bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4554: Regulation of intracrine androgen synthesis by NF-kappaB2/p52
Authors: Nadiminty Nagalakshmi , Tummala Ramakumar , Chun Jae Yeon , Evans Christopher P. , Gao Allen C. 
Published: June 2012

Abstract
Introduction: Benign prostatic hyperplasia and the initial stages of prostate cancer (CaP) exhibit androgen dependence, but androgen ablation results only in temporary regression of CaP, with progression to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling remains active in CRPC due to aberrant activation of the AR. Synthesis of intracrine androgens has emerged as one of the mechanisms by which AR is activated in CRPC after androgen ablation. Even though levels of androgen biosynthetic enzymes have been shown to be elevated in CRPC, their regulation is not completely understood. In this study, we examined the role of NF-kappaB2/p52 in intracrine androgen synthesis and castration-resistant progression of CaP.
Methods: Expression levels of androgen biosynthetic enzymes were measured in CaP cells with or without expression of NF-kappaB2/p52 using real-time RT-PCR and western blotting. Regulation by NF-kappaB2/p52 was examined using luciferase reporter assays and plasmids containing regulatory elements of androgen biosynthetic enzymes. Intracrine levels of androgens were measured using EIA in tumors obtained from castrated mice.
Results: Expression levels of androgen biosynthetic enzymes including AKR1C3, CYP17A1, HSD3B2, and SRD5A1 were found to be elevated in CaP cells expressing NF-kappaB2/p52. Luciferase assays showed that NF-kappaB2/p52 regulates their expression directly by binding to their promoters and inducing transcription. The levels of total testosterone in CaP cells expressing NF-kappaB2/p52 were approximately 3-fold higher than control cells as measured using EIA. Intraprostatic androgen levels were found to be at 1002 ± 232 pg/g tissue, compared to 377.8 ± 105 pg/g tissue in control tumors obtained by orthotopic implantation of CaP cells expressing NF-kappaB2/p52. These data suggest that CaP cells synthesize detectable levels of testosterone in the absence of exogenous steroid precursors and overexpression of NF-kappaB2/p52 can increase this process, possibly by enhancing the expression of genes encoding steroidogenic enzymes.
Conclusions: Intraprostatic androgen synthesis in recurrent prostate tumors contributes significantly to resistance to androgen ablation and development of CRPC. NF-kappaB2/p52 regulates the expression levels of steroidogenic enzymes and thereby enhances synthesis of intracrine androgens and aberrant activation of the AR. Coupled with our previous studies, these data suggest that antagonizing NF-kappaB2/p52 signaling may prove beneficial in CRPC therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4554. doi:10.1158/1538-7445.AM2011-4554
Abstract 456: 25-Hydroxyvitamin D3 inhibits clonogenic growth and regulates expression of multiple cytokines/chemokines in co-culture of colon cancer and macrophage-like THP-1 cells
Authors: Peng Xinjian , Alimirah Fatouma , Roy Sarbani , Yuan Liang , Murillo Genoveva , Mehta Rajeshwari R. , Mehta Rajendra G. 
Published: June 2012

Abstract
Colon cancer cells interact with immune cells in vivo, creating a microenvironment which affects both tumor growth and treatment. Macrophages are often the most abundant immune cells in the tumor microenvironment and are involved in inflammation. Since inflammation is tightly associated with colon carcinogenesis, it is important to understand how vitamin D affects the interaction between colon epithelial cells and macrophages. In this study, we used a co-culture system to examine the role of 25-hydroxyvitamin D3 (25(OH)D3) on the clonogenic growth of colon cancer cells and on the profiling of cytokines/chemokines. 25(OH)D3 at 250 nM had minor effect on clonogenic growth in CaCo-2 cells, co-culture of macrophage-like THP-1 cells with CaCo-2 cells significantly stimulated the clonogenic growth of CaCo-2 cells in the absence of 25(OH)D3. However, in the presence of 25(OH)D3, THP-1 cells failed to stimulate the the clonogenic growth of CaCo-2 cells. Cytokine antibody array demonstrated that several cytokines were differentially expressed in the medium after co-culture of the two cell lines for 2 days in the absence of 25(OH)D3. These include increased expression of GROα, MCP-1 and decreased expression of TNFα, Angiogenin; however, in the presence of 25(OH)D3, MCP-2 and MDC were significantly induced and TNFα level was restored. Proliferation assay showed that MCP-2 and MDC had minor or no effect on cell proliferation in CaCo-2 cells, suggesting that these chemokines mainly target macrophages. 25(OH)D3 treatment of THP-1 cells for 24h also induced CYP24, an immediate vitamin D target gene and enhanced MDC and MCP-2 expression as evaluated by qRT-PCR. These results demonstrate that 25(OH)D3 at 250 nM might selectively target macrophages in a co-culture system with colon cells and block the interaction between colon cancer cells and macrophages, which may result in prevention of inflammation. [Supported by NCI R01 CA121157].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 456. doi:10.1158/1538-7445.AM2011-456
Abstract 4563: Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma
Authors: Carpenter Erica L. , Haglund Elizabeth A. , Chow Adrian K. , Wood Andrew C. , Belcastro Lili T. , Christensen James G. , Vigny Marc , Maris John M. , Lemmon Mark A. , Mosse Yael P. 
Published: June 2012

Abstract
The purpose of this study was to provide the first pre-clinical evidence for antibody targeting of anaplastic lymphoma kinase (ALK) in human neuroblastoma. ALK is a receptor tyrosine kinase expressed by the majority of neuroblastoma tumors. Germline mutations of ALK, shown to account for most cases of familial neuroblastoma, as well as somatically acquired ALK aberrations, induce increased auto-phosphorylation and constitutive ALK activation and increased downstream signaling. Antibody targeting of receptor tyrosine kinases, as monotherapy or together with small-molecule inhibitors, is highly effective in other cancers such as breast and lung cancer. While antibody-mediated immunotherapy targeting of disialoganglioside GD2 has recently been reported to significantly increase 2-year survival in high-risk neuroblastoma patients, over half the patients receiving this therapy ultimately succumb to their disease and therapeutic alternatives are urgently needed to improve survival rates of this devastating pediatric cancer. Therefore, we hypothesized that antibody targeting of ALK in neuroblastoma was a therapeutically appropriate strategy. To first confirm the potential of anti-ALK antibody-mediated immunotherapy, we used in vitro assays to demonstrate enhanced immune-cell induced cytotoxicity of antibody-treated human neuroblastoma-derived cell lines. We next showed that in vitro antibody treatment of neuroblastoma cell lines expressing activated ALK led to growth inhibition and cell death. These effects were enhanced by treatment with PF-02341066, an orally available small-molecule inhibitor of the ALK tyrosine kinase. To identify the mechanism behind this enhanced combined effect, we used flow cytometry to show that PF-02341066 sensitizes cells to antibody treatment by inducing accumulation of cell-surface ALK, thus increasing the accessibility of antigen for antibody binding. Finally, to further predict in vivo cytotoxic mechanisms of dual ALK targeting, we used flow cytometry to demonstrate enhanced apoptosis and proliferation inhibition resulting from combined antibody and inhibitor treatment as compared to either drug alone. Taken together, these findings provide strong evidence for the therapeutic relevance of antibody targeting of ALK in neuroblastoma and argue for the rapid development and further testing of a clinical grade anti-ALK antibody.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4563. doi:10.1158/1538-7445.AM2011-4563
Abstract 4567: Polyubiquitin K63-related CD137 signalsomes in T cells stimulated with agonist anti-CD137 monoclonal antibodies
Authors: Forero Ivan Martinez , Azpilicueta Arantza , Villan Estanislao Nistal , Palazon Asis , Rouzaut Ana , Aragon Tomas , Dubrot Juan , Murillo Oihana , Hervás-Stubbs Sandra , Melero Ignacio 
Published: June 2012

Abstract
Agonist anti-CD137 monoclonal antibodies are employed to enhance CD8-mediated antitumor immunity both in mouse models and in clinical trials. A panel of agonist anti-human CD137 mAb was prepared recognizing three different epitopes on the CD137 surface glycoprotein. All mAb costimulated T cell activation irrespectively of interference or not with natural ligand-binding. Interestingly, CD137 perturbation with agonist mAb results in internalization towards a vesicular endosomal compartment derived from the plasma membrane. Such internalization was observed on CD137 transfectants in 293 cellsas well as on primary activated T cells from humans and mice. In vivo treatment with anti-CD137 mAb of immunodeficient mice harboring activated human or mouse T cells results in internalization of CD137 to this vesicular compartment. CD137 is known to associate with TRAF2 at the plasma membrane. TRAF-2 is an adaptor protein endowed with E3 ubiquitin ligase activity that synthesizes k63-polyubiquitin chains. K63 polyubiquitin, as opposed to K48 polyubiquitin, constitute a docking site for downtream signaling proteins that lead to NF-kB and AP-1 activation. CD137 vesicles are decorated with k63-polyubiquitin and CD137 stimulation leads to the formation of K63-polyub containing complexes. Therefore CD137 stimulation under therapy like conditions with mAbs leads to the assembly of an intracellular signaling compartment that we term as CD137 -signalsomes
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4567. doi:10.1158/1538-7445.AM2011-4567
Abstract 4568: Anti-tumor effect of an anti-human müllerian inhibiting substance type II receptor antibody in mouse models for ovarian cancer: towards a new targeted therapy
Authors: Kersual Nathalie A. , Garambois Veronique , Salhi Imed , Chardès Thierry , Colombo Pierre Emmanuel , Bascoul-Mollevi Caroline , Cambon-Roques Sylvie , Bibeau Frédéric , Pouget Jean Pierre , Behrens Christian , Gaucher Christine , Urbain Rémy , Prost Jean François , Pèlegrin André , Navarro-Teulon Isabelle 
Published: June 2012

Abstract
Often diagnosed at an advanced stage, ovarian cancer is responsible for the highest mortality rate among patients with gynecologic malignancies. Due to the limitations of the current therapeutic approaches, there is a strong need for novel, more efficient, therapies, among which targeted immunotherapy. The monoclonal antibody 12G4 specifically recognizes the human Müllerian Inhibiting Substance type II Receptor (MISRII). Expressed at high levels on most human Granulosa Cell Tumors (GCT) as well as on a majority of human epithelial ovarian cancer (EOC) cells, MISRII represents a good target for antibody-based tumor targeting.
Characterization of murine antibody 12G4 has been previously reported, in particular epitope mapping and in vitro assays showing that 12G4 binding does not affect MIS interaction with MISRII. In the present study we further assess 12G4 activity in vitro and in vivo. 12G4 was shown to induce 37% and 30% apoptosis in vitro (FACS, DNA fragmentation) on the two MISRII expressing cell lines cov434-MISRII and OVCAR3, respectively. Internalization of the antibody-MISRII complex was also observed in vitro on cov434-MISRII. Using 12G4 antibody we confirmed by immunohistochemistry the expression of the MISRII target in all GTC samples and all but one EOC tissue sections (13/14). Furthermore, we have developed several immunodeficient Nude mouse models of ovarian tumor xenografts expressing human MISRII. In these models the efficacy of 12G4 could be clearly demonstrated with a significant effect on tumor growth.
According to our data, MISRII, expressed on a majority of EOCs appears as a good target for ovarian cancer immunotherapy. Furthermore, based on the good efficacy observed in vivo for 12G4, the development of a humanized anti-MISRII antibody, derived from 12G4, has been initiated and represents a new promising targeted therapeutic approach.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4568. doi:10.1158/1538-7445.AM2011-4568
Abstract 4569: Cell death-inducing ICAM-1 antibody has broad and potent anti-myeloma activity in vivo
Authors: Veitonmaki Niina , Hansson Markus , Li Zhan-chun , Ljungars Anne , Danielsson Lena , Bjorn Frendeus 
Published: June 2012

Abstract
We previously developed combined target and drug discovery methodology enabling isolation of tumor cell death-inducing antibodies from the human antibody library n-CoDeR®. Among several antibodies targeting different tumor cell associated receptors with documented cell death-inducing properties, antibodies specific for intercellular adhesion molecule-1 (ICAM-1) – a receptor not previously associated with tumor cell death- were obtained.
We here characterize the ICAM-1 specific antibody BI-505 with respect to in vivo anti-tumor activity in different well-established tumor disease models, and explore mechanisms underlying its anti-tumor activity. We demonstrate in different tumor xenograft models that BI-505 is equally or more efficacious in preventing CD20 positive B cell tumor growth and in pro-longing tumor-bearing mouse survival compared to CD20 mAb Rituximab in vivo. Moreover, BI-505 showed significant anti-tumor activity against a panel of CD20 negative myeloma tumors in vivo, and BI-505 conferred enhanced mouse survival compared to the proteasome inhibitor bortesomib – approved for treatment of relapsed refractory multiple myeloma – in an experimental model of advanced multiple myeloma. Preliminary data indicate that the BI-505 epitope is highly expressed on myeloma cells in patients with multiple myeloma.
The differential in vitro and in vivo anti-tumor activities of BI-505 Fc-variants correlated with binding to recombinant human FcγRIIIa and mouse FcγRIV receptors, respectively. These differences could not be explained by altered antigen-binding properties as all Fc-variants retained near identical EC50 values for binding to recombinant or cell surface expressed ICAM-1 protein. These observations are consistent with cell death and FcγR-dependent anti-tumor immunity being important mechanisms underlying BI-505 therapeutic activity.
Collectively, our results demonstrate proof-of-principle for our human antibody based combined target and drug discovery methodology, and provide a rationale for further pre-clinical and clinical evaluation of BI-505 in the treatment of MM. An open multicenter phase I dose-escalation clinical trial with BI-505 in relapsed/refractory MM has recently started in the United States and Sweden.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4569. doi:10.1158/1538-7445.AM2011-4569
Abstract 4579: CSPG4 monoclonal antibodies inhibit the growth of human malignant mesothelioma
Authors: Zeyana Rivera , Ferrone Soldano , Wang Xinhui , Jube Sandro , Yang Haining , Gaudino Giovanni , Carbone Michele 
Published: June 2012

Abstract
Malignant Mesothelioma (MM) is a very aggressive cancer, resistant to current chemotherapy, with a median survival of 1 year from diagnosis. The membrane bound Chondroitin Sulphate Proteoglycan 4 (CSPG4) is involved in tumor onset and progression, as well as in angiogenesis. Because of high expression on the surface of cancer cells, CSPG4 represents an attractive target for immunotherapy. CSPG4 was detected in 24 out of 40 MM biopsies, with minimal expression on surrounding normal cells. CSPG4 expression in MM cells was induced upon engagement on extracellular matrix components (ECM). Cell attachment and survival was greater to fibronectin than other ECM. Therefore, we aimed at using CSPG4 monoclonal antibodies (mAb) to impair MM growth. CSPG4-specific TP41.2 mAb inhibited MM cell attachment to ECM, the resulting intracellular signaling and cell survival, with a two-fold increase in apoptosis, compared to isotype IgG control treated cells. Moreover, interfering with the function of CSPG4 by TP41.2 significantly reduced MM cell motility, invasiveness and wound healing. CSPG4 is involved also in the maintenance of the transformed phenotype, as assessed by anchorage-independent growth assay. A significant reduction in soft-agar colony size and numbers was observed when MM cells were treated with TP41.2, compared to control cells. Preliminary studies of in vivo tumorigenesis, performed on SCID mice xenografts, reveal that TP41.2 mAb is able to either prevent MM tumor establishment or reduce tumor mass volume. Our results strongly suggest that CSPG4 mAb-based immunotherapy may represent a novel valid approach for the treatment of MM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4579. doi:10.1158/1538-7445.AM2011-4579
Abstract 4580: A novel role for Junctional Adhesion Molecule-A (JAM-A) in tumor proliferation: modulation by a humanized anti-JAM-A monoclonal antibody
Authors: Goetsch Liliane , Haeuw Jean-François , Broussas Matthieu , Wurch Thierry , Beau-Larvor Charlotte , Robert Alain , Bailly Christian , Corvaia Nathalie 
Published: June 2012

Abstract
Biotherapeutic drugs in oncology are generating a great enthusiasm, and tremendous amount of effort is made to identify new targets for the development of new therapeutics. Functional approaches using tumor cells as immunogens have been performed in order to select on the basis of their function, molecules that, targeted by monoclonal antibodies (Mabs), would induce inhibition of cell proliferation both in vitro and in vivo. Using this type of approaches coupled to a target identification plateform, we had identified an antibody, named 6F4 that was inhibiting in vitro and in vivo tumor growth. A proteomic analysis using 6F4-tagged beads coupled to a MS analysis indicated that 6F4 Mab specifically recognized the human junctional adhesion molecule A (JAM-A). These results indicate that the 6F4 anti-JAM-A Mab is able to induce tumor growth inhibition.
Mouse 6F4 Mab was humanized by conventional CDR-grafting methods. Immunogenetic analysis was performed based on IMGT databases and bioinformatic tools. The human frameworks (FRs) used as the acceptors for CDR grafting were chosen using the “best-fit” selection procedure. Engineered variants were designed and genes were chemically synthetized, produced as human IgG4/kappa antibodies and evaluated by ELISA and competition with biotinylated mouse 6F4 Mab. One humanized antibody (IgG4 isotype) was selected, it efficiently and potently bound to JAM-A ECD and inhibited binding of mouse 6F4. Its germinality index is &gt; 95 % (CDRs excluded). Humanized 6F4 was further tested in vitro and in vivo models and showed ability to induce tumor regression in animal models in particular in A431 and DU145 tumor models. These results confirm that JAM-A is a potential novel target in Oncology and demonstrate that a functional approach coupled to proteomic analysis can be successfull to identify new antibody target molecules that lead to promising new antibody-based therapies against cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4580. doi:10.1158/1538-7445.AM2011-4580
Abstract 4582: Characterization of a new antibody that reacts with a tumor-specific variant of CEACAM-5 and CEACAM-6
Authors: Du Xiulian , Kantor Judith , Luka Janos , Stafford Lewis J. , Bristol Andrew 
Published: June 2012

Abstract
Introduction: h16C3 is a humanized monoclonal antibody being developed as a novel biological treatment for several types of solid tumor. By mass spectroscopy identification and target validation research, we determined that h16C3 appears to recognize a variant form of CEACAM-5 and CEACAM-6, molecules with a well-known association to cancer. Here we show the pre-clinical activities of this new mAb which shows great potential as a therapeutic agent to treat solid tumors.
Methods: The 16C3 antibody was selected from hundreds of hybridoma clones generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. In vitro assays and in vivo studies were performed to characterize the potential of h16C3 as a therapeutic modality for solid tumors that express the variant CEACAM antigens.
Results: Here we show that unlike most modalities targeting the CEACAM molecules, h16C3 reacts with variant CEACAM-5/6 expressed specifically by human tumor tissues as follows: 98% of human colorectal tumor tissues, 80% of pancreatic tumor tissues, 76% of lung tumor tissues, 43% of uterus tumor tissues, and 29% of breast tumor tissues stained positively with h16C3. Importantly, h16C3 did not cross-react significantly with normal human tissues, except for occasional, weak binding to certain GI tract tissues, which may indicate a pre-malignant state. We showed further that the h16C3 antibody exhibits cell-specific binding and ADCC activity against human colorectal and pancreatic tumor cells, but not against antigen-negative control tumor cell lines. In vivo, the anti-tumor efficacy of h16C3 was tested using pre-established subcutaneous human tumor xenograft models. The data showed significant anti-tumor action compared to control treated mice, including some complete tumor regressions. The bio-distribution of radiolabeled h16C3 in mice with pre-established human tumors exhibited specific accumulation of h16C3 at the tumor site, with little or no binding or accumulation in several major organ systems.
Conclusions: The pre-clinical studies of h16C3 to date indicate that it has significant, specific anti-tumor potency, and suggest that it may have clinical activity in cancer patients whose tumor expresses the variant CEACAM-5/6 epitope. The therapeutic humanized 16C3 antibody is being developed for testing in a Phase I clinical trial.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4582. doi:10.1158/1538-7445.AM2011-4582