bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A33: CuraBase: An integrated relational database and online collaboration platform for cancer drug development
Authors: Husler William , Nosrati Mehdi , Rothenberg Mace L. , Korn W. Michael 
Published: June 2012

Abstract
The extraordinary increase in the number of novel, targeted agents for the treatment of cancer has resulted in the generation of a vast amount of clinical and preclinical data at an ever-quickening pace. Currently, no standardized system exists allowing for systematic collection, organization, and analysis of such data. Curabase was developed to provide scientists involved with cancer drug development with quick access to relevant data on molecular targets, targeted agents, and clinical trial results. The system consists of a relational database capturing information on new drugs, drug targets and pathways, and clinical trial outcomes using a standardized format. Incorporated into this database is a pathword-protected, firewalled online collaboration platform allowing for secure information exchange within workgroups. Database content can be annotated and thus expanded based on individual needs. The relational database structure allows for generation of comprehensive and relevant data output. For example, tables summarizing clinical trial results from various drugs targeting particular molecular targets or pathways can be generated on demand. This relational database has the potential to enhance analysis, communication, and collaboration on drug development projects in academia and industry.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A33.
Abstract A42: Characterization of EGFR and leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1–3) in esophageal carcinoma with emphasis on patient survival
Authors: Wu Xuping , Hedman Håkan , Bergqvist Michael , Bergström Stefan , Henriksson Roger , Gullbo Joachim , Lennartsson Johan , Hesselius Patrik , Ekman Simon 
Published: June 2012

Abstract
Background: Esophageal carcinoma is the seventh most common cause of cancer-related death in the Western world and the incidence is increasing. The signal transduction system of epidermal growth factor receptor (EGFR) is of major importance for tumor growth in several types of malignancies and EGFR-targeted therapy has been shown to able to regulate tumor growth. Leucine-rich repeats and immunoglobulin-like domain protein 1 (LRIG1) is an endogenous negative regulator of EGFR signaling. The functions of LRIG2 and −3 are at present not known, however, it has been postulated that they might also be involved in the regulation of growth factor signaling and tumor growth. In the present study, we investigated the clinical implications of the expression of EGFR and LRIG1–3 in esophageal carcinoma as well as the correlation between their expression levels and the chemosensitivity of esophageal carcinoma cell lines.
Patients and Methods: A total of 86 patients diagnosed with esophageal carcinoma were included in the study and their tumors were investigated for the expression of EGFR and LRIG proteins by immunohistochemistry. Further, a total of nine esophageal carcinoma cell lines were investigated for their expression of EGFR, LRIG1, −2 and −3 by quantitative RT-PCR and for their sensitivity to commonly used chemotherapeutics by a cytotoxicity assay.
Results: Survival analysis using Kaplan-Meir analysis showed that the staining intensities of EGFR and LRIG2 were significantly associated with short survival (p=0.025 and p=0.03, respectively), whereas the extent of staining of LRIG1 was associated with long survival (p= 0.045).
Chemosensitivity studies demonstrated a significant correlation between LRIG1 expression levels and sensitivity to cisplatin (r=−0.74), docetaxel (r=−0.69) and vinorelbine (r=−0.82) in the investigated esophageal carcinoma cell lines.
Conclusion: In the present study, the expression of EGFR and LRIG2 correlated negatively, whereas LRIG1 correlated positively, with survival of the esophageal carcinoma patients. Furthermore, a correlation between LRIG1 expression and chemosensitivity was observed, indicating a possible role in chemoresistance. The functions of LRIG1 and −2 and their connection with EGFR warrants further investigation.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A42.
Abstract A45: Upregulation of the small GTPase Rap1 and the insulin-like growth factor I receptor in breast epithelium occurs in carcinoma in situ
Authors: Furstenau Dana K. , Mitra Nandita , Wan Fei , Lewis Robert , Feldman Michael D. , Fraker Douglas L. , Guvakova Marina A. 
Published: June 2012

Abstract
With use of screening mammography, the diagnosis of breast carcinoma in situ (CIS) is increasing worldwide. Although classified as a noninvasive precancer, the presence of this lesion increases risk for developing invasive cancer. The molecular markers associated with this transition remain uncertain. Recent reports indicated that activation of the small GTPase Ras - related protein 1 (Rap1) in human breast cancer cells associated with cell invasion in vitro and tumorigenicity in nude mice (Itoh, M. et al.. Cancer Res, 67: 4759–4766, 2007). The objective of this study was to test the hypothesis that the alteration in the levels of Rap1 protein expression is associated with invasion of breast cancer cells in humans. Using an image-based uniplex method, we performed quantitative protein profiling on 90 surgical samples representing breast cancer progression series and including 17 histologically normal tissues, 16 benign lesions; 10 pure CIS, 5 CIS with co-existing invasion, and 42 invasive carcinomas. The expression of Rap1 was found increased in pure CIS and significantly increased in CIS with co-existing invasion (P=0.0010) and invasive carcinoma (P&lt;0.0001) compared with noncancerous tissue. Furthermore, the expression of Rap1 positively correlated with the expression of the insulin-like growth factor type I receptor (IGF-IR) in invasive carcinomas (Spearman's = 0.39; P = 0.014; n = 42), but not in normal/ benign epithelia (= -0.39; P = 0.841; n = 33). Moreover, both Rap1 and IGF-IR significantly discriminated invasive from non-invasive tissues, with receiver operating characteristic (ROC) area under the curve, AUC=0.78 for Rap1, AUC= 0.82 for IGF-IR. Our studies identified measurable changes in Rap1 and IGF-IR protein expression during the transition of breast epithelium to CIS and invasive cancer. These findings warrant further investigation on IGF-IR-Rap1 as a potential dual biomarker of early alterations associated with breast epithelium transition from CIS to invasive breast cancer in humans.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A45.
Abstract A46: Pharmacodynamic biomarkers for OSI-906, an insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in cancer patients with advanced solid tumors
Authors: Gedrich Richard , Poondru Srini , Stephens Andrew , Logan Tiffany , Hart Karen , Buck Elizabeth , Carden Craig , Lindsay Colin , Kaye Stanley , Kim Edward , Evans Jeff , Puzanov Igor , Epstein David , Miglarese Mark 
Published: June 2012

Abstract
Background: OSI-906 is a potent small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R), a receptor tyrosine kinase that is overexpressed in several human cancer types and implicated in resistance to chemotherapy. Disruption of the growth hormone-IGF1 signaling axis can affect levels of biomarkers such as IGF1, growth hormone (GH) and insulin and can affect glucose homeostasis, making these potentially useful markers for demonstrating the activity of IGF-1R inhibitors in solid tissues.
Methods: Two phase I dose escalation trials were initiated in cancer patients with advanced solid tumors who received OSI-906 on either continuous or intermittent dosing schedules. Pharmacodynamic (PD) and pharmacokinetic (PK) assessments were included as secondary objectives of these studies. Circulating biomarkers, including total IGF1, IGFBP3 and non-fasting GH and insulin levels, were measured at various times during the dosing cycle (21 days for continuous dosing; 14 days for intermittent dosing) and changes were correlated with plasma concentrations of OSI-906.
Results: To date, patients have been treated with up to 450 mg QD and 200 mg BID on the continuous dosing schedule and up to 750 mg QD on the intermittent dosing schedule. Maximum tolerated dose (MTD) was determined to be 400 mg QD and 150 mg BID for continuous dosing and 600 mg QD for intermittent dosing. Preliminary analysis of the PK data suggests that the exposure of OSI-906 increased with dose. Median plasma concentrations of OSI-906 at MTD exceeded the predicted concentration required for efficacy based on the preclinical models (1 µM). Total IGF1 concentrations in plasma were increased relative to predose levels at doses ≥ 450 mg QD on the intermittent dosing schedule and ≥ 150 mg QD or 40 mg BID on the continuous dosing schedule. Elevations in non-fasting plasma insulin levels were also observed in patients with plasma concentrations of OSI-906 exceeding 5000 ng/mL. PK/PD relationships were observed for IGF1 and insulin. OSI-906 did not affect plasma IGFBP3 levels in most patients. Analysis of additional biomarkers, including GH, is ongoing.
Conclusions: At or below MTD, plasma concentrations of OSI-906 could be achieved that exceed concentrations required for anti-tumor efficacy based on the preclinical models. The pharmacodynamic data indicate that pharmacologically-relevant concentrations of OSI-906 were achieved in tissues involved in regulating the GH-IGF1 signaling axis. Together, these PK and PD data indicate that the current recommended dosing regimens may provide sufficient exposure for activity against solid tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A46.
Abstract A47: Somatic mutations in human cancer cell lines predict sorafenib response
Authors: Rhodes Daniel R. , Kaufmann Scott H. , Meng Xue Wei , Wyngaard Peter , Leopold Judith S. 
Published: June 2012

Abstract
It is now widely accepted that a spectrum of somatic alterations occur in human cancer and that particular alterations are associated with response or lack of response to anti-cancer therapies. Here, we undertook a systematic correlation analysis of somatic mutations, copy number aberrations and drug response across 300+ human cancer cell lines. We studied the RAF and VEGFR inhibitor, sorafenib, evaluating associations between sorafenib response and somatic mutations in 35 common cancer genes and high-level amplifications and homozygous deletions in more than 100 minimal common regions of gain and loss, which include many known oncogenes and tumor suppressor genes. Notably, we found that NRAS mutations, among other alterations, were significantly associated with sensitivity to sorafenib (odds ratio = 7, p-value = 0.003), whereas activating BRAF mutations were strongly associated with a lack of response (odds ratio = 4.9, p-value = 0.012). Specifically, 64% (7 of 11) of NRAS mutant cell lines were sensitive to sorafenib, while only 20% (34 of 170) of NRAS wild-type lines were sensitive. On the contrary, just 6.7% (2 of 30) of BRAF mutant lines were sensitive to sorafenib. Because NRAS mutations occur frequently in leukemia and no leukemia cell lines were included in the original analysis, we selected 5 NRAS mutant and 5 NRAS wild-type leukemia cell lines for further evaluation. Consistent with our previous observation, the four most sensitive leukemia cell lines were all NRAS mutant, each line exhibiting greater than 50% growth inhibition after 72 hours of exposure to 4uM sorafenib. These results confirm the original association and suggest that across both solid tumors and hematologic malignancies, NRAS mutations may identify a subset of cancers that are likely to respond sorafenib. In addition, this work demonstrates that systematic analysis of somatic alterations and drug response across a large collection of cancer cell lines is capable of discovering novel predictive biomarkers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A47.
Abstract A56: Chemically induced alkaline phosphatase on osteosarcoma stem cells derived from a novel osteosarcoma cell line as a potential molecular target
Authors: Saini Vaibhav , Shoemaker Robert H. 
Published: June 2012

Abstract
Osteosarcoma is the sixth most common pediatric tumor in the under 15 age group. Relapse observed after chemotherapy is associated with &lt; 20 % survival. Osteosarcoma stem cells (OSCs) have been implicated in the poor response to chemotherapy and ultimate relapse of osteosarcoma. Thus, to achieve successful osteosarcoma therapy, it may be crucial to target OSCs. To this end, a molecular target that is overexpressed in osteosarcoma cells and OSCs and either not expressed or underexpressed in normal cells is desirable. While the search for such a targeting molecule is ongoing, we endeavored to test the utility of a chemical treatment to induce overexpression of a potential molecular target in osteosarcoma cells and OSCs. We hypothesized that a chemical cocktail could be used to induce overexpression of bone specific alkaline phosphatase (bsALP) in both osteosarcoma cells and OSCs derived from a novel osteosarcoma cell line (CHA59). Towards this goal, an OSC-enriched culture was derived from CHA59 using serum-free culture medium. This was accomplished by changing the cell growth media, as recently reported for other cell lines, from 10% fetal bovine serum-containing medium to serum-free medium containing 15% KnockOut Serum Replacement (serum substitute (SS)). This resulted in a rapid change in cell growth from adherent monolayers (in serum) to floating spheres (in SS). Monolayers, containing osteosarcoma cells and a few OSCs, and OSC-enriched spheres were then treated with a chemical cocktail (0.1 µM dexamethasone, 50 M ascorbic acid, and 10 mM beta-glycerolphosphate) that has been previously reported to induce the expression of bsALP in mesenchymal stem cells. A colon tumor cell line, HT-29, served as the negative control for ALP induction. Nine days post-treatment, ALP expression was monitored by Fast Red staining. Cocktail treated monolayer and OSC-enriched spheres stained intensely for ALP compared with the untreated control and the HT-29 (cocktail treated) negative control. To conclude, the results support our hypothesis that ALP can be overexpressed in both monolayer and OSC-enriched spheres. This opens the possibility of targeting therapeutic drugs, gene therapy vectors, and novel nanotechnology to OSCs along with the osteosarcoma cells using anti-bsALP monoclonal antibodies, which is our future goal.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A56.
Abstract A57: The telomere targeting agent sodium metaarsenite (KML001) exhibits activity in taxane-resistant prostate cancer (PC) cells
Authors: Burger Angelika M. , Zhang Bin , Nolan Patrick , Brucz Bradley , Hussain Arif 
Published: June 2012

Abstract
Background: Tumor growth is sustained by cancer stem cells (CSC), a rare fraction of cells expressing high levels of drug efflux pumps responsible for therapy failure and tumor recurrence. The enzyme telomerase is critical to maintaining the self-renewal properties of CSC. We have recently found that sodium metaarsenite (KML001), a drug in phase I/II clinical trials in Europe and the US, can target both the catalytic subunit of telomerase and telomeres. PC cell lines appear to be among the most sensitive tumor cell types to KML001. In this study, we examined chemotherapy-naïve and taxane (paclitaxcel/Pac and docetaxel/Doc)-resistant DU145 PC cell lines for stem cell content, and the potential for KML001 to inhibit their mature and stem cell subpopulations.
Methods: Methyltetrazolium (MTT)-based assays were used to determine the IC50 and IC100 values, and the relative resistance of DU145, DU145/Doc50 and DU145/Pac200 cells to KML001, docetaxel and paclitaxel. Fluorescence activated cell sorting (FACS) was employed to determine the prostate stem cell surface marker CD44, the side population and Pgp content in these cells. Telomerase activity was evaluated by a PCR ELISA assay and telomere length was assessed by Southern blots. Cells were treated with IC50 and IC100 concentrations of KML001 for 72 hrs to investigate its effects on the side population.
Results: We found that while DU145/Doc50 and DU145/Pac200 cells were 2,000- and 400-fold resistant to docetaxel and paclitaxel, respectively, they retained sensitivity to KML001 (IC50 = 4µM). Resistance to taxanes was associated with expression of Pgp; parental DU145 cells expressed Pgp in 0.24% of the cell population, DU145/Doc50 in 47% and DU145/Pac200 in 79% of the cells. Moreover, Pgp expression correlated with the detection of a side population (SP), a cell fraction known to be enriched for CSC. The SP was 3.7% in DU145 cells and 56%–67% in the taxane-resistant cells. In contrast, telomerase activity and telomere lengths remained unchanged in all three cell lines. Exposure of the various DU145 cell lines to KML001 for 72 hrs resulted in a dramatic reduction in the SP. Similar to the Pgp inhibitor verapamil, KML001 reduced SP cells to ∼93% of controls in both parental and taxane-resistant cell lines. However, unlike verapamil, KML001 was able to reduce the mature cell population to the same extent as the SP.
Conclusion: Overall, our data in the DU145 model demonstrate that KML001 can eradicate both mature drug-resistant and prostate cancer stem cells, which may offer a new treatment approach in this disease.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A57.
Abstract A74: Activation of EGFR by proteasome inhibition requires HB-EGF in pancreatic cancer cells
Authors: Sloss Callum M. , Wang Fang , Palladino Michael , Cusack James C. 
Published: June 2012

Abstract
Resistance to drug treatments underlies the high lethality of pancreatic ductal adenocarcinoma (PDA). We have previously shown that the EGFR/HER4 ligand HB-EGF plays an important role in chemoresistance of pancreatic cancer cell lines to various chemotherapeutics. Additionally we and others have recently identified that proteasome inhibition is a promising therapeutic option in this highly refractory disease. The pleiotropic effects of proteasome inhibition include the activation of anti-apoptotic signaling pathways as well as the expected pro-apoptotic signals. These anti-apoptotic pathways include increased heat shock protein expression, cFLIP induction and activation of EGFR, AKT and the MAP kinases all of which can reduce the apoptotic potential of this class of drug.
In the current study, we sought to determine the mechanism behind the activation of EGFR in response to proteasome inhibition in pancreatic cancer cells. We found that the second generation proteasome inhibitor NPI-0052 induced EGF, HB-EGF and epiregulin mRNA expression. Using both a specific inhibitor of HB-EGF activity (crm-197) and lentiviral mediated shRNA knock down of ligand expression, we discovered that HB-EGF but not EGF or epiregulin is required for activation of EGFR in response to proteasome inhibition. Additionally we found that a broad spectrum inhibitor of MMP/ADAM activity (GM6001) was able to prevent proteasome inhibitor induced activation of EGFR. Taken together these results indicate that HB-EGF expression and cleavage is required for EGFR activation in response to proteasome inhibition. This suggests that HB-EGF plays a prominent role in pancreatic cancer chemoresistance to proteasome inhibition and that targeting both HB-EGF and the proteasome may make an effective combination treatment for this highly refractory disease.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A74.
Abstract A77: Hydrostatic pressure sensitizes TRAIL-mediated apoptosis through activating mitochondrial pathway in H460, lung carcinoma cell
Authors: Oh Sangnam , Lee Eunil , Kwon Daeho 
Published: June 2012

Abstract
TRAIL (tumor necrosis factor related apoptosis inducing ligand) is a member of the TNF superfamily and one of the promising anticancer drugs with high specificity for cancer cells. Accumulating preclinical studies demonstrate that the TRAIL can effectively induce the apoptosis of tumor or transformed cells, but not normal cells; hence, promoting the development of TRAIL-based cancer therapy. Recent studies for strategy of enhancement of the TRAIL-mediated apoptosis have been investigated for improving typical cancer therapy by combining treatment with other chemo- or radiation and small molecules.
Environmental stimuli such as physiological or mechanical conditions can influence the proliferation, differentiation, apoptosis and premature senescence through activating critical signaling pathways with the dependent on the kinds of stimuli or cell types like as chemicals. However, until present, there are a few reports to postulate molecular mechanisms of cancer therapy combined with environmental stimuli. Here, using new culture system, compressed air into two atmospheres (hydrostatic pressure, HP), we explore the molecular mechanism of HP stimulation coupled with TRAIL-mediated apoptosis in lung carcinoma cell H460 (one of non small cell lung carcinoma cells). Interestingly, HP treatment combined with TRAIL significantly induced the apoptosis by 2.0-fold in H460 cells compared to TRAIL only treated cells.
We show the HP-potentiating apoptosis of H460 is characterized by activation of intrinsic pathway which defined as caspase 8-mediated Bid cleavage and subsequent the disruption of mitochondrial membrane potential and cytochrome c releases. This was accompanied by the increased ROS generation and down-regulated inhibitor of apoptosis (IAPs) such as XIAP and survivin. HP-enhanced apoptosis is completely abrogated by Z-IETD-FMK, caspase8 inhibitor. Furthermore about 37% increased expression of DR5 was observed in cells treated with TRAIL and HP. Although the HP-induced sensitization of apoptosis also shows in another lung cancer cells and cells from different organs, human normal cells remains resistant without any damages from the treatment coupled with HP.
Taken together, these findings suggest that HP as one of the mechanical and physiological stimuli, can act as an adjuvant tool for attractive cancer treatment mediated by TRAIL. Our ongoing studies are evaluating the specific mechanism of anticancer activity via TRAIL and HP using transcriptome and proteome tools and controlling initiation of apoptosis signaling in TRAIL-based cancer therapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A77.