bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C173: Anti-tumor activity of SCH 900105 (AV299), an anti-HGF antibody, in non-small cell lung cancer models
Authors: Meetze Kristan A. , Boudrow Andrea , Connolly Kelly , Huang Riyun , Rideout William , Gyuris Jeno , Han May 
Published: June 2012

Abstract
Hepatocyte growth factor (HGF) is the soluble ligand for the c-Met receptor tyrosine kinase. Signaling through the HGF/c-Met pathway mediates a plethora of cellular activities that are involved in cancer cell dysregulation, tumorigenesis, and metastasis including cell proliferation and survival, angiogenesis, migration, invasion and drug resistance. HGF/c-Met autocrine and paracrine regulatory loops have been reported in a number of non-small cell lung cancer studies. Furthermore, studies have shown that HGF/c-Met pathway upregulation via either c-Met amplification or HGF secretion can result in intrinsic or acquired resistance to EGFR TKIs in lung adenocarcinoma.
SCH 900105, formerly known as AV-299, is a humanized IgG1 antibody with high affinity to HGF that neutralizes all its biological functions tested with sub-nM potency. It is currently in phase 1 clinical trials that demonstrated good safety and tolerability. Anti-tumor activity of SCH 900105 was observed in HGF autocrine and paracrine in vivo tumor models, such as GMB, pancreatic cancer and multiple myeloma.
Anti-tumor efficacy of SCH 900105 was evaluated in paracrine models of the HGF-dependent NCI-H596 NSCLC cell line xenografted in SCID mice engineered to produce human HGF. In these models, SCH 900105 treatment resulted in dose-dependent decrease in tumor growth with concurrent increases in serum and tumor concentration of SCH900105 and increases in serum SCH 900105/HGF complex. Treatment also led to significant reduction in phospho-c-Met and phospho-Akt levels in tumor lysates. Concurrently, increases in cleaved caspase-3 and decreases in Ki67 and CD31 staining were also observed. Anti-tumor activity of SCH 900105 was also explored in combination with EGFR inhibitors, erlotinib and Cetuximab that resulted in increased efficacy. SCH900105 treatment resulted in decreased phospho-c-Met levels with concurrent increases in phospho-EGFR levels. Conversely, erlotinib treatment decreased phospho-EGFR with concurrent increases in phospho-Met levels. The combination of SCH900105 with Cetuximab resulted in complete response in all animals treated without tumor re-growth 50 days after treatment withdrawal.
Potent anti-tumor activity of SCH 900105 in combination with EGFR inhibitors observed in these preclinical models suggests testing the combination in NSCLC is warranted in the clinic.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C173.
Abstract C177: Src and ADAM17-mediated shedding of heregulin is a mechanism of acute resistance to chemotherapy in gastro-oesophageal cancer cells
Authors: Campbell Lynn Rachel , Van Schaeybroeck Sandra , Kyula Joan , Eatock Martin , Johnston Patrick 
Published: June 2012

Abstract
Background: We previously reported that, in response to chemotherapy, gastro-oesophageal cancer cells (GEC) activate a human epidermal receptor (HER)-mediated survival response abrogated by HER inhibitors. In order to elucidate potential biomarkers for response to chemotherapy treatment and potential novel targets, we investigated the pathways which mediate chemo-induced HER activity in GEC cells.
Methods: Apoptosis was measured by Flow Cytometry or PARP, Caspase 8/3 cleavage. HER1/HER2/HER3, Akt expression/activity and Heregulin (HRG) expression levels were determined by Western blotting. ADAM17 activity was measured using a fluorometric (MCA) assay kit while sTGF-α levels were analysed by ELISA.
Results: Following treatment with chemotherapy, we found that increased HER1/HER2/HER3 activity was associated with increased Src-family kinase (SFK) activity. Using the SFK inhibitor AZD0530, we found that chemotherapy-induced HER1 activation was abolished, indicating that HER1 activation was mediated via SFKs. Furthermore, we found that the dual HER1/HER2 inhibitor lapatinib had no effect on chemo-induced SFK activity, indicating that SFKs act upstream of HER. Furthermore, we found that chemotherapy treatment resulted in increased ADAM-17 activity, TGF-α and heregulin levels in culture medium of GEC cells. ADAM17 inhibition attenuated chemotherapy-induced TGF-α and heregulin levels and HER1/3 activity. When cells were co-treated with heregulin-neutralizing antibodies, we found strongest inhibition of chemotherapy-induced HER1/HER3 and Akt activity. In addition, following treatment with AZD0530, we found complete inhibition of chemotherapy-induced ADAM17 activity and ligand shedding. Finally, when HER1/HER2/HER3, ADAM17 or SFK inhibitors were combined with chemotherapy, we found a potent increase in apoptosis in GEC cells.
Conclusions: We provide strong evidence that chemotherapy induces HER1/HER2/HER3 activation via a ligand dependent mechanism in GEC cells and have demonstrated that SFK's, ADAM17 and heregulin are critical mediators of HER1/HER2/HER3 activation following chemotherapy. We propose a model in which chemotherapy results in SFK activation that in turn activates ADAM17-mediated shedding of heregulin. Heregulin then activates HER1/HER2/HER3 pro-survival signalling in an autocrine and paracrine fashion. Thus, inhibiting HER1/HER2/HER3, SFKs or ADAM17 may have therapeutic potential for sensitizing GEC tumors to chemotherapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C177.
Abstract C184: Validation of an ELISA for the determination of Rituximab pharmacokinetics in clinical trials subjects
Authors: Ward Tim H. , Hampson Grace , Cummings Jeff , Bayne Mike , Tutt Alison , Cragg Mark , Dive Caroline , Illidge Tim 
Published: June 2012

Abstract
Rituximab is a chimeric anti-CD20 monocolonal antibody directed against the CD20 antigen on the B cell surface. Rituximab was originally developed by IDEC Pharmaceuticals from a high affinity murine monoclonal Antibody (mAb). CD20 is expressed on mature B cells, present on 95% of B cell lymphomas and is thought to act as a calcium channel that regulates progression through the cell cycle. Cross-linking of CD20 by anti-CD20 mAb results in apoptosis through a caspase dependent pathway and may trigger complement dependent cytotoxicity (CDC) or antibody directed cell cytotoxicity. Rituximab has revolutionised the treatment of many B-cell malignancies and is now increasingly being used in non-malignant conditions such as auto-immune disorders. Serum Rituximab levels are highly variable in patients receiving similar ‘standard’ approved doses, and little is known regarding the factors that affect serum Rituximab concentration and that in turn may influence clinical outcome. In order to provide a pharmacokinetic (PK) tool that may ultimately enable patient specific dosing of Rituximab therapy; we have generated a reliable, robust ELISA to quantitate serum Rituximab levels and to provide accurate PK data that will guide the optimisation of rituximab dosing regimes.
An extensive validation of the assay was performed in order to use the assay in the clinical setting. The plate coating efficiency (within and between days) proved reliable resulting in a robust starting platform for the assay. The within day precision for the assay determined using spiked serum samples and was shown to be &lt; 25% with accuracy between 96–109%. The between day precision was &lt;10% with accuracy between 91–125%. Dilution linearity and parallelism were demonstrated with spike recovery for all concentrations and donors within +/− 15% with a coefficient of variation below 10%. The assay has been validated for use on clinical serum samples and consequently stability is a critical factor affecting analysis both in terms of freeze thaw cycles as well as length of storage. To establish sample stability criteria a retrospective study was undertaken using clinical samples collected four years previously as part of a previously published clinical trial. Reanalysed samples showed no statistically significant decrease in measured Rituximab levels compared to the first analysis. These same samples can be freeze thawed and analysed up to five times if necessary.
This assay is highly accurate and reproducible in determining the pharmacokinetic levels of Rituximab in patient serum samples. This assay represents a powerful new tool for clinical evaluation of this widely used therapeutic, it meets stringent acceptance criteria, is fit for purpose, and is currently being applied to several clinical trials incorporating Rituximab in the treatment of Lymphoma.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C184.
Abstract C21: Hypoxia-induced down-regulation of BRCA1 nuclear protein in human breast cancer tissues
Authors: Li Jia , Sullivan Catherine AW. , Numeister Veronique , Rimm David L. , Glazer Peter M. , Harris Lyndsay 
Published: June 2012

Abstract
Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated significant anti-tumor activity not only in tumors with BRCA1 or 2 gene mutations due to synthetic lethality, but also in triple-negative breast cancers (TNBC). The triple negative group of tumors may be more sensitive to PARP inhibitors due to loss of BRCA pathway activity, although this has not been proven. Several mechanisms may affect BRCA1 protein level such as epigenetic modification, negative transcriptional regulators, as well as hypoxia. Yale investigators have demonstrated that tumor hypoxia leads to loss of critical DNA repair activities, including BRCA1, RAD-51 and γ-H2AX (Bindra RS, et al. Cancer Res 2005;65(24):11597-604). We propose BRCA1 nuclear protein is the determinant of response to PARP inhibitors in sporadic breast cancer, a phenotype we will term ‘BRCA-like’. This study was designed to explore the relationship of BRCA1 loss and hypoxia in human breast tumors.
Methods: Yale archival materials consisting of 660 human breast cancer specimens were used to establish a tissue microarray (TMA). Automated QUantitative Analysis (AQUA) was used to detect the intensity of BRCA1 and CAIXwithin a specific subcellular compartment. Carbonic Anhydrase IX (CA-IX), a downstream target of hypoxia-induced factor 1a (HIF-1a), is an accepted surrogate biomarker for tumor hypoxia. CA-IX antibody M75 was provided by the J Zavada lab (1:10000), BRCA1 monoclonal antibody M110 (Ab-1) was purchased from Calbiochem (1:1000).
Results: In the cohort of 660 specimens, 22 were found to have high CA-IX expression score (above cut-off value of 10). Cut-off was based on known positive cell lines and corresponding AQUA scores, as well as visual confirmation of positivity. A negative correlation (Rho=−0.6, p=0.0165) of BRCA1 nuclear protein with CA-IX level was found in hypoxic tumors. Of note, 14 out of 22 hypoxic breast tumors were from triple negative breast cancers (TNBC) (p=0.0034). Total number of TNBC in this cohort is 112 out of 660. BRCA1 nuclear expression alone did not correlate with overall survival (p=0.76). Conclusions: In human breast tumors BRCA1 nuclear expression is negatively correlated with tumor hypoxia, measured by CAIX. Ongoing clinical trial will determine if tumors with high CA-IX or low BRCA1 benefit from PARP inhibitor therapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C21.
Abstract C240: Protein photoadducts of acridine photosensitizers
Authors: Snapka Robert M. , Salama Samir A. 
Published: June 2012

Abstract
Photodynamic therapy is used to treat many cancers and some non-cancerous conditions. It exploits photosensitizers, compounds that are only toxic to cells when light exposure causes them to generate reactive oxygen species that damage many cellular molecules and organelles. A common observation is the shrinkage of distant unirradiated tumors as the result of photodynamic treatment of a single tumor. This systemic response against tumors is thought to be immunological and to involve inflammation and cytokines generated by the treated tumor in response to photodynamic damage. The possible role of photodynamic damage to proteins in such a global immune response has been underexplored. We hypothesized that photodynamically damaged tumor cell proteins might act as immunological adjuvants, stimulating an immune response to tumor specific proteins so that the photodynamically treated tumor acts as a tumor vaccine. Photoaddition of the photosensitizing molecule to cellular proteins could be one molecular mechanism for this since such adducts would be expected to produce highly immunogenic haptens on tumor cell proteins. In a test of this hypothesis, we have investigated photoaddition of acridines to cellular proteins. Cultured mammalian cells were treated with radiolabeled proflavine or acriflavine and light. SDS gel electrophoresis and gel fluorography revealed that a wide range of cellular proteins were radiolabeled. Proteinase treatment of samples before SDS PAGE resulted in label migrating with the dye front. Proteins from cells treated with the acridines but not exposed to light were not radiolabeled. Cesium chloride ultracentrifugation of cell lysates also confirmed that the only macromolecules labeled were proteins. The singlet oxygen quencher histidine and the singlet oxygen stabilizer deuterium oxide had little effect on photolabeling of cellular proteins, suggesting that the mechanism does not rely on singlet oxygen. Experiments with purified proteins and fluorography of SDS polyacrylamide gels demonstrated photoadducts of proflavine and acriflavine to these proteins. Finally, proflavine was shown to form photoadducts to angiotensin by proteomic analysis. The detailed photochemistry and the identity of the amino acid residues involved in photoadduct formation are currently being studied. We conclude that photodynamic treatment of cells can result in photoaddition of the photosensitizing drug to cellular proteins and can generate potentially immunogenic haptens.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C240.
Abstract C259: pVHL function is involved in cell death induced by YC-1 in renal cell carcinoma
Authors: Unno Yuka , Oikawa Tsuyoshi , Sawada Jun-ichi , Asai Akira 
Published: June 2012

Abstract
Renal cell carcinoma (RCC) is quite resistant to chemotherapy, whereas immunotherapeutic agents, including IL-2 and IFN-α, are only modestly effective with response rates of 10–20%. Novel and more effective therapeutic agents are aspired to alter the natural history of advanced RCCs. Since the protein level of von Hippel-Lindau tumor suppressor (pVHL) was extremely low in 75% of RCCs, importance of small molecules that selectively target pVHL-deficient RCC has been highlighted recently. In this study, we evaluated several known anti-cancer agents to find small molecules that induce growth inhibition according to pVHL level in RCC cells.
Our screening efforts identified YC-1, known as an anti-cancer agent that has two distinct biological actions, elevation of intracellular cGMP and inhibition of transcription factor HIF-α. In RCC cell lines we examined, YC-1 showed more effective growth inhibition to pVHL-positive RCC cells as compared to RCC cells expressing reduced level of pVHL. Cell cycle analyses revealed that YC-1 caused delay of S-phase progression and subsequent induction of apoptosis more effectively in pVHL-positive RCC cells. Under the treatment of YC-1, phosphorylation of S-phase checkpoint proteins ATM and CHK2 were elevated dramatically, and cleavages of caspase-3/9 and PARP-1, molecular hallmarks of cells undergoing apoptotic events, were promoted. However, no obvious DNA damage was observed when the cells were exposed to YC-1 at the sufficiently high concentration.
This YC-1-induced preferential apoptotic cell death in pVHL-positive RCC cells did not result from its known effects, assessed by sensitivity to the other soluble guanylate cyclase activators and by HIF-1α level. No difference was observed in growth rates of RCC cells in spite of pVHL level when the cells were exposed to BAY41-2272, a YC-1 analog, at the concentration enough to up-regulate intracellular cGMP level. In addition, as pVHL plays a key role in down-regulation of HIF-1α protein, pVHL-deficient RCC cells usually showed less sensitivity to YC-1, even though they contain remarkably higher expression of HIF-1α.
Our findings demonstrated that VHL expression sensitizes RCC cells to YC-1. Taken together with the previous report that pVHL functions as an inhibitor to RCC cell apoptosis induced by cellular stress, the results imply that YC-1 targets the pVHL-dependent survival pathway by unknown mechanisms. Thus, YC-1 is considered as a new lead compound of anticancer agents for target therapy of pVHL-positive RCCs.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C259.
Abstract C40: Phase 0 cancer trials: Ethical and regulatory issues
Authors: Silvia Camporesi 
Published: June 2012

Abstract
The aim of my PhD project is the analysis of the ethical and regulatory issues of Phase 0 oncological trials. In 2003, the European Agency for the Evaluation of Medicinal Products (EMEA) published a concept note followed by a Position Paper on the nonclinical safety studies needed to support human clinical trials with a single microdose of a pharmacologically active compound. In 2004, the American FDA published a draft guidance regulating early human screening studies, and in 2006 new industry guidelines for early exploratory drug studies in humans have been issued. After the publication of the US FDA guidelines, the NCI in Bethesda started the' Phase 0 program' and launched the first Phase 0 trial.
Given the recent development of such trials, there are few empirical data available on which to evaluate the ethical concerns they raise. I will pursue my analysis on the data of the NCI Phase 0 program, and by performing a comparison with the ethical concerns raised by other early cancer trials. I will also compare FDA to EMEA guidelines.
The ‘therapeutic misconception’, which is a widespread ethical problem for participants to Phase 1 cancer trials, should not be an issue of Phase 0 trials, as they declare their lack of therapeutic intent. Another ethical issue appears controversial, though, as in Phase 0 studies the interests of society seem to play a greater role than the interests of the subjects, who contribute to the progression of medical knowledge, without receiving any direct benefit from their participation. Some ethicists suggest that paragraph # 6 of Helsinki Declaration, according to which the ‘interests’ of human subjects must always take precedence over the interests of science and society, is being violated. It is time to reflect upon the nature of statements contained in Helsinki Declaration, as recently scholars such as the British bioethicist John Harris and the US Rosamund Rhodes have argued. I will discuss how the concept of ‘interest’ in participating to research should be understood, and contribute to the debate about who should be entitled to decide regarding participation to clinical trials.
On the basis of my preliminary analysis, I will conclude that Phase 0 trials appear ethically less problematic than Phase 1 cancer trials. I will also argue that the widespread presumption, that participation to clinical research is super-erogatory, needs to be changed, in favor of an approach with considers participation to research within the broadly conceived interests of the participants.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C40.
Abstract C41: Phase II pilot study of induction erlotinib therapy in patients with resectable non-small cell lung cancer to select postoperative adjuvant therapy
Authors: Lee Dae Ho , Hong Yong Sang , Kim Tae Won , Jung Kyung Hae , Kim Sang-We , Suh Cheolwon , Lee Jung-Shin , Kim Heung Tae 
Published: June 2012

Abstract
Background: Adjuvant chemotherapy has been widely accepted as the standard therapy for stage I-IIIA NSCLC, but resulted in significant toxicity and short-term deterioration of quality of life. In addition, not all patients can receive cytotoxic adjuvant chemotherapy. On the other hand, erlotinib demonstrated to significantly improve survival outcome for previously treated NSCLC patients regardless of their clinical characteristics. Based on those findings, we conducted a prospective pilot study of short-term induction erlotinib to select responders who might benefit from adjuvant erlotinib therapy in patients who were scheduled to undergo surgical resection.
Methods: Patients had previously untreated, potentially surgical resectable, stage IB-IIIA NSCLC with ECOG PS of 0–1 and adequate organ functions. Induction erlotinib 150 mg once a day was administered for 28 days. Subsequently patients underwent restaging and planned surgery. Erlotinib responders, defined as their tumor shrinkage of more than 10%, would receive adjuvant erlotinib for 12 weeks while the others would receive any kind of adjuvant platinum doublets. Postoperative radiotherapy could be given in case of incomplete resection or clinician's decision.
Results: Between October 2006 and March 2009, 16 patients participated in this study; median age was 59 (41–71); 13 were male; 6 were never-smoker; and 13 had adenocarcinoma. Preoperative clinical stage was as follows; IB 4, IIA 1, IIB 5, IIIA 6. All patients received induction erlotinib monotherapy and all but one, who declined surgery but received curative radiotherapy, underwent planned surgical resection. Out of 16 patients, 5 patients (3 PRs and 2 SDs) received adjuvant erlotinib therapy, while an adjuvant platinum doublet was given in 6, concurrent chemoradiation in 3 due to incomplete resection in 3 and no adjuvant therapy in 1 due to his pathologic stage of IA. There was no complete response. With a median follow-up of 24 months, 8 patients progressed and 3 patient died of progressive disease. No relationships were observed between the responsiveness and biomarkers, such expression levels of VEGF, EGFR, Ki67 and P53. Additional biomarker studies are now ongoing.
Conclusions: Induction erlotinib is tolerable and modestly active in patients with resectable NSCLC. The role of adjuvant erlotinib is still not defined yet, but short-term erlotinib before curative surgical resection could predict patients who might benefit from adjuvant erlotinib therapy and avoid toxic adjuvant chemotherapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C41.