bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C3: Selective denuding of nanoparticles for tumor targeting
Authors: Berlin Jacob M. 
Published: June 2012

Abstract
Targeted delivery of therapeutics to tumors is highly desired both to deliver fragile compounds that cannot reach the tumor on their own and to limit off-target toxicity. Nanovectors, nanoparticles capable of transporting and delivering one or more bioactive molecules, are an emerging class of targeted drug delivery platforms. Targeting of nanovectors to tumors is conventionally achieved both by designing them to be approximately 50–200 nm in diameter in order to take advantage of the enhanced permeation and retention (EPR) effect common to tumors and/or functionalizing the nanovectors with ligands that bind specifically in the tumor environment. In order for these strategies to be successful, the nanovectors must have an extended circulation time in the blood. One result of this is accumulation and prolonged retention of many nanovectors in the liver and spleen, which raises toxicity concerns. Here we demonstrate a dramatically different strategy making use of nanovectors composed of insoluble ultrasmall nanoparticles cores functionalized with responsive solubilizing polymer shells. The responsive polymers are designed to be cleaved from the insoluble nanoparticles core in the tumor microenvironment, which results in the deposition of the insoluble nanoparticles at the tumor site. On the other hand, because the particles are ultrasmall, if they remain unchanged they are rapidly cleared from the body, dramatically reducing potential side effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C3.
Abstract C33: N-terminal fragment of Bit1 apoptotic protein induces autophagy in tumor cells
Authors: Chen Renwei , Braun Gary B. , Luo Xiuquan , Sugahara Kazuki N. , Teesalu Tambet , Ruoslahti Erkki 
Published: June 2012

Abstract
Bit1 is a proapoptotic mitochondrial protein associated with anoikis, cell death resulting from the loss of cell attachment to extracellular matrix. Upon cell detachment, Bit1 is released into the cytoplasm, where it complexes with the Groucho family protein amino-terminal enhancer of split, and triggers cell death through a caspase-independent pathway. Bit1 consists of 179 amino acids; the N-terminal 62 amino acid mitochondrial localization domain, a transmembrane domain, and the C-terminal peptidyl-tRNA hydrolase domain. In the present study, we localized the Bit1 cell death domain (BCDD) to the N-terminal 62 amino acids of Bit1 by introducing truncated Bit1 proteins into the cytoplasm with cDNAtransfection and protein transduction. BCDD was more potent than the full-length Bit1 protein, when equivalent amounts of cDNA was transfected. Treatment of cultured prostate and breast cancer cells with recombinant proteins in which BCDD was fused with two cell-internalizing peptides, one of which is tumor specific, also caused cell death. Bit1 and BCDD shared the characteristics previously attributed to Bit1-induced cell death. In addition, we found that the cells exhibited the signs of autophagy. These results define the cell death domain in Bit1 and reveal autophagy as the main mechanism of Bit1-induced cell death. Tumor-targeted exogenous BCDD may have potential as an anticancer agent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C33.
Abstract C4: Inhalational chemotherapy for malignant gliomas
Authors: Chen Thomas C. , Hofman Florence H. , Cho Heeyon , Wang Weijun 
Published: June 2012

Abstract
Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer, based on its mechanism of action as a ras inhibitor and a cell cycle inhibitor. Unfortunately, it had significant gastrointestinal side effects, and was never well received as an oral anticancer agent. Recently, POH has been administered intranasally in a Phase I/II trial for the treatment of recurrent malignant gliomas in Brazil. It is well tolerated when delivered intranasally, with a 50% progression free survival (PFS) of 6 months in patients with recurrent GBM, with radiographic reduction in size in some patients. Similar efficacy compared to bevacizumab (Avastin; Genentech) was obtained in recurrent GBM patients treated with intranasal POH alone. We have recently synthesized a pharmaceutical grade of POH with &gt;98% purity. Synthesized POH inhibits vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and transforming growth factor-beta 2 (TGF-B2). Cytotoxicity, as measured by colony formation assay (CFA), demonstrated a IC50 of 0.5 mM. We have since conjugated POH to a number of different pharmaceutical agents, including temozolomide (TMZ). Data on these conjugates demonstrate increased cytotoxic activity compared to individual drugs alone or in combination. TMZ-POH is much more potent than POH alone (IC50 10–30 uM), and is effective in TMZ resistant glioma cells, inhibits glioma cancer stem cells, and is not toxic to normal astrocytes. Our goal is to use our synthesized POH and TMZ-POH in upcoming Phase I/II trials for recurrent malignant gliomas. Further definition of the perillyl alcohol derivatives will lead to a pipeline of new compounds which will enable further expansion of the intranasal delivery repertoire. Animal models demonstrating efficacy of intranasal delivery of POH and TMZ-POH is currently underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C4.
Abstract C45: Inhibition of antiapoptotic BCL2 members facilitates interferon regulatory factor-1 (IRF1) mediated prodeath signaling in breast cancer cells
Authors: Schwartz Jessica L. , Hu Rong , Shajahan Ayesha N. , Clarke Robert 
Published: June 2012

Abstract
Antiestrogens (AEs) have long been a standard treatment for estrogen receptor-positive (ER+) breast cancer patients. However, antiestrogen resistance, either de novo or acquired, is a major hurdle for effective therapy in breast cancer patients. To address this, the underlying mechanisms of antiestrogen resistance must be understood. Antiestrogens are known to induce apoptosis in sensitive breast cancer cells. The tumor suppressor gene interferon regulatory factor-1 (IRF1) plays a key role in signaling to proapoptotic BH3 only BCL2 (B-cell lymphoma 2) family members (i.e., BIK, PUMA, and BMF). In an attempt to understand IRF1-mediated signaling in AE sensitivity, AE-sensitive and -resistant breast cancer cells were made to overexpress IRF1 or a dominant negative IRF1 (dnIRF1; lacks the transactivation domain of IRF1 but retains the DNA-binding domain). We found that IRF1 regulates the transcription of proapoptotic BIK, BMF, and PUMA, which are necessary to induce apoptosis in AE-sensitive cells. Conversely, AE-resistant breast cancer cells have low IRF1 expression and increased levels of antiapoptotic BCL2 and BCLW. Previous work by our group showed that the inflammatory cytokine IFNγ can be used to induce IRF1 expression in AE-resistant cells, and restores the responsiveness of these cells to fulvestrant (Faslodex; ICI 182,780) through BH3-mediated apoptosis, suggesting a key role of IRF1 in endocrine-resistant breast cancer. We also discovered that the pan BCL2 inhibitor GX15-070 (obatoclax) significantly reduces cell proliferation and, in combination with fulvestrant or tamoxifen, results in a synergistic inhibition of cell growth in AE-resistant breast cancer cells. Treatment with obatoclax in AE-resistant cells results in a reduction in Beclin1 (BECN1) protein levels with a corresponding increase in cleaved caspase-7, indicating a possible role of autophagy and apoptosis in GX15-070-induced cell death. Moreover, overexpression of BECN1 in AE-resistant cells enhances obatoclax-mediated cell death. Collectively, our data demonstrate that a combination of obatoclax and an antiestrogen increases the levels of free BH3 domain proteins, thus facilitating mitochondrial dysfunction, and rendering breast cancer cells more susceptible to tumor cell death by IRF1-mediated signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C45.
Abstract C46: ErbB-1 and ErbB-2 overexpression in canine mammary cancer and their role as targets in comparative oncology
Authors: Weichselbaumer Marlene , Singer Josef , Jensen-Jarolim Erika , Stockner Thomas , Mechtcheriakova Diana , Sobanov Yury , Bajna Erika , Wrba Friedrich , Horvat Reinhard , Thalhammer Johann G. , Willmann Michael 
Published: June 2012

Abstract
In human medicine, passive immunotherapy is a well-established tool to fight cancer. Cetuximab and trastuzumab are famous examples of effective monoclonal antibody therapies for the treatment of ErbB-1 (EGFR) overexpressing colon tumors and for ErbB-2 (HER2/neu) overexpressing metastatic breast cancer.
Mammary carcinomas of dogs are the most important cause of tumor-related death in females. It is known that these tumors also express tumor markers similar to human breast cancer and that regarding the idea of comparative oncology cancer in pet dogs are a valuable model for speeding up drug development. Therefore, we aimed to investigate more closely canine ErbB-1 and ErbB-2 and the applicability of cetuximab and trastuzumab in the dog.
Screenings with FDA-approved immunohistochemical diagnostic tests of canine mammary tumor samples showed 3/10 ErbB-1 and 4/10 ErbB-2 overexpression, which seems similar to the expression pattern in human breast cancer patients. Sequence analyses revealed amino acid sequence identities of 91% between human and canine ErbB-1 and 92% for ErbB-2. Modeling of those proteins showed that the human cetuximab epitope differs in only four amino acids compared to the canine counterpart and that the trastuzumab binding site is identical in human and canine ErbB-2 except for only one amino acid. Using flow cytometry analyses cetuximab and trastuzumab binding could be confirmed in four canine mammary carcinoma cell lines. Furthermore, cell viability assays showed that incubation of canine cell lines with both antibodies inhibited tumor cell proliferation, even though there are lower numbers of ErbB molecules on canine than on human cells, which was confirmed by a flow cytometry-based assay.
This comparative oncology study indicates that ErbB-1 and ErbB-2 are highly conserved molecules with significant concordance in terms of structure and expression pattern between human and canine cancer. Importantly, the canine homologous molecules are susceptible to cetuximab and trastuzumab targeting, which may open up new avenues towards antibody-based immunotherapies in companion dogs and improvements in anticancer drug development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C46.
Abstract C58: Heterotetramers of ERBB2 and ERBB3 generate qualitatively distinct signals from heterodimers and provide most of the neuregulin-induced phosphorylation of ERBB2
Authors: Zhang Qian , Park Eisun , Kani Kian , Landgraf Ralf 
Published: June 2012

Abstract
The efficient tyrosine phosphorylation of the orphan ERBB2 (HER2) receptor in heterodimer with the kinase-impaired ERBB3 presents a highly potent source of mitogenic signal. However, it is also a conceptual challenge to our established model of dimer-based signal generation through transphosphorylation. Proposed and mutually not exclusive models for ERBB2 phosphorylation in complex with ERBB3 include autophosphorylation in cis after complex formation and allosteric activation of its kinase domain by ERBB3 in trans, phosphorylation of ERBB2 in trans by the low but detectable kinase activity of ERBB3, or phosphorylation of ERBB2 in proxy. Proxy activation refers to phosphorylation between ERBB2 receptors of activated heterodimers in higher order complexes.
We previously reported that the ligand-induced activation and growth stimulation through ERBB2/ERBB3 can be efficiently inhibited by an aptamer directed against the extracellular portion of ERBB3. Studies of the exact mode of inhibition now reveal that the aptamer neither acts by interfering with ligand binding nor by suppressing heterodimer formation. Combined biochemical studies and homology models identified the binding site of the aptamer and suggest that it interferes with the transition from activated heterodimers to heterotetramers. This inhibits the proxy activation of ERBB2 and associated MAPK activation while heterodimerization, the phosphorylation of ERBB3, and downstream activation of AKT are largely insensitive to inhibition.
The fact that ERBB2 appears to receive most of its tyrosine phosphorylation through a proxy mechanism is consistent with reports of a prevalence of tetramers in the context of EGFR activation. Furthermore, our study demonstrates for the first time that mechanistically definable and dissectible higher order ERBB complexes contribute to signaling in a manner that is qualitatively distinct from the signal that emanates from isolated dimers. This forces us to fundamentally reinterpret approaches to therapeutic intervention that are at present conceptually centered around modulating the formation of dimers but often generate experimental and clinical outcomes that do not readily reconcile with dimer-based models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C58.
Abstract C66: Impacts of ERK signaling on the regulation of antioxidant enzymes and ROS levels in human lung cancer cells exposed to lead acetate
Authors: Yang Jia-Ling , Wang Chun-Yu 
Published: June 2012

Abstract
Lead compounds (Pb) are widespread environmental contaminants that have been evaluated as group 2A carcinogens. Recently, we showed that EGFR activation is an immediate response to Pb as a primary upstream molecule to initiate SFK and PKCα activation, and subsequently links to the Ras→Raf-1→MKK1/2→EKK signaling cascade. Also, activation of this signaling plays a defensive role against Pb genotoxicity. Here, we explore whether Pb disturbs the intracellular levels of antioxidant enzymes and reactive oxygen species (ROS), and whether ERK signaling modulates the oxidative stress elicited by Pb in CL3 human non-small-cell lung adenocarcinoma cells. We found that Pb lowered the protein levels of glutathione peroxidase-1 (GPX1) and catalase, yet it induced superoxide dismutase 2 (SOD2). The phenomena were reverted upon ERK inactivation or depletion. By contrast, forced expression of the MKK1/2→ERK signaling decreased GPX1 and catalase, but enhanced SOD2 protein levels. The activities of GPX1 and catalase, but not SOD2, were declined in Pb-treated cells, and blockage of ERK activation partially rescued the decreased GPX1 activity. On the other hand, Pb elevated intracellular ROS, and ERK inactivation further enhanced its levels. The antioxidant N-acetyl-cysteine markedly prevented the cytotoxicity of Pb during ERK inactivation. These results suggest that ERK activation could mediate in scavenging ROS toxicants following Pb; yet, this signaling also participates in down-regulation of GPX1 and catalase as well as up-regulation of SOD2 at the protein levels, which probably enhances the intracellular H2O2. Thus, ERK exhibits dual and opposing roles in modulating oxidative stress caused by Pb.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C66.
Abstract C70: Integrative analysis of pharmacologic, genomic, and transcriptomic assays in cancer
Authors: Liu Manway , Reddy Anupama , Huang Alan , Caponigro Giordano , Lehar Joseph 
Published: June 2012

Abstract
We describe an integrative analysis approach leveraging the publicly available Cancer Cell Line Encyclopedia to uncover regulatory pathways in cancer. Six different lines of evidence are considered in identifying candidate factors associated with disease: 1) gene mutation status, 2) copy number variations, 3) RNAi growth inhibitions, 4) pharmacological growth inhibitions, 5) baseline gene expression data, and 6) physical protein-protein interactions. As each of these evidence sources measure a different aspect of cellular regulation, they may be considered in combination to uncover regulatory mechanisms associated with tumorigenesis. For example, gene mutation status or copy number variation data may be combined with baseline gene expressions to identify genes that are differentially expressed in cell lines with aberrant or deactivated versions of specific tumor suppressors and oncogenes.
To assess our approach, we applied it to identification of genes involved in the well-known RAS-RAF regulatory signaling pathway in both tissuespecific and nonspecific contexts. The RAS-RAF signaling pathway plays a key role in cellular differentiation and proliferation and is frequently associated with tumorigenesis. Specifically, we identified differentially expressed genes in BRAF mutant vs. wild-type cell lines, genes associated with high and low RAF copy number alteration cell lines, genes correlating in expression to growth inhibition by RAF-targeting compounds, and genes that either rescue or sensitize cell lines to BRAF knockdown by RNA interference. We further considered these genes within the overall context of physical interactions between their protein products. Highlighting the significant, research potential of our approach, our RAF-focused analysis identified both well-known and novel genes, supported by different lines of evidence, that mediate RAS-RAF signaling across multiple tissues. Positive control genes include members of the classical pathway, such as MAPK1, MAP2K1, and PI3K.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C70.
Abstract IA3: Discovery in cancer genomics by next-generation sequencing and data analysis
Authors: Mardis Elaine 
Published: June 2012

Abstract
The combined use of next-generation sequencing and advanced analytical approaches has transformed our view of the cancer genome. Not only has large-scale characterization of the genomes of tumors been informative but we also can produce important companion datasets of expressed RNAs and of methylation sites, and then integrate these data to obtain a fuller picture of tumor biology. Scaling these methods and analyses to investigate hundreds of tumors with shared tissues of origin has enabled an appreciation of the multitude of genes that can be impacted by various forms of alteration from point mutations through gross structural changes, along with a pathways-based understanding of somatic alterations. The availability of extensive clinical data allows correlation of specific alterations to clinical outcomes, response to therapy and other critically important factors that enable the translation of genomic discoveries into clinical practice. My talk will survey the different data-driven approaches currently being applied to tumor:normal pairs, then discuss results from whole genome sequencing and analysis of large numbers of breast tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA3.
Abstract IA4: Normalizing the tumor microenvironment to enhance therapeutic outcome
Authors: Jain Rakesh K. 
Published: June 2012

Abstract
A solid tumor is like an aberrant organ – comprised of cancer cells and a variety of host cells embedded in an extra-cellular matrix – nourished by blood vessels and drained by lymphatic vessels. Using an array of imaging technologies and animal models, we have shown that blood and lymphatic vessels as well as matrix associated with tumors are abnormal and these abnormalities can create a hostile tumor microenvironment (e.g., hypoxia, high interstitial fluid pressure). These abnormalities can fuel tumor progression as well as prevent treatments from reaching and attacking tumor cells. To this end, we proposed that “normalizing” tumor vessels and matrix would allow cancer therapies to penetrate the mass more uniformly and to function more effectively. We then showed first in mice and then in cancer patients that antiangiogenic drugs - originally designed to destroy tumor vessels - could, paradoxically, also “normalize” them, creating a window of opportunity to attack the cancer most effectively. More crucially, the extent of vascular normalization closely associated with the overall survival of patients receiving anti-angiogenic therapy. More recently, we have shown that the drugs approved by the FDA for lowering blood pressure can “normalize” the collagen matrix and improve the delivery of molecular and nanomedicine (3, 4). At this meeting, I will present emerging data on new targets for normalizing the tumor microenvironment and how normalization can potentiate the outcome of tumor vaccine therapy.
References:
1. Jain RK. Normalization of the tumor vasculature: An emerging concept in anti-angiogenic therapy of cancer. Science. 2005;307:58–62.
2. Goel S et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiological Reviews. 2011;91:1071–1121.
3. Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nature Reviews Clinical Oncology. 2010;7:653–64.
4. Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. PNAS. 2011;108:2909–14.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA4.