bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 460: The role of Cdc42 in cancer cell perineural invasion
Authors: Chernichenko Natalya , Omelchenko Tatiana , Deborde Sylvie , Bakst Richard , He Shuangba , Chen Chun-Hao , Hall Alan , Wong Richard J. 
Published: August 2012

Abstract
Perineural invasion (PNI) is the ability of cancer cells to invade in, around, and along nerves. PNI is widely recognized as an adverse pathologic feature of many malignancies. Glial-derived neurotrophic factor (GDNF) is secreted by nerve and glial cells, and is important in neural development. We previously showed that GDNF activation of the RET/GFR-alpha tyrosine kinase in cancer cells induces chemotaxis towards nerves and PNI. Cdc42 is a member of the Rho family of G proteins and a key regulator of cell polarity. We demonstrate here that GDNF-mediated activation of RET/GFR-alpha leads to activation of Cdc42 as a mediator of cancer cell chemotaxis and PNI. Exposure of MiaPaCa2 cells to GDNF or dorsal root ganglia (DRG) activates Cdc42. SiRNA inhibition of Cdc42 impairs MiaPaCa2 chemotaxis towards GDNF or DRG in Boyden chamber assays. SiRNA inhibition of RET decreases Cdc42 activity under GDNF stimulation and MiaPaCa2 chemotaxis. To study dynamic interactions between nerves and cancer cells in vitro, we used a DRG and cancer cell co-culture model of PNI in matrigel. Analysis of individual cell trajectories reveals that cell velocity remains unchanged, while directional migration is disrupted with shRNA inhibition of Cdc42. The disruption of directional response impairs the ability of shRNA Cdc42 MiaPaCa2 cells to migrate along neurites, as visualized by time lapse microscopy and measured by area of PNI. MRI imaging of live mice with sciatic nerves injected with shRNA Cdc42 MiaPaCa2 cells reveals significantly diminished length and volume of PNI as compared with injected shRNA control cancer cells when matched for equivalent overall tumor volume. Murine sciatic nerves injected with shRNA Cdc42 MiaPaCa2 cells exhibited preserved hindlimb and hind paw neurologic function, and diminished perineural invasion by histopathologic examination as compared with shRNA control MiaPaCa2. To identify potential activators of Cdc42 in this model, we performed a comprehensive siRNA screen of guanine nucleotide exchange factors (GEFs), identifying specific GEFs which are necessary for MiaPaCa2 migration towards DRG in Boyden chambers. We identified and validated six GEFs (FLJ10521, DOCK9, ARHGEF7, RASGRF1, ARHGEF5, PLEKHG1) that impair chemotaxis without affecting proliferation. These findings provide novel insights into the molecular mechanisms underlying cancer cell perineural invasion. The RET-GEF-Cdc42 axis may be an attractive target for novel therapies that may potentially interrupt perineural invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 460. doi:1538-7445.AM2012-460
Abstract 4603: Optically-guided surgical approach using fluorescence visualization can significantly improve locoregional recurrence and overall survival for early stage oral cancer
Authors: Poh Catherine F.Y. , Anderson Donald W. , Durham J. Scott , Berean Kenneth W. , Williams P. Michele , MacAulay Calum E. , Rosin MIriam P. 
Published: August 2012

Abstract
Recurrence following excision of high-grade dysplasia (HGD, severe dysplasia and carcinoma in situ) or squamous cell carcinoma (SCC) implies that the presence of subclinical changes at the margins is not apparent at surgery, resulting in incomplete excision. Fluorescence visualization (FV) has shown its value in identifying clinically not apparent high-risk oral lesions. The objective of this study is to assess the effectiveness of FV-guided surgery in reducing the loco-regional recurrence and improving overall survival. Method: From September 1st 2004 to August 31, 2009, 264 consecutive patients diagnosed with T1/T2 SCC or HGD were registered at the BC Cancer Agency and treated with surgical excision with intent to cure. Among these, 246 patients (93%; SCC, 132; HGD, 114) had a follow-up period of at least 6 months. Among these patients, 149 had the surgery done under FV guidance (FV group) while the other 97 were treated with conventional surgery procedure (control group). The outcome measurements include pathology-proven local recurrence to severe dysplasia or higher requiring another surgical procedure, regional failure, and death at follow-up. Time to outcome curve was estimated by the Kaplan-Meier method. Results: There is no significant difference between FV and control groups in age, smoking habit, lesion anatomical site, diagnosis, tumor size, and previous cancer history. There were more females in the FV group (51% vs. 33%, P = 0.006). With an average of 40 months follow-up, the FV group shows significantly lower local recurrence (7% vs. 38%), regional failure (6% vs. 23%), and death (5% vs. 20%), and significant longer time to recurrence (P &lt; 0.0001), regional failure (P = 0.0007), and death of disease (P = 0.004). Conclusion: Although they are retrospectively collected from a single centre, the data have strongly demonstrated that the use of FV for surgical margin decision can significantly improve outcomes of the early stage oral cancer. An on-going 5-year multi-centre phase III randomized surgical trial (the COOLS trial), funded by Terry Fox Research Institute, has started to recruit patients and the data will be used to validate the results of this study. (Supported by R01 DE17013 from the National Institute of Dental and Craniofacial Research, CCSRI-20336 from Canadian Cancer Society Research Institute, and TFRI-2009-24 from Terry Fox Research Institute. CFP is currently supported by a Scholar Award from the Michael Smith Foundation for Health Research).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4603. doi:1538-7445.AM2012-4603
Abstract 4613: A role of integrin-associated CD151 in human ovarian cancer
Authors: Jin Hongyan , Hoff John T. , Deng Xinyu , Drapkin Ronny I. , Yang Xiuwei H. 
Published: August 2012

Abstract
Despite being implicated in multiple types of human epithelia-origin cancer, laminin-binding (LB) integrins (e.g., α3α1 and α6β4) have rarely been investigated for their roles in human ovarian tumors. More recently, we and others have shown that CD151, a member of the tetraspanin family, not only forms tight surface complexes with these adhesion receptors, but also mediates the malignancy of human carcinomas largely in a LB integrin-dependent manner. Here we report our studies on the role of CD151 in human ovarian cancer. Initially, we stained human ovarian tumor tissue microarrays with CD151-specific antibody. Our data showed that the majority of ovarian tumors exhibited a reduced expression of CD151 protein, compared to the fallopian tube, implying a putative suppressing role of this tetraspanin in ovarian cancer. With this hint we next evaluated the impact of CD151 ablation on the behaviors and proliferation of cultured human ovarian cancer cells. While CD151 removal had a minimal impact on cell motility or invasion, it markedly enhanced cell proliferation. Also, CD151-deficeint cells appeared to have reduced cell-cell contacts, suggestive of epithelial-mesenchymal transition (EMT)-like changes. However, there was no dramatic difference in the surface expression of E-cadherin protein, according to our FACS analyses. To substantiate these observations, we also injected ovarian cancer cells with or without CD151 knockdown into immuno-deficient nude mice subcutaneously or orthotopically (intra-peritoneal). Results from these ex vivo analyses showed that disruption of CD151 accelerated ovarian tumor growth and production of ascites fluid in mice, further supporting a role of CD151 in ovarian tumor progression. While tumors in the control group had homogenous epithelial-like appearance, those derived from CD151-ablated cells exhibited mucin-related vacuoles and diverse morphologies. Our subsequent DNA array and protein analyses indicated that there was indeed a marked increase in the expression of a mucin family member in CD151-deficient tumor cells. Collectively, these results provide strong evidence that CD151 suppresses human ovarian cancer progression by regulating tumor cell proliferation and extracellular microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4613. doi:1538-7445.AM2012-4613
Abstract 462: Fer protein-tyrosine kinase promotes lung tumor progression and metastases
Authors: Ahn Joseph , Truesdell Peter , Boag Alexander H. , Craig Andrew W.B. 
Published: August 2012

Abstract
FER is a ubiquitously expressed non-receptor protein-tyrosine kinase implicated in regulating cell-cell and cell-matrix interactions, cell growth and migration. Although no activating mutations have been described for FER, recent studies implicate FER as a positive regulator of cancer progression in the prostate and liver. FER is composed of Fer/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR), extended F-BAR (FX), SH2, and kinase domains. FER oligomerization and membrane targeting is conferred by F-BAR/FX domains, while the SH2 domain allows FER recruitment to tyrosine phosphorylated ligands, including activated Epidermal growth factor (EGF) receptor (EGFR). Since gene amplification or gain-of-function mutations in EGFR are frequently observed in non-small cell lung carcinoma (NSCLC), we tested whether FER participates in EGFR-driven NSCLC migration, progression, and metastases. Here we show that FER is expressed in normal lung epithelial cells and at variable levels in NSCLC cell lines. In a panel of NSCLC homogenates we observed 5 out of 12 cases of increased FER expression over normal adjacent tissue. Furthermore, in a tissue microarray containing a range of lung cancer histological types we observed high FER expression in the NSCLC adenocarcinoma subtype and in SCLC. In human lung epithelial carcinoma H1299 cells that overexpress wild-type EGFR, we detected rapid EGF-induced activation of FER, and subsequent phosphorylation of several putative FER substrates including STAT3, Cortactin, and Vav2. To probe the function of FER, we used a lentiviral shRNA system to achieve stable knock-down (KD) of FER in H1299 cells. Compared to control cells, FER KD cells displayed a significant reduction in EGF-induced migration in scrape wound assays. FER KD cells were also defective in frequency and velocity of invasion under an agarose drop containing EGF. Of the putative FER substrates tested, we observed a significant decrease in Vav2 phosphorylation in Fer KD cells. Since Vav2 promotes Rac activation, we compared localization of active, GTP-bound Rac1 in control and FER KD cells treated with EGF. Interestingly, FER promotes localization of GTP-Rac1 to the leading edge of these cells. To test the role of FER in NSCLC progression and metastasis, H1299 vector control and FER KD cells were grown as subcutaneous tumors in immune compromised mice (Rag2-/-γc-/-) for four weeks. Although we observed no significant differences in tumor mass for FER KD cells compared to control, the potential role of FER in metastasis is currently under investigation. Together, this study may implicate FER as a viable new therapeutic target for treatment of EGFR-driven metastasis of lung cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 462. doi:1538-7445.AM2012-462
Abstract 4630: Integrin αVα6 is expressed on multiple solid tumors and is a potential therapeutic target for auristatin-based antibody-drug conjugates
Authors: Ryan Maureen C. , Kostner Heather , Meyer E. Bradley , Sussman Django , Torrey Lindsay , Anderson Martha , Lyon Robert , Meyer Dave , Jonas Mechthild , van Epps Heather , Benjamin Dennis 
Published: August 2012

Abstract
Antibody-drug conjugates (ADCs) are designed to deliver a targeted, potent payload directly to the tumor cell. This targeted cytoxicity can greatly augment the antitumor activity of a naked antibody and reduce the off target toxicity of free drug. Cancers of the head and neck, pancreas, bladder, lung, ovary and breast show frequent expression of integrin α6, suggesting they may be amenable to therapeutic targeting with an anti-integrin β6 ADC. We identified a therapeutic antibody that is optimal for drug delivery by screening a large panel of anti-integrin β6 ADCs on antigen-positive tumor lines. Monoclonal antibody 15H3 showed consistent potency as an ADC on solid tumor cell lines representative of the target indications. The ADC activity of 15H3 was detectable using either monomethyl auristatin E with a protease-cleavable linker (vcMMAE) or monomethyl auristatin F (mcMMAF), which requires antibody degradation. 15H3 was selected as the lead and humanized for in vivo testing. Humanized 15H3 (h15H3) retained all the properties of the mouse parental antibody, including the ability to cross-bind multiple species (human, monkey, rat, and mouse integrin α6). In vitro analysis showed that h15H3-vcMMAE and h15H3-mcMMAF internalize within a few hours and result in antigen-specific cytotoxicity of carcinoma lines. In vivo studies of integrin-α6 positive xenografts demonstrated antitumor activity. Our data suggest that integrin β6 is a promising potential ADC target for antigen-positive solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4630. doi:1538-7445.AM2012-4630
Abstract 4634: Engineered cysteine drug conjugates show potency and improved safety
Authors: Sussman Django , Torrey Lindsay , Westendorf Lori , Miyamoto Jaime B. , Meyer David W. , Lyon Robert , Duniho Steve , Hayes Dawn C. , Anderson Martha , Benjamin Dennis R. 
Published: August 2012

Abstract
Antibody-drug conjugates (ADCs) are emerging as an important therapeutic option for new oncology drugs. In this abstract we present data on engineered cysteine antibodies (EC-mAbs) with an additional unpaired cysteine residue introduced at position 239 on each heavy chain to facilitate more uniform drug loading while interfering with Fc gamma receptor function. With the EC-mAb, we have identified a site that blocks Fc gamma receptor III (CD16) binding and has a number of additional desirable biochemical and biophysical properties. We demonstrate that EC-mAb-drug conjugates, with two drugs per antibody, retain antitumor activity in mouse xenograft experiments and are well tolerated in non-human primates. These data suggest that engineered cysteine antibodies are a potential alternative to conjugation of native cysteines for future ADCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4634. doi:1538-7445.AM2012-4634
Abstract 4635: Development of monoclonal antibodies against the GPCR CXCR4 and the ion channel Hv1 using virus-like particles
Authors: Rucker Joseph , Payne Riley , Mabila Manu , Patel Sonal , Hall Moniquetta , Willis Sharon , Doranz Benjamin J. 
Published: August 2012

Abstract
Antibodies against cancer targets are routinely used for facilitating early detection of disease, for diagnosing and predicting disease severity, and for guiding and monitoring therapeutic treatment. Ten of the 11 FDA-approved cancer therapeutic monoclonal antibodies (MAbs) target membrane proteins, and membrane proteins comprise &gt;30% of existing cancer biomarkers. MAbs that recognize conformation-dependent epitopes on membrane proteins are usually the most valuable type of antibody because they can bind to critical structures of the receptor that can be exploited for its detection or inhibition. However, the development of conformational MAbs against membrane proteins is especially challenging because these proteins require a lipid environment to maintain their native structure, can be difficult to purify, and are usually poorly represented by peptide immunogens. To overcome these limitations, we have developed a novel technology, the ‘Lipoparticle’, which incorporates high concentrations (10-100 fold greater than cells or membrane preparations) of properly folded and oriented membrane proteins onto the surface of virus-like particles (VLPs). Here, we have used Lipoparticles as immunogens to generate monoclonal antibodies against two important membrane protein targets: the GPCR CXCR4, associated with tumor metastasis, and the ion channel Hv1, implicated in B cell activation. Lipoparticles containing each target were used to immunize mice, eliciting sera with strong and specific immunoreactivity. Screening of &gt;900 hybridomas using Lipoparticles resulted in the identification of CXCR4-specific MAbs validated for reactivity against surface expressed antigen by immunofluorescence. Epitope mapping and functional studies demonstrate that each MAb binds a conformational-dependent epitope on the second extracellular loop capable of inhibiting ligand-dependent signaling in vitro. Similar studies are currently ongoing to isolate MAbs against the Hv1 ion channel, with strong sera responses against Hv1 detected in immunized mice. Our data highlight the utility of Lipoparticles for generating MAbs and screening hybridomas to isolate antibodies against challenging cancer membrane protein targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4635. doi:1538-7445.AM2012-4635
Abstract 4638: Suppression of tumorigenicity by targeting anterior gradient-2 (AGR2) through multiple epitopes binding of the monoclonal antibody 18A4
Authors: Li Dawei , Wu Zhenghua , Zhu Qi 
Published: August 2012

Abstract
Monoclonal antibody is playing an increasingly important role in the treatment of cancer. Specifically, secreted proteins and cell surface receptors that promote tumor growth and metastasis are emerging as important targets for antibody-based anti-cancer therapy. Recent discoveries reveal that Anterior Gradient-2(AGR2), a secreted signal molecule, is over-expressed in a series of adenocarcinoma cancer types and promotes cell growth and migration in vitro and in vivo that can be blocked by polyclonal antibodies. Thus, AGR2 might be a promising target for antibody-based anti-cancer therapy. Here, with a newly developed monoclonal antibody, we report evidence supporting the feasibility of antibody-based therapy against AGR2 as the target. Our study established a unique AGR2-blocking monoclonal antibody 18A4 which requires the co-existence of separate AGR2 epitopes and regions for efficient antibody-antigen binding. This monoclonal antibody against AGR2 can specifically inhibit the AGR2-induced growth and migration of several lines of tumor cells in vitro. Xenograft experiments showed marked repression of tumor growth by 18A4 treatment in nude mice. These results further validated the anti-AGR2 strategy in cancer therapy. In addition, our results suggest, at least in some cases, the necessity of using large regions or whole protein, not short peptides, in developing therapeutic antibodies against certain antigens.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4638. doi:1538-7445.AM2012-4638
Abstract 4646: Toward engineering of novel anticancer bio-agents
Authors: SHAH GOPITKUMAR R. , Wesener Shane , Cheng Yi-Qiang 
Published: August 2012

Abstract
Our research goal is to engineer the next generation of novel anticancer bio-agents that will target and eradicate a broad spectrum of solid tumors including breast cancer. Our research design was based on the hypotheses that (1) the next generation of bio-agents could be engineered to continuously produce doses of an anticancer drug (e.g. FK228 or tryprostatin) at the sites of bacterial spore germination and vegetative growth in the hypoxic/necrotic regions of solid tumors, and (2) the synergistic actions of bacterial consumption of tumor mass and anticancer drug activities could destroy many kinds of solid tumors regardless of cancer genotype, without the need for prodrug injections and could overcome the common side effects and less efficacy of current cancer therapies. Our research focuses on biosynthetic pathways of FK228 and tryprostatins. FK228 is an anticancer drug approved by FDA in 2009 in the name of Istodax® and acts as a potent histone deacetylase (HDAC) inhibitor. Tryprostatins are natural products of Aspergillus fumigatus BM939, with reported bioactivity as potent inhibitor of mammalian cell cycle and as an inhibitor of breast cancer resistance protein (BCRP). The specific aims of the project are (1) reconstitution of FK228 or tryprostatin biosynthetic pathways; (2) integration and expression of FK228 or tryprostatin biosynthetic genes in anaerobic/facultative anaerobic bacteria; (3) evaluation of antitumor efficacy of recombinant bacteria using animal model. In pilot experiments, we have succeeded in reconstituting the FK228 and tryprostatin biosynthetic gene cluster individually into E. coli using plasmid expression system and the engineered E. coli strains were able to express the genes and produced FK228 or tryprostatin under both aerobic and anaerobic fermentation conditions. Integration of the gene clusters into anaerobic/facultative anaerobic bacterial genome is in process. Successful integration and stable expression of anticancer compounds by bacteria would generate a new class of anticancer bio-agents that can target and eradicate solid tumors irrespective of genotypes. Project scheme:
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4646. doi:1538-7445.AM2012-4646