherapy is often transient and development of resistance is one of the most significant obstacles to effective cancer therapy. Although various tumor-cell intrinsic mechanisms of drug resistance have been identified, it is becoming increasingly clear that the tumor micro-environment plays a key role in the development of drug resistance We recently identified two unique polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)) that are produced by MSCs upon stimulation by platinum analogues (J. Roodhart, et al., Cancer Cell, in press). These PIFA render, at picomolar concentrations, tumors insensitive to various chemotherapeutics.
Aim: To prevent MSC-induced chemoresistance by blocking PIFA production through inhibition of tromboxane synthase (TxS) and cyclooxygenase (COX-1).
Method: Various mouse tumor models were used. Furthermore, cultured MSCs were treated with various drugs in order to block the release of PIFA. Conditioned media were subsequently analyzed in vivo.
Results: KHT, a by-product of thromboxane A2 synthesis, is a downstream product of the (COX)-1 and thromboxane synthase (TxS) pathway. Conditioned medium of platinum-activated MSC containing PIFA conferred resistance to various forms of chemotherapy in vivo. However, pretreatment of platinum-activated MSCs with SC-560, a highly selective COX-1 inhibitor, indomethacin, a relatively selective COX-1 inhibitor or one of two specific TxS inhibitors (ozagrel and furegrelate) did not induce chemoresistance in vivo. Of note, selective COX-2 inhibition in MSC by celecoxib did not affect their capacity to induce chemoresistance, suggestive of a specific COX-1/TxS-dependent PIFA production. When mice were treated with a combination of indomethacin or ozagrel and cisplatin tumor growth inhibition was improved and no tumor resistance was observed. Of note, no anti-tumor effect was observed of single agent indomethacin or ozagrel.
Conclusion: We show that blocking the release of PIFA from MSC during chemotherapy with agents that are clinically available improved the effectiveness of chemotherapy in vivo. These findings warrant further exploration in clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C37.