bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3626: Targeting of essential gene products in breast cancer with cell penetrating neutralizing antibodies
Authors: Agnes Richard S. , Wang Jing , Basilion James P. 
Published: June 2012

Abstract
We present a novel nuclear, targeted therapeutic strategy that disrupts intracellular essential gene products selectively in tumors. Therapeutic antibodies against external cell surface receptors are effective. However, the limited permeability of antibodies through cellular and nuclear membranes restricts their use as therapeutics for targeting intracellular gene products of cancer cells. Many of the oldest and most efficacious cancer chemotherapeutic agents target cellular elements essential to the growth and proliferation of all cells (e.g. DNA with alkylating agents or dihydrofolate reductase with methotrexate) accentuating the utility of targeting essential gene products. However, the toxicity of traditional broad-based drugs to normal cells is high, limiting its utility. Thus, we seek to inactivate essential gene products by selectively delivering targeted biologic therapeutics, i.e. neutralizing monoclonal antibodies, against specific intracellular essential gene products thereby killing cancer cells. To selectively target tumors, we are employing tumor-associated protease “activatable” cell penetrating peptide (CPP) motif described by Tsein and co-workers. To demonstrate our novel approach, we are initially focusing on the intracellular delivery of RPA70 which is an essential gene product that functions in DNA replication and is found to be an attractive therapeutic target in breast and prostate cancers. Thus far, we synthesized a cell penetrating peptide (CPP) and a tumor-associated “activatable” CPP that can be conjugated to IgGs. We screened various bioconjugation techniques and found that thiolation of IgG with thiolane followed by incubation with CPP-maleimide was the most efficient with good CPP-to-antibody ratio. With these antibody bioconjugates, we are able to show that anti-RPA70 and control antibodies were taken up to the cytoplasm as well as into the nucleus of cells. Monitoring of cell growth and proliferation of cancer cell lines in the presence of CPP-anti-RPA70 are underway. Progress in these studies will also be presented.
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 3626. doi:10.1158/1538-7445.AM2011-3626
Abstract 3641: Breaking through the ceiling: A program to significantly increase efficacy in KRAS and BRAF mutant colorectal cancer xenograft tumors whose growth is arrested by Cetuximab + irinotecan therapy
Authors: Corcoran Erik , Pennello Anthony , Surguladze David , Paz Keren , Tonra James 
Published: June 2012

Abstract
Cetuximab has significant clinical benefits alone or in combination with irinotecan in metastatic colorectal cancer (mCRC) patients with KRAS wild type tumors, but efficacy in patients with KRAS mutant tumors has thus far been elusive. Mutant BRAF in mCRC tumors may also predict for reduced benefit with EGFR antibodies. Interestingly, in preclinical CRC models, cetuximab, alone or in combination with irinotecan, has significant efficacy in tumor models with mutant KRAS or BRAF. Here we examine if this preclinical efficacy can be significantly increased in a screen for add-on therapies that may provide clinically meaningful efficacy in mCRC patients requiring an EGFR antibody.
HT-29 (BRAF mutant-V600E) and HCT-116 (KRAS mutant-G38D) cell lines were utilized as models of CRC. We screened 14 compounds that could potentially add to the effects of cetuximab+irinotecan (C+I) treatment, including inhibitors of inflammation, enzymes, receptor tyrosine kinases, HSP90, cyclins, mTOR, an ATP mimetic, activators of apoptosis and PPARγ.
Of the compounds evaluated only 17-AAG (HSP90 inhibitor), everolimus(mTOR inhibitor) and DC101 (antibody targeting murine VEGFR2) significantly broke the ceiling of tumor stasis established with C+I treatment alone in both models. 17-AAG+C+I resulted in T/C% values of 14 and 32% in HCT-116 and HT-29, respectively, compared to 25 and 62% in the C+I treatment group. Follow up studies showed this benefit to be due to an additive interaction between 17-AAG and irinotecan, which was also associated with significant weight loss. Everolimus+C+I treatment resulted in a T/C% of 15 and 22% in HCT-116 and HT-29, respectively, compared to 22 and 35% in the C+I treatment group. The benefits of everolimus+C+I on the other hand required all three agents. The combination of DC101+C+I was significantly more efficacious than C+I in both models, with a T/C% of 11 and 33% in HCT-116 and HT-29, respectively, compared to 19 and 53% in C+I treatment group. In contrast to these three therapies, all other compounds evaluated did not improve the antitumor effects of C+I alone.
Results demonstrate a ceiling effect in CRC models with KRAS or BRAF gene mutations that may be associated with the limited clinical benefits observed with cetuximab in patients. The fact that this ceiling can be broken with everolimus in a manner that requires cetuximab, supports the potential utility of cetuximab in these patients in a combination 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 3641. doi:10.1158/1538-7445.AM2011-3641
Abstract 3657: Upregulation of PD-1 and Tim-3 expression on tumor antigen-specific CD4+ T cells is associated with reversible T cell dysfunction in patients with advanced melanoma
Authors: Fourcade Julien , Sun Zhaojun , Guillaume Philippe , Luescher Immanuel F. , Sander Cindy , Kirkwood John M. , Kuchroo Vijay , Zarour Hassane M. 
Published: June 2012

Abstract
The paradoxical coexistence of spontaneous tumor antigen-specific immune T cell responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction and exhaustion. We have previously observed in patients with advanced melanoma that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1-specific CD8+ T cells that upregulate PD-1 expression and that a fraction of PD-1+ NY-ESO-1-specific CD8+ T cells upregulates Tim-3 expression. We have found that Tim-3+PD-1+ NY-ESO-1-specific CD8+ T cells represent highly dysfunctional T cells in terms of cytokine production and proliferation. Importantly, Tim-3/Tim-3L blockade together with PD-1/PD-L1 blockade enhanced cytokine production and proliferation of NY-ESO-1-specific CD8+ T cells upon prolonged antigen stimulation. Whether the upregulation of PD-1 and Tim-3 is associated with tumor antigen-specific CD4+ T cell dysfunction/exhaustion in patients with advanced melanoma remains unknown. Here, our findings show that in contrast to EBV-specific, CMV-specific and total CD4+ T cells, PD-1 and Tim-3 expression is upregulated by NY-ESO-1-specific CD4+ T cells isolated from peripheral blood lymphocytes of patients with advanced melanoma. Interestingly, PD-1/PD-L1 blockade synergized with Tim-3/Tim-3L pathway blockade to restore the numbers of cytokine-producing and proliferating NY-ESO-1-specific CD4+ T cells. Collectively, our findings support the use of Tim-3/Tim-3L blockade in association with PD-1/PD-L1 blockade to reverse tumor-induced CD8+ and CD4+ T cell exhaustion/dysfunction in patients with advanced melanoma. Our findings have significant implication in terms of novel immunotherapeutic strategies aiming at promoting T cell-mediated tumor regression in patients with advanced cancers.
This work was supported by NIH/NCI Grants CA90360 and CA112198 (HMZ) and Cancer Research Institute grant (HMZ).
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 3657. doi:10.1158/1538-7445.AM2011-3657
Abstract 3661: The impact of tumor-infiltrating natural killer cells on ovarian cancer progression
Authors: El-gazzar Ahmed , Eckelhart Eva , Perco Paul , Horvat Reinhard , Sexl Veronika , Krainer Michael 
Published: June 2012

Abstract
Cancers adopt diverse strategies to safeguard their survival by evading tumor surveillance. Natural killer (NK) cells and CD8 T-lymphocytes are capable of destroying tumor cells thus playing a critical role in tumor immunity. In previous studies, we showed that NK cell derived TRAIL is essential for the cytotoxic activity of the DR5 agonistic antibody AD5-10, since depletion of NK cells abolished the antitumor activity of AD5-10 in a xenograft ovarian cancer (OC) mouse model. In the present study, we investigated whether NK cells are associated with clinical outcome as well as with the immune infiltrate showing anti-tumor immunity in OC. We analyzed NK cell infiltration in human primary ovarian tumor tissues using immunohistochemical analysis of a representative population of OC patients on a tissue microarray. NK tumor-infiltrating cells were detected within tumor tissues, whereas CD3 tumor-infiltrating T-lymphocytes were almost undetectable. NK cells in addition inversely correlated with FIGO stage (r=−0.51, p&lt;0.001) and tumor grade (r=−0.3, p=0.03). These data indicate that the presence of intratumoral NK cells correlates with improved clinical outcome in OC.
When we analyzed the cytotoxic capacity of human NK cells against OC cells in vitro, we found that human NK cells were capable to induce apoptosis in a concentration-and time-dependent manner in several OC cell lines. Interestingly, the addition of the DR5 agonistic antibody AD5-10 sensitized TRAIL resistant OC cell lines to NK cells mediated cytolysis.
To study tumor surveillance of OC in vivo, we are currently setting up mouse models. Transformed murine ovarian surface epithelial (MOSE) cell lines derived from C57BL/6 mice have been implanted intraperitoneally into syngenic wild type, RAG2 -/-, RAG2 -/- γ -/-, NK depleted, CD8 depleted C57BL/6 recipient mice. The outcome of these studies will be presented.
In summary, our findings point at a critical role for NK cell mediated tumor surveillance for OC development. Importantly, NK cell infiltration correlates with prognosis in human ovarian carcinoma. Thus, our study may open novel therapeutic opportunities by interfering with host immunity in the future.
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 3661. doi:10.1158/1538-7445.AM2011-3661
Abstract 3662: Absence of leukotriene B4 receptor-1 (BLT1) protects against lung cancer
Authors: Satpathy Shuchismita R. , Krishnan Elangovan , Sharma Rajesh K. , Jala Venkatakrishna R. , McGregor W. Glenn , Bodduluri Haribabu 
Published: June 2012

Abstract
Chemokines direct leukocyte trafficking, which plays a major role in immune and inflammatory responses, thus contributing to (or) modulating a number of disease conditions. During carcinogenesis leukocytes infiltrate the site of the tumor microenvironment and could exert a major influence on promotion or suppression of cancer depending on their activation status. Leukotriene B4, a pro-inflammatory lipid chemokine, mediates many of its activities through BLT1, a high affinity G-protein coupled receptor. BLT1 is expressed on an array of immune cells and has been implicated to play a critical role in many inflammatory diseases. We investigated whether BLT1 also influences lung carcinogenesis, the leading cause of cancer-related deaths worldwide. In this study, we used BLT1-deficient mice (BLT1-/-) to determine their susceptibility to lung cancer development in a transgenic model expressing an oncogenic form of K-ras (K-ras LA1) as well as in carcinogen (3-Methylcholanthrene; 3MCA)-induced and inflammation (butylated hydroxy toluene; BHT) – promoted murine lung cancer model. We found that in the activated K-ras transgenic background the BLT1-/- mice showed fewer and smaller lung tumors as compared to the BLT1+/+ mice. In the MCA-BHT induced lung cancer model also the BLT1-/- mice showed fewer and smaller lung tumors than the BLT1+/+ mice. Lung lesions in BLT1-/- mice were more of adenomatous hyperplasia type and fewer adenomas when compared to those in BLT1+/+ mice. Moreover, the frequency of induced mutations in cells derived from the lungs of BLT1-/- mice was greatly reduced compared to BLT1+/+ mice. Pulmonary inflammation was assessed in bronchoalveolar lavage (BAL) fluids following one, three or six weekly injections of BHT. At one and three week time points macrophages, and at six weeks lymphocytes constituted the predominant leukocyte subtypes in the BAL fluids of BLT1+/+ mice. In BLT1-/- mice both of these responses were significantly attenuated leading to an overall reduction in pulmonary inflammation. Based on these results, we conclude that BLT1 mediated pulmonary inflammation has a promoting role in lung cancer.
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 3662. doi:10.1158/1538-7445.AM2011-3662
Abstract 3667: Reduction of in vivo tumor growth and angiogenesis by a humanized IgG4 monoclonal antibody to SEMA4D
Authors: Jonason Alan S. , Fisher Terrence L. , Torno Sebold , Bussler Holm , Winter Laurie A. , Kirk Renee , Howell Alan , Caplan Jeff , Kenney Patrick , Reilly Christine , Scrivens Maria , Huang He , Croy Leslie , Evans Elizabeth E. , Paris Mark , Watkins Raymond , Zauderer Maurice , Leonard John E. , Smith Ernest S. 
Published: June 2012

Abstract
Semaphorin 4D (SEMA4D; CD100) has been implicated in several key mechanisms of tumor progression, including neovascularization, tumor invasion, and metastasis. SEMA4D binding to its receptor plexin-B1 (PLXNB1) on endothelial cells transactivates MET and promotes formation of new blood vessels and tumor growth in vivo. SEMA4D is over-expressed in a wide array of tumor types, and is also produced by recruited inflammatory cells present in the tumor microenvironment. Several recent papers have shown that in an environment lacking SEMA4D, the ability of mouse cancer cells to originate tumor masses and metastases is severely impaired. Furthermore, SEMA4D produced by tumor-associated macrophages has been shown to support tumor angiogenesis and growth.
In addition to its effects on endothelial cells, SEMA4D has a direct effect on tumor invasive growth and migration. A recent clinical study in soft tissue sarcomas correlates strong SEMA4D expression in tumors with a higher mitotic count and poor prognosis. SEMA4D binding to PLXNB1 on tumor cells results in MET transactivation and migration of tumor cells. It has been further reported that overexpression of PLXNB1 and MET in breast and ovarian cancers is a negative prognostic factor. Tumors co-expressing PLXNB1 and MET were characterized as having a higher grade and an increased frequency of metastases.
Collectively, these results suggest that expression of SEMA4D, either by tumor cells or by tumor associated inflammatory cells, functions as a crucial factor in tumor neovascularization, and that expression of the SEMA4D and/ or its high affinity receptor in tumors may further induce tumor growth rate and metastatic potential.
Antibody neutralization of SEMA4D thus may represent a new therapeutic strategy for cancer treatment. We selected a humanized IgG4 antibody that binds with high affinity to rat, mouse, primate, and human SEMA4D, and utilized several in vitro functional assays to demonstrate that this antibody blocks SEMA4D – PLXNB1 interactions. Using syngeneic, xenograft and orthotopic tumor models we demonstrated that antibody mediated neutralization of SEMA4D in vivo inhibits tumor growth and tumor angiogenesis. This humanized antibody has successfully completed IND-enabling toxicology testing and we anticipate the initiation of human clinical trials in early 2011.
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 3667. doi:10.1158/1538-7445.AM2011-3667
Abstract 368: MUC1-targeted gold nanoparticle-based theranostic approach
Authors: Danysh Brian P. , Constantinou Pamela E. , Lukianova-Hleb Ekaterina , Broaddus Russell , Carson Daniel D. 
Published: June 2012

Abstract
MUC1 is a large transmembrane glycoprotein, extending 200-400 nm from the apical surface of normal polarized epithelial cells in a variety of mucosal tissues. The large ectodomain contains a series of heavily glycosylated tandem repeats and serves as a protective barrier to enzymatic degradation and microbial attack, as well as prevents embryo attachment during the non-receptive phase in the uterus. Many cancers, including endometrial carcinomas, overexpress MUC1 which is believed to promote tumor progression by protecting tumor cells from the immune system, inhibiting apoptosis, and increasing resistance to various chemotherapeutic agents. The availability of MUC1 glycoform-specific antibodies creates an opportunity to exploit the increased or aberrant MUC1 expression in carcinoma cells by creating MUC1-targeted therapies. Gold nanoparticles (AuNPs) conjugated to a human MUC1 ectodomain specific antibody (214D4) are readily endocytosed by MUC1 expressing human endometrial cells (HES) in vitro and, following exposure to a short laser pulse, can be used to form transient vapor bubbles (plasmonic nanobubbles) capable of destroying a cell by mechanically disrupting the cell membrane. In this work, we compare the selective targeting capabilities of MUC1-targeted AuNPs using the human endometrial epithelial cell line HES and endometrial carcinoma cell lines HEC1A and HEC1B. In addition, we have used human MUC1-expressing transgenic mouse lines to examine the feasibility of using AuNP-214D4 targeting in mouse endometrium. These results demonstrate the potential use of MUC1-targetted AuNPs to detect and destroy, as well as deliver cargo, to MUC1 expressing tumors. (Supported by NIH grants HD29963 to DDC, and MD Anderson Gynecologic SPORE for Uterine Cancers 2 P50 CA098258-06 to DDC and RB).
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 368. doi:10.1158/1538-7445.AM2011-368
Abstract 3685: C-Jun modulates alcohol-induced RNA Pol III-dependent transcription through Brf1 and TBP pathway
Authors: Zhang Qingsong , Evans Austin G. , Levy Daniel , Zhong Shuping 
Published: June 2012

Abstract
Cancer cells have a consistent cytological feature of nucleolar hypertrophy, enlarged nucleoli, where RNA polymerase III genes (Pol III genes) are transcripted. This implies that transformation in situ is closely linked to the deregulation of Pol III gene transcription, because the size of the nucleolus reflects the levels of rRNA synthesis. Deregulation of Pol III genes is tightly associated cell transformation and tumorgenesis. However, very little is known about whether alcohol consumption affects Pol III gene transcription. By using cell culture model and animal model, we have found, for the first time that alcohol induces Pol III gene transcription in JNK1 and ADH dependent manner. Alcohol increases c-Jun expression in HepG2-ADH cells. To determine whether the alcohol-mediated increases c-jun required to stimulate TBP and Brf1 expression are due to enhance occupancy of c-jun at their promoters, chromatin immunoprecipitation (ChIP) assays were performed. Ethanol induces a marked increase in the recruitment of c-jun to the TBP promoter, while a modest increase in the occupancy of both c-fos and Elk-1 was observed. These results support the idea that alcohol mediates an increase in TBP expression primarily through enhanced expression of c-jun and its recruitment to the TBP promoter. Sequence analysis reveals both putative AP-1 and Elk-1 binding sites in regions 5’ of the transcription start site of the Brf1 gene. ChIP analysis reveals that ethanol induces an increase in the occupancy of c-jun to the region containing an AP-1 binding site, while no significant increase in binding of Elk-1 to the Elk-1 binding site is observed. Interestingly, c-jun, c-fos and Elk-1 are also found to occupy the tRNALeu gene. Upon ethanol treatment, an increase in TBP recruitment to the tRNALeu gene is observed, as well as a marked increase in the occupancy of c-jun. However, alcohol does not induce any apparent change in recruitment of either c-fos or Elk-1 to the tRNA gene. These results suggest that c-jun may function directly at sequences near tRNA genes to induce transcription. Together, these results support the idea that alcohol enhances expression of TBP, Brf1, and tRNA gene by facilitating c-jun recruitment to these promoters.
*: This project was supported by NIH grant AA017288 to S.Z.
**: Corresponding author: szhong@usc.edu. Tel: 626-628-7693 or 323-442-114
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 3685. doi:10.1158/1538-7445.AM2011-3685