bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C95: Role of 5-alpha reductase inhibitor in regulating ETS transcription factors in prostate cell lines
Authors: Ateeq Bushra , Vellaichamy Adaikkalam , Chiannaiyan Arul M. , Varambally Sooryanarayana 
Published: June 2012

Abstract
Androgens play a crucial role in normal and cancerous growth and hence the androgenic pathway has become an important target of therapeutic intervention. We have discovered the gene fusions of the 5′-untranslated region (UTR) of androgen regulated gene TMPRSS2 (21q22.3) with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4 (17q21), in the majority of prostate cancers. This provides a mechanism for over-expression of ETS genes leading to tumor progression. Dutasteride (Avodart®) is a 5-alpha-reductase inhibitor that blocks the synthesis of the intracellular androgen dihydrotestosterone (DHT).
Here we tested the effect of dutasteride on TMPRSS2-ERG fusion positive VCaP cells. Our data showed 5-alpha-reductase SRD5A1 and SRD5A3 isoenzymes are highly expressed in metastases as compared to benign and prostate cancer cases. On the contrary, SRD5A2 is highly expressed in benign and prostate cancer cases. We found dutasteride treated VCaP cells at 10 and 50uM concentration showed a significant decrease in cell proliferation along with distinct morphological changes. Cells treated with synthetic androgen R1881, testosterone or DHT showed a drastic increase in invading cells, while dutasteride at 50uM concentration showed a significant decrease in cell invasion alone or in combination with testosterone or DHT.
VCaP cells grown under androgen deprivation or treated with 10uM dutasteride showed reduction in ERG and PSA expression. Conversely, cells treated with testosterone or DHT resulted in a marked induction of PSA and ERG as anticipated, while in cells pre-treated with dutasteride, there was a further decrease in the ERG and PSA expression. Addition of testosterone to cells treated with dutasteride slightly increased the ERG expression. Our data clearly suggest that inhibition of 5-alpha reductase by dutasteride significantly reduces the fusion gene expression.
We further tested our hypothesis in an in vivo VCaP-luciferase xenograft model. We found bicalutamide alone showed a decrease in tumor volume in VCaP-Luc xenografts, whereas the combination of dutasteride and bicalutamide reduced tumor burden significantly. Our findings provide insights into the function of dutasteride within the tumor microenvironment, potentially allowing for development of therapeutics that can be used in combination with this drug to further enhance its effectiveness in ETS positive prostate cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C95.
Abstract C99: Panitumumab conjugated gold nanoparticles induce hyperthermic cytotoxicity in pancreatic carcinoma cell lines after noninvasive radiofrequency field exposure
Authors: Glazer Evan S. , Curley Steven A. 
Published: June 2012

Abstract
Introduction: Many cancer cells that highly express epidermal growth factor receptor-1 (EGFR-1) have been demonstrated to endocytose antibody specific targeted nanoparticles such as cetuximab conjugated gold nanoparticles. These gold nanoparticles are subsequently delivered throughout the cell. When gold nanoparticles are exposed to near infrared laser (NIR) radiation or non-invasive radiofrequency fields, they heat in a concentration dependent manner. Radiofrequency (RF) fields are advantageous because they easily penetrate through body tissues without injury. We investigated the effects of a clinically available EGFR-1 antibody, panitumumab, conjugated to gold nanoparticles in noninvasive RF fields.
Methods: Solid gold nanoparticles (10 nm) were covalently linked to panitumumab, a monoclonal antibody against EGFR-1. Two pancreatic carcinoma cell lines, Panc-1 and Capan-1, were treated with 200 nM panitumumab linked gold nanoparticles in media for four hours. After replacing the media with fresh media not containing the antibody linked gold nanoparticles, the cells were exposed to an RF field at a generator power of 600W for a total of 3 minutes. The media temperature was kept below 42°C in order to prevent non-specific apoptosis. Viability and apoptosis were evaluated with flow cytometry three days later. Statistical analysis was performed with the Student's t-test and uncertainties represent standard errors of the mean.
Results: The viability of control cells not treated with the conjugate remained greater than 90% for both cell lines. The antibody-nanoparticle conjugate alone decreased the viability of Panc-1 cells to 81.0% ± 1.1%. However, after RF field exposure, the viability decreased to 57.2% ± 7.9% (p &lt; 0.03). After antibody-conjugate treatment, Capan-1 cells viability was 89.5% ± 3.9%. After RF field exposure, however, the viability decreased to 67.8% ± 3.8% (p &lt;0.03).
Conclusions: The susceptibility of pancreatic carcinoma cell lines to gold nanoparticle mediated noninvasive RF field hyperthermic therapy may be related to the combined effects of monoclonal antibody treatment and intracellular hyperthermia. Based on this simple model, it appears that there is a relationship between EGFR-1 expression, cytotoxicity associated with monoclonal antibody therapy, and hyperthermic cytotoxicity after RF field exposure. Combined rational therapy utilizing non-invasive RF fields may provide for opportunities where traditional radiotherapy has failed and NIR therapy is not readily possible due to tumor location deep within a body cavity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C99.
Abstract PR-5: Signal pathway profiling of cancer cell lines derived from serially passaged human tumorgrafts for guiding drug development
Authors: Yang Feng , Li Yue , Aggarwal Amit , Manro Jason , Li Shuyu Dan , Donoho Greg , Kelter Gerhard , Beckers Thomas , Fiebig Heinz-Herbert , Yingling Jonathan M. , Tucker-Kellogg Greg , Stancato Louis 
Published: June 2012

Abstract
Effective chemotherapeutic treatment of cancer is stymied by a lack of understanding of tumorigenic pathway defects in individual tumors. Combining large scale measurement technologies with appropriate informatics and statistical approaches is a promising approach to detect such aberrations in signaling pathways and provide rationale(s) for driving the choice of targeted chemotherapies. We have attempted to address these by generating a high resolution understanding of pathway defects in 30 solid tumor cell lines, which were established directly from patient-derived xenografts representing 13 histologies. We simultaneously interrogated ∼100 unique protein signaling events using reverse phase protein arrays (RPPA), along with profiling the same cell lines on Affymetrix expression and Agilent CGH platforms. An in silico validation of the RPPA data was conducted by a) clustering analysis that revealed lineage-independent pathway perturbations, b) combining it with baseline genomic and expression data that elucidated and confirmed several underlying genomic defect(s) associated with protein-level changes, c) studying similarity of protein-protein correlations and KEGG cancer pathways that showed high concordance between the two. We developed signaling cascade maps that estimate tumorigenic pathway activation level for individual samples, which can then be used to propose an appropriate therapeutic intervention. Using proliferation assay data from several known targeted agents, we confirmed our observations and ascertained patterns of protein expression that predict for chemosensitivity. In summary, we propose that the methods described here represent a novel approach to analysis of gene/pathway changes associated with tumorigenesis and will be useful in building models of cancer cell protein circuitry applicable to the development of both drugs and patient stratification biomarkers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PR-5.
Abstract A105: A small RNA interference screen of genes involved in DNA repair identifies genes mediating radiosensitivity in glioblastoma.
Authors: Tandle Anita T. , Shankavaram Uma , Tofilon Philip J. , Caplen Natasha , Camphausen Kevin 
Published: June 2012

Abstract
Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in the USA. Standard treatment for primary GBM includes surgical resection, followed by concurrent chemotherapy and radiotherapy (RT). As a result of the major role RT plays in the treatment of GBM, there is much interest in identifying the determinants of radiosensitivity to improve the efficacy of clinically tolerable radiation doses. Also, presence of GBM stem cells within tumor makes it remarkably resistant to current radio- and chemotherapies. Here we have studied DNA repair genes as a determinant of radiosensitivity in GBM.
Materials and Methods: We performed a small interfering RNA (siRNA) screen of 206 genes involved in DNA damage repair to identify genes whose knockdown can increase tumor sensitivity to RT. siRNA screens were performed in two different GBM tumor cells; U251 and U87-MG and in one GBM stem cell line, GBAM1. At 72 hrs, after transfection, cells were irradiated for 24 hrs. As a marker of DNA damage and repair, γH2AX activity was analyzed by ELISA after 24 hrs in unirradiated and irradiated cells.
Results: We identified several genes which upon downregulation increased radiosenstiivity of GBM tumor cells. The various genes includes DNA double strand break repair genes, genes involved in translesion DNA synthesis and DNA damage signaling genes. Nevertheless, we observed differences between GBM tumor cells and stem cells. In tumor cells, some of the radiosensitizer genes were BRCA2, PHB, PTCH, SMC5, ERCC5 and POL G. On the other hand, GBM stem cells showed radiosensitization with downregulation of RFC1, UBE2A, RPA1 RAD54L, XPA, FANCL and TOP2A genes. There was one gene common between GBM tumor cells and stem cells, REV1L. Rev1-like protein is as a scaffold that recruits DNA polymerases involved in translesion DNA synthesis (TLS) of damaged DNA. This is an ongoing study. We are further validating role of some of these targets in both tumor cells and stem cells.
Conclusions: We observed inherent differences in radiosensitivity between GBM tumor cells and stem cells. Identification of tumor cell specific and stem cell specific targets may help us in determining better treatment options for GBM.
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 A105.
Abstract A11: Antitumor activity of targeted and cytotoxic agents in xenograft models correlates with clinical response: A pharmacokinetic-pharmacodynamic analysis.
Authors: Wong Harvey , Choo Edna F. , Alicke Bruno , Ding Xiao , La Hank , McNamara Erin , Thiel Frank-Peter , Tibbitts Jay , Friedman Lori S. , Hop Cornelis ECA , Gould Stephen E. 
Published: June 2012

Abstract
Immunodeficient mice transplanted subcutaneously with human tumors (xenografts) are a widely used model of preclinical efficacy in the discovery and development of anti-cancer agents. We performed a retrospective population pharmacokinetic-pharmacodynamic (PK-PD) analysis of xenograft efficacy data that accounts for differences in clinical and preclinical drug exposure in order to improve their predictive value. In addition, we investigated the ability of xenograft studies to predict clinical response with newer molecular targeted agents. Data from preclinical and clinical studies with three cytotoxic chemotherapeutic agents (docetaxel, carboplatin, and 5-fluorouracil) and five molecular targeted agents (erlotinib, sunitnib, dasatinib, trastuzumab, and vismodegib) were included in this analysis. Anti-cancer agents were administered at a range of doses to xenograft mice bearing tumors relevant to the cancer of interest. No correlation was observed when comparing clinical response to % tumor growth inhibition (%TGI) at the maximum tolerated dose (MTD) in mice. PK-PD modeling was used to simulate %TGI in xenografts using human exposures at clinically relevant doses. These simulated %TGI in xenografts driven by human drug exposures were found to correlate (r=0.92; p=0.0005) with clinical response, illustrating the importance of taking into account species differences in drug exposure when interpreting xenograft data. Distinct differences were observed in the anti-tumor activity of sunitinib in Colo205 colorectal (simulated %TGI = 64%) and 786-O renal cell adenocarcinoma (simulated %TGI = 81%) xenografts, and vismodegib in medulloblastoma allografts (simulated %TGI =102%) and D5123 colorectal xenografts (simulated %TGI = 33%). These differences were consistent with the underlying biology of these models and demonstrate the importance of understanding tumor biology when selecting relevant xenograft models for molecular targeted agents. Based on these analyzes, agents that lead to greater than 60% tumor growth inhibition in preclinical models at clinically relevant exposures are more likely to lead to responses in the clinic.
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 A11.
Abstract A149: Quantitative detection of the EGFR activating and resistance mutations in plasma DNA of lung cancer patients.
Authors: Taniguchi Kazuya , Uchida Junji , Yoji Kukita , Nishino Kazumi , Kumagai Toru , Akazawa Yuki , Okuyama Takako , Okami Jiro , Higashiyama Masahiko , Imamura Fumio , Kato Kikuya 
Published: June 2012

Abstract
EGFR-TKIs are effective therapeutic agents for EGFR-mutation-positive lung cancer patients, but most patients develop resistance to EGFR-TKIs. A secondary EGFR T790M mutation is reported to correlate with acquired resistance and accounts for about half of the resistance cases.
Circulating tumor DNA (ctDNA) is a promising target for monitoring T790M mutations in non-invasive cancer diagnostics and evaluations, although detection of rare mutation alleles is technically demanding. BEAMing (beads, emulsion, amplification, magnetics) is currently the most sensitive technique which can quantitate the mutated allele. With the technique, we can detect one mutated allele in 10,000 normal alleles.
Activating mutations were identified from plasma DNA in 72% (31/43). The T790M mutation was identified in 43% (10/23) of the patients with progressive disease during EGFR-TKI treatment. The T790M mutation appeared in 13–94% of alleles with activating mutations.
Judging from this incidence, BEAMing could detect T790M in the majority of eligible cases. The major advantage over other techniques is the ability to calculate the fraction of T790M-positive alleles in cancer cells, irrespective of normal cell DNA contamination.
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 A149.
Abstract A156: GA201 (RG7160) pretreatments and combination therapies improve efficacy without negatively affecting antitumoral ADCC.
Authors: Nicolini Valeria , Herter Sylvia , Lang Sabine , Walhauer Inja , van Puijenbroek Erwin , Dunn Claire , Umana Pablo , Gerdes Christian A. 
Published: June 2012

Abstract
GA201 is a humanized and glycoengineered IgG1 antibody which targets EGFR with boosted antibody dependent cell cytotoxicity (ADCC) in phase 2 clinical trials.
Pretreatment with corticosteroids and/or anti-histaminics are of normal practice for monoclonal antibody therapy to prevent potential infusion reactions. GA201 follows a premedication regimen of anti-histaminics and hydrocortisone. Due to the dual GA201 mode of action, evaluation on the impact of these drugs on ADCC is critical and was previously assessed preclinically for potential negative impacts on immune effector cells and their capacity to mediate tumor cell killing.
Combination phase II studies with GA201 + chemotherapy regimens are currently under investigation in NSCLC as first-line treatment (chemotherapy selection based on histology Cisplatin + gemcitabine for squamous and cisplatin + pemetrexed for non squamous) and in CRC as second-line treatment (FOLFIRI for KRAS-mutant CRC or cetuximab + FOLFIRI for KRAS-wildtype CRC). These combinations and others where tested prior use in the clinics to evaluate preclinical efficacy and their impact on the immune effectors in vitro, and in vivo.
Chemotherapy combos showed additive or synergistc effect in anti-tumor efficacy as assessed in orthotopic xenograft models and all pre-medications and chemotherapies tested showed no negative impact on ADCC supporting their combination with GA201 in the clinics.
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 A156.
Abstract A163: A role for epigenetic reprogramming in retinoblastoma tumorigenesis.
Authors: Benavente Claudia A. , Dyer Michael A. 
Published: June 2012

Abstract
Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of the RB1 gene. In addition to its role in tumor initiation, loss of the RB1 gene has been shown to induce genome instability, thus promoting tumor progression. In an attempt to identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. However, the overall mutational rate was very low, with RB1 being the only known cancer gene mutated. We then evaluated RB1's role in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. Since RB1 has been implicated in regulating major epigenetic processes, including miRNA regulation, DNA methylation, and histone modification, we hypothesized that RB1 inactivation may contribute to the rate of retinoblastoma tumorigenesis through non-genetic mechanisms that deregulate tumor suppressor and oncogenic pathways. We performed sister chromatid cohesion, kinetochore structure, and spectral karyotype analyzes, and evaluated double strand break repair using comet assay, γ-H2AX and TP53BP1 foci immunostaining, and found that the human retinoblastoma genome is stable. Nonetheless, chromatin immunoprecipitation (ChIP-on-chip) and DNA methylation analyzes pointed that multiple cancer pathways are epigenetically deregulated in human retinoblastoma. For example, the proto-oncogene spleen tyrosine kinase (SYK) is epigenetically upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, RB1 inactivation may allow preneoplastic cells to acquire multiple hallmarks of cancer through epigenetic mechanisms, resulting directly or indirectly from RB1 loss. These data provide novel targets for chemotherapeutic interventions of retinoblastoma.
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 A163.
Abstract A179: Structural and biochemical analysis of ERBB4 mutations in cancer.
Authors: Kurppa Kari , Denessiouk Konstantin , Johnson Mark S. , Elenius Klaus 
Published: June 2012

Abstract
Genes encoding the ErbB receptor tyrosine kinases (EGFR/ERBB1, ERBB2, ERBB3, and ERBB4) are key regulators of cellular proliferation, survival, and differentiation, and thus represent potent proto-oncogenes. In particular, mutations or copy number variations of EGFR or ERBB2 are present in human malignancies and serve as biomarkers for targeted therapies. Recently, somatic mutations of the ERBB4 gene have been identified in various cancer types, such as non-small cell lung cancer and melanoma, indicating a role for mutated ERBB4 as a potential drug target. However, the structural and functional consequences of the ERBB4 mutations remain to be fully elucidated.
We used both a structural as well as a biochemical approach to address the functional effects of the ERBB4 mutations for ErbB4 signaling. A 3D model of the active ErbB4 dimer was generated and the effects of the mutations were modeled in both active and inactive ErbB4 conformation. The biochemical effects of the mutations on ErbB4 signaling were analyzed in vitro using assays measuring the kinase activity of ErbB4 as well as activation of downstream signaling pathways.
Although all structural subdomains of ERBB4 have been reported to be affected by somatic mutations, our analyzes indicated that the mutations cluster to regions important for activation of the receptor, such as the dimerization interface and the kinase domain active site. Some of the mutations were structurally non-hazardous and probably represent passenger mutations. Consistently, the biochemical analyzes indicated for the presence of both functionally non-significant and activating mutations.
These observations suggest for the presence of both driver as well as passenger mutations of ERBB4 in human cancer.
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 A179.
Abstract A244: Characterization of a novel potent and selective CDK4/6 inhibitor and a resistance mechanism.
Authors: Dai Kang , Li Cong , Liang Lingming , Rong Minqing , Orf Jessica , Keegan Kathy , Li Zhihong , Fu Jiasheng , Ma Ji , Carlson Timothy , McGee Larry , Medina Julio , Kamb Alexander , Wickramasinghe Dineli 
Published: June 2012

Abstract
CDK4 and CDK6 are two highly related cyclin D-dependent cell cycle regulatory kinases. CDK4/6 activity promotes G1 to S phase transition by phosphorylating the retinoblastoma (Rb) tumor suppressor protein. Here, we report the characterization of a potent, selective and orally-available small molecule inhibitor of CDK4/6 for treating Rb-positive cancer. The inhibitor was over 1000-fold more potent in inhibiting CDK4 than CDK1. It also showed Rb-dependent anti-proliferative activity both in cancer cell lines and in xenograft tumor models. A greater degree of variation in sensitivity to the inhibitor was observed in colon cancer cell lines compared to the other cell lines tested. To understand this difference in sensitivity, we isolated CDK4/6 inhibitor-resistant colon cancer cells by growing sensitive cells in the presence of the inhibitor. Gene expression in the parental and the resistant cells was analyzed and compared. Cyclin E1, a CDK2 cyclin, was found to be the most significantly overexpressed gene in the resistant cells. Consistent with this, CDK2-associated cyclin E1 protein and CDK2 kinase activity were also significantly increased in the cells. These results suggest that high expression of cyclin E1 may make tumors less sensitive to CDK4/6 inhibition and could be a potential sensitivity marker for patient selection for treatment with a CDK4/6 inhibitor.
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 A244.