bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A136: Proteome analysis reveals candidate genes regulated by BLID, a novel drug-inducible apoptotic target, in breast cancer cells.
Authors: Yadavalli Sivaramakrishna , Eidelman Ofer , Srivastava Meera , Kasid Usha N. 
Published: August 2014

Abstract
BLID, BH-3 Like motif containing Inducer of cell Death, is a strong prognostic factor in invasive breast cancer (1). Frequent lack of BLID in breast cancer has been associated with triple-negative breast cancer (TNBC), African American ethnicity and younger women. Significant correlations exist between BLID negative breast cancer and declines in overall survival, local relapse-free survival and distant metastasis-free survival. In dose response and time course studies, BLID expression was found to be induced by chemotherapeutic drugs including doxorubicin, 5-fluorouracil and cisplatin in MCF-7 breast cancer cells. In addition, exogenous expression of BLID cDNA nanocomplex led to significant increase in chemosensitivity in SKBr3 (ER-ve/PR-ve) and MDA-MB231 (TNBC) breast cancer cell lines. Here we have investigated the effects of BLID knockdown on protein expression profiles in representative hormone responsive (MCF-7) and TNBC breast cancer cells (MDA-MB231) with a goal to identify a core translational component signifying BLID activity in breast cancer cells. BLID shRNA lentiviral particles were generated using pLKO.1-TRC containing BLID shRNA clone 47 according to the supplier's manual (Sigma-Aldrich). Breast cancer cells were stably transfected with BLID shRNA or scrambled shRNA. The pooled stable clones were tested for BLID expression by western blot analysis. Significant knockdown of BLID protein was achieved in breast cancer cells transfected with BLID shRNA (% inhibition of BLID expression vs. scrambled shRNA: MCF-7, 69%; MDA-MB231, 63%). The BLID proteome analysis was performed using antibody microarrays as we reported earlier (2). We have observed distinct and overlapping BLID-centric protein profiles in MCF-7 and MDA-MB231 cells. Among the top-ranked genes, BLID knockdown correlated with increased expression of PI3-kinase catalytic subunit α and DEK oncogene in MCF-7 cells, and increased expression of myeloid cell leukemia sequence 1 (MCL-1) in MDA-MB231 cells. Remarkably, BLID depletion correlated with decreased expression of tumor protein p73 and cAMP-dependent protein kinase (PKA Type Iα) in both cell lines. Thus, we have identified a working platform of genes signifying BLID expression in breast cancer cells. Validation of the top-ranked genes in various models of breast cancer is ongoing and data will be presented.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A136.
Citation Format: Sivaramakrishna Yadavalli, Ofer Eidelman, Meera Srivastava, Usha N. Kasid. Proteome analysis reveals candidate genes regulated by BLID, a novel drug-inducible apoptotic target, in breast cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A136.
Abstract A146: Preclinical models relevant to the treatment of post-menopausal breast cancer.
Authors: Pazolli Ermira , Mazzola Anne Marie , Curwen Jon , Weir Hazel , Kiessel Casey , Grondine Michael , D'Cruz Celina , Zinda Mike 
Published: August 2014

Abstract
The past decades have witnessed immense progress in the treatment of hormone-sensitive breast cancer. However, despite the success of agents targeting estrogen activity, a significant proportion of patients will experience relapse due to endocrine therapy resistance. In order to better understand the underlying causes and enable successful targeting of implicated pathways, preclinical models that recapitulate the post-menopausal setting are essential. To this end, we have developed a panel of estrogen receptor (ER+) models with varying senstivity to endocrine therapies. Our panel includes models of long-term estrogen-deprivation (LTED), a surrogate for longterm exposure and relapse on aromatase inhibitors. Using both xenograft (MCF7LTED, HCC1428LTED) and primary tumor models (BR0555fLTED and CTC-174LTED), we have utilized them to benchmark standard of care treatments and test the efficacy of novel agents. Importantly, we demonstrate that these models closely mimick the post-menopausal hormonal millieu found in patients and recapitulate pharmacodynamic responses observed in the clinic. As such, these are instrumental tools to uncovering endocrine resistance mechanisms and provide a potentially predictive platform for clinical efficacy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A146.
Citation Format: Ermira Pazolli, Anne Marie Mazzola, Jon Curwen, Hazel Weir, Casey Kiessel, Michael Grondine, Celina D'Cruz, Mike Zinda. Preclinical models relevant to the treatment of post-menopausal breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A146.
Abstract A151: Identification of antibody fragments specific for high-grade prostatic intraepithelial neoplasia cells via SELEX.
Authors: Hajiran Cyrus J. , Sooter Letha J. 
Published: August 2014

Abstract
The purpose of this study is to develop a minimally invasive molecular tool for the early detection and specific treatment of prostate cancer. A human non-immune single-chain Fragment variable (scFv) library with 10∧9 diversity has been displayed by a yeast host surface with the ability to bind to whole cell targets. This protein library was cloned into plasmids and transformed into the yeast strain Saccharomyces cerevisiae. Surface expression of the scFv library was achieved by expressing the scFv under control of a galactose promoter preceding incubation with the target cell line.
A molecular recognition element (MRE) specific for HGPIN cells will be selected for through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX). From an initial scFv library with 10∧9 diversity, seven rounds of selection will be completed in order to enrich the antibody fragment library that binds only to the prostate cancer cell line HGPIN and not those that bind to normal and cancerous cells of the prostate epithelium. This involves screening a library of random molecules for their ability to bind to a target; non-binding molecules are removed and binding molecules are amplified. Amplified molecules are subjected to negative targets, and molecules that don't bind to these are amplified, thus completing a round of selection. Stringency is increased through each round of selection by shortening the yeast + prostate cell incubation period and decreasing the number of target cells used in incubation. After multiple rounds, one or a few strong binding, highly specific molecules are selected for.
Diversity of the library is decreased with each round of selection. This is followed by amplification of the remaining yeast. Sequencing is performed throughout the selection process in order to monitor both the decrease in diversity and the emergence of the most selective sequences. The obtained MRE will be useful for specific diagnosis in the pre-malignant stages of prostate cancer. It may also be conjugated to drugs for targeted therapeutic applications.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A151.
Citation Format: Cyrus J. Hajiran, Letha J. Sooter. Identification of antibody fragments specific for high-grade prostatic intraepithelial neoplasia cells via SELEX. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A151.
Abstract A155: The Rac and PAK inhibitor EHop-016 inhibits mammary tumor growth and metastasis in a nude mouse model.
Authors: Castillo-Pichardo Linette , Humphries-Bickley Tessa , Hernandez Eliud , de la Parra Columba , Cubano Luis , Vlaar Cornelis , Dharmawardhane Flanagan Surangani F. 
Published: August 2014

Abstract
The Rho GTPase Rac is a central regulator of cancer cell migration/invasion that has been implicated with cancer metastasis. Therefore, we designed and developed small molecule compounds that specifically target Rac in metastatic cancer cells. We recently reported the characterization of EHop-016 as a Rac inhibitor in metastatic cancer cells, where EHop-016 was shown to inhibit Rac activity with an IC50 of 1 μM. At higher concentrations (&gt;10 μM) EHop-016 reduced cell viability and inhibited the related Rho GTPase Cdc42, but not Rho. EHop-016 decreased the activation of Rac by the oncogenic guanine nucleotide exchange factor Vav, the activity of the Rac effector p21-activated kinase (PAK), and the extension of actin cytoskeletal structures and migration of metastatic cancer cells. Next, we determined the efficacy of EHop-016 in vivo, using a mouse model of experimental metastasis. Green fluorescent protein (GFP) tagged MDA-MB-435 human metastatic cancer cells were inoculated at the mammary fat pad of nude mice and treated with 0, 5, 10, 25, or 40 mg/kg body weight (BW) EHop-016 3X a week for ∼8 weeks. Mammary tumor growth and metastases in lungs, spleens, kidneys, livers, hearts, and femurs were quantified by fluorescence image analysis. At concentrations &gt;10 mg/kg BW, EHop-016 significantly inhibited mammary tumor growth and metastasis to distant organs. EHop-016 had no effect on mouse weight or their gross phenotype, indicating that EHop-016 did not exert toxic effects in athymic nude mice. This data demonstrate that EHop-016 and derivatives hold promise for further development as targeted anti-cancer therapeutics.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A155.
Citation Format: Linette Castillo-Pichardo, Tessa Humphries-Bickley, Eliud Hernandez, Columba de la Parra, Luis Cubano, Cornelis Vlaar, Surangani F. Dharmawardhane Flanagan. The Rac and PAK inhibitor EHop-016 inhibits mammary tumor growth and metastasis in a nude mouse model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A155.
Abstract A157: Metastatic PDX modeling displays correlation between CTC and metastatic potential, both inhibited by chemotherapy.
Authors: Jiang Jiahua , Wang Daisy D. , Yang Mengmeng , Chen Dawei , Guo Sheng , Cai Jie , Li Linda , Wery Jean-Pierre , Lin Peter Ping , Li Henry 
Published: August 2014

Abstract
Gastric carcinoma is a common cancer of high mortality and is particularly prevalent in East Asia. There are only a few treatment options: surgery, chemotherapy, as well as Herceptin® for a small subset of patients with erbb2 amplification. Metastasis usually renders surgery ineffective. Drug therapy becomes only meaningful option. One of the keys to a successful search for effective treatment is development of experimental model that truly mimics patient conditions. Patient derived xenograft (PDX or HuPrime®) is believed to be among the best mimicking human diseases (1). Recently, we have established a cohort of ∼70 gastric cancers from Asian and Caucasian patients. This report describes that two of them (GA0046, GA0087), while established as subcutaneous xenografts, were confirmed to metastasize to lung at high frequency (100% for GA0087). GA0087 is a neuroendocrine cancer of gastric origin. Its high metastasis potential, as measured by counting the colony nudules in lung of subcutaneous tumor bearing mice, suggests that it would be a useful experimental model for studying cancer metastasis and exploring inhibitory agents. The observed metastasis is particularly significant since metastasis is rarely occurin subcutaneous xenograft. Circulating tumor cells, or CTCs, have been identified in the blood of some cancer patients and believed to be responsible for cancer metastasis (2, 3). We recently developed a new method, based on subtraction enrichment combined with immunofluorescence staining (anti-human cytokeratin 18 and CD45 monoclonal antibodies) and FISH (iFISH), for effective identification and enumeration of CTCs enriched from bloods of patients (4). In this study, we investigated the presence of CTCs in GA0087 metastatic PDX and their potential correlation to metastastic potential. As a result, we, for the first time, detected CTCs in PDX (GA0087), with a range of 1-61 CTCs per 200μL mouse blood. Our preliminary observation seems to also indicate that the CTC frequency is correlated to the numbers of metastasis nodules in lung. Furthermore, a chemotherapy agent can inhibited both CTC and metastasis. Our data seem to confirm the proposed correlation of metastasis and CTC in this first experimental metastasis/CTC PDX model.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A157.
Citation Format: Jiahua Jiang, Daisy D. Wang, Mengmeng Yang, Dawei Chen, Sheng Guo, Jie Cai, Linda Li, Jean-Pierre Wery, Peter Ping Lin, Henry Li. Metastatic PDX modeling displays correlation between CTC and metastatic potential, both inhibited by chemotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A157.
Abstract A178: Epigallocatechin-3-gallate (EGCG) induces catalase-sensitive cell growth inhibition and AKT activation in Burkitt lymphoma cells.
Authors: Van Doorn Carl-Christian , Domina Aaron M. 
Published: August 2014

Abstract
Burkitt lymphoma is an aggressive non-Hodgkin's B cell lymphoma. It is typically treated with high intensity chemotherapy, which is associated with toxicities. Therefore, it is important to develop novel treatments for this disease. Studies have found that the green tea-derived compound, epigallocatechin-3-gallate (EGCG), may be effective in treating Burkitt lymphoma (Nakazato T. et. al., 2005 and Noda C. et. al., 2007). Another study showed that the phosphatidylinositide 3-kinase (PI3K)/AKT pathway is important for Burkitt lymphoma proliferation and survival (Schmizt R. et. al., 2012). Therefore the purpose of this current study is to investigate the connection between EGCG and the PI3K/AKT pathway in Burkitt lymphoma cells. To begin, it was evaluated whether EGCG would induce dose-dependent, catalase-sensitive growth inhibition of the sporadic Burkitt lymphoma cell lines, BL41-3, DG75, and Ramos. These cells were treated with EGCG at varying doses and also in the presence or absence of catalase followed by MTT analysis. EGCG induced a dose-dependent growth inhibition of all three Burkitt lymphoma cell lines and co-treatment with catalase prevented this effect. To determine the effects of EGCG on the PI3K/AKT pathway, BL41-3, DG75, and Ramos, were treated with 0, 20, 40, or 80 μM EGCG followed by Western analysis for phosphorylated AKT and total AKT. The results indicated that AKT phosphorylation is increased in all three cell lines following EGCG treatment. Lastly, it was investigated how inhibition of PI3K during EGCG treatment impacts the anti-proliferative effects seen with EGCG alone. To test this, BL41-3, DG75, and Ramos cells were treated with EGCG and an inhibitor of PI3K, LY294002, followed by MTT analysis. EGCG and LY294002 inhibited Burkitt lymphoma cell growth, although the degree of inhibition and the effect of combination treatment varied between the three cell lines. In conclusion, EGCG induced AKT phosphorylation along with a catalase-sensitive growth inhibition and the addition of a PI3K inhibitor had an additive growth inhibitory effect with EGCG. These results provide novel insight into the use of EGCG for the treatment of sporadic Burkitt lymphomas.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A178.
Citation Format: Carl-Christian Van Doorn, Aaron M. Domina. Epigallocatechin-3-gallate (EGCG) induces catalase-sensitive cell growth inhibition and AKT activation in Burkitt lymphoma cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A178.
Abstract A180: Selective inhibition of K-Ras G12C through allosteric control of GTP affinity and effector interactions.
Authors: Peters Ulf , Ostrem Jonathan M. , Sos Martin L. , Wells James A. , Shokat Kevan M. 
Published: August 2014

Abstract
Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to directly target this oncogene have faced difficulties due to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent upon relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here, we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras G12C. These compounds rely on the mutant cysteine for binding and therefore do not affect the wild type protein (WT). Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras G12C disrupts both switch-I and switch-II, subverting the native nucleotide preference to favor GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a novel allosteric regulatory site on Ras that is targetable in a mutant specific manner.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A180.
Citation Format: Ulf Peters, Jonathan M. Ostrem, Martin L. Sos, James A. Wells, Kevan M. Shokat. Selective inhibition of K-Ras G12C through allosteric control of GTP affinity and effector interactions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A180.
Abstract A189: The combination of NPV-LDE-225 (Erismodegib) and BEZ-235 is superior to single agent alone in inhibiting glioblastoma initiating cell growth in vitro and in vivo.
Authors: Sharma Narinder , Kumar Dhruv , Ma Yiming , Yu Wei , Shankar Sharmila , Srivastava Rakesh K. 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most common form of primary brain tumor and often characterized by poor survival. Glioblastoma initiating cells (GICs) regulate self-renewal, differentiation and tumor initiation properties, and are involved in tumor growth, recurrence, and resistance to conventional treatments. The objectives of this study were to examine the molecular mechanisms by which inhibition of PI3K/mTOR and Sonic hedgehog (Shh) pathways cooperate together to suppress GIC growth in vitro and in vivo. PI3K/mTOR and Shh pathways were inhibited by NPV-LDE-225 (Erismodegib) and BEZ-235, respectively. Cell viability and apoptosis were measured by XTT and annexin/IV-PI assays, respectively. Gli transcriptional activity was measured by luciferase reporter assay. Gene and protein expressions were measured by qRT-PCR and Western blot analyses, respectively. NPV-LDE-225 inhibited Gli1 and Gli2 expression and transcription activity. BEZ-235 inhibited the phosphorylation of PI3K and mTOR. NPV-LDE-225 and BEZ-235 acted in a synergistic manner to inhibit cell viability, neurosphere formation, and Gli transcriptional activity, and to induce apoptosis by activation of caspase-3 and cleavage of PARP. Furthermore, NPV-LDE-225 and BEZ-235 cooperates together to inhibit pluripotency maintaining factors (Nanog, Oct4, Sox-2, and cMyc) and epithelial-mesenchymal transition. Finally, the interactive effects of NPV-LDE-225 and BEZ-235 on GIC tumor growth in nude mice was higher than single agent alone. Our data suggest that the combined inhibition of PI3K/mTOR and smoothened can be used for the treatment of GBM by targeting GICs.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A189.
Citation Format: Narinder Sharma, Dhruv Kumar, Yiming Ma, Wei Yu, Sharmila Shankar, Rakesh K. Srivastava. The combination of NPV-LDE-225 (Erismodegib) and BEZ-235 is superior to single agent alone in inhibiting glioblastoma initiating cell growth in vitro and in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A189.
Abstract A200: Toward quantitative PI3K pathway PD analysis in clinical samples using an automated capillary electrophoresis-immunoassay platform.
Authors: Mccoon Patricia E. , Pablo Lourdes , McEachern Kristen , Foster Emily , Womack Chris , Castriotta Lillian , Brown Jeff , Barrett Carl 
Published: August 2014

Abstract
Here we report results of an independent evaluation of an automated capillary electrophoresis-immunoassay system for its utility in generating quantitative and reproducible pharmacodynamic (PD) biomarker data for the PI3K pathway using clinical specimens. Quantitative measurement of PD biomarkers associated with drug -target engagement in tumor tissue is an increasingly important part of evaluating new cancer therapies in early clinical trials. PD data are currently being used along with safety, pharmacokinetics, and efficacy data to make more informed clinical decisions regarding likelihood of success and progression of drugs into Phase II testing. Despite this increased focus, there are still very few assay platforms that support automated, reproducible and quantitative methods amenable to the small tumor biopsies available for these analyses. The Peggy™ (ProteinSimple) platform provides automated separation of proteins by size or charge and quantitation of analytes over a broad dynamic range from tissue samples using as little as 40 ng protein. Accompanied by the ability to process 96-samples in a single run, this platform is amenable to both pre-clinical and clinical PD determination.
Our initial studies focused on evaluating the feasibility of developing a set of robust, quantitative PD biomarker assays that could be used systematically across our oncology portfolio to monitor the PI3K pathway. Here we present results for a panel of biomarkers associated with the PI3K pathway using cell lines and tumor xenografts in which we measured responses to drug treatments using AKT and mTOR inhibitors. Further, in a set of prospectively collected breast cancer core needle biopsies, we were able to detect baseline levels of these biomarkers. Taken together, these data suggest that this platform will be useful in quantitatively measuring changes in multiple PD biomarkers in a single tumor biopsy. Going forward, we propose to utilize this approach alone or in tandem with other immunoassay formats, such as immunohistochemistry, to provide greater insight into tumor biology and the effects of drug treatment following PI3K -AKT inhibition in the clinic to help inform important clinical decisions.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A200.
Citation Format: Patricia E. Mccoon, Lourdes Pablo, Kristen McEachern, Emily Foster, Chris Womack, Lillian Castriotta, Jeff Brown, Carl Barrett. Toward quantitative PI3K pathway PD analysis in clinical samples using an automated capillary electrophoresis-immunoassay platform. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A200.