bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5005: Androgen-mediated genomic and non-genomic regulation of TRPM8 in prostate cancer
Authors: Asuthkar Swapna , Zakharian Eleonora 
Published: August 2015

Abstract
Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing and Ca2+ permeable channel protein. The TRPM8 mRNA is overexpressed in early prostate tumors with high androgen levels, while anti-androgen therapy greatly reduces its expression. Thus, androgens, which are at the crossroads of several signaling pathways, appear to be associated with TRPM8-mediated Ca2+ -dependent signaling. Genomic regulation; From the chromatin-immunoprecipitation (ChIP) analysis, we observed that an androgen response element (ARE) mediates androgen regulation of trpm8. Although TRPM8 mRNA is expressed at high levels in prostate cancer (PC) cells, we found that the TRPM8 protein undergoes UBA1-mediated ubiquitination and degradation. PYR-41, a potent inhibitor of initial enzyme in the ubiquitination cascade, UBA1 increased TRPM8 activity on the plasma membrane of LNCaP cells. Further, PYR-41-mediated PMTRPM8 activity was accompanied by enhanced activation of p53 and Caspase-9. In addition, we found that the promoter region of trpm8 possesses putative binding sites for p53 and that the overexpression of p53 increased the TRPM8 mRNA levels. Our findings support previous studies that suggest the fine balance between androgen receptor (AR) and p53 expression that regulates androgen-dependent growth of PC. Non-genomic regulation; Furthermore, using immunofluorescence, calcium-imaging and planar lipid bilayers, we identified that TRPM8 channel is functionally associated with androgens in the prostate. Most importantly, we report that testosterone can directly activate TRPM8 channel at low picomolar concentrations and resulted in full openings of the purified TRPM8 channel in planar lipid bilayers. Our data demonstrated that testosterone is an endogenous and highly potent agonist of TRPM8 channel. In light of these observations our data of non-genomic effect of testosterone on PMTRPM8 may support a strategy for targeting the androgen-TRPM8-AR interaction or rescuing PMTRPM8 expression as a new therapeutic application for PC.
Note: This abstract was not presented at the meeting.
Citation Format: Swapna Asuthkar, Eleonora Zakharian. Androgen-mediated genomic and non-genomic regulation of TRPM8 in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5005. doi:10.1158/1538-7445.AM2015-5005
Abstract 5012: Establishment of a transplantable, NY-BR-1 expressing breast cancer model in HLA-transgenic mice
Authors: Das Krishna , Gardyan Adriane , Vormehr Mathias , Mueller-Decker Karin , Zörnig Inka , Jäger Dirk , Osen Wolfram , Eichmüller Stefan B. 
Published: August 2015

Abstract
Introduction: Breast cancer is one of the leading causes of cancer related deaths in women worldwide and current standard therapies show limited efficacy. However, immunotherapeutic approaches like adoptive T cell transfer might represent an attractive option for the treatment of breast carcinoma. The differentiation antigen NY-BR-1 appears as a suitable target for T cell immunotherapy against breast cancer as it is overexpressed in 60% of breast carcinomas compared to healthy breast.
Objectives: The aim of this project is to establish a NY-BR-1-expressing, transplantable tumor model in HLA transgenic mice that would allow to investigate the functional role of NY-BR-1-specific HLA-restricted CD4+ T cells in vivo with respect to their capacity to sustain cytotoxic T lymphocytes (CTL)-mediated tumor attack. Furthermore, the capability of NY-BR-1-specific CD4+ T cells to interact with tumor-associated macrophages (TAMs) thereby potentially promoting differentiation of TAMs into immunostimulatory type-1 macrophages (M1) will be investigated.
Materials and methods: Stable transfectant clones of the C57BL/6 derived lymphoma cell line EL4 and of the mammary adenocarcinoma cell line EO771 expressing NY-BR-1 were established. Furthermore, an H2Db-restricted, NY-BR-1-specific CTL epitope could be identified which upon peptide immunization of C57BL/6 mice resulted in the generation of NY-BR-1 specific, H2Db-restricted CTL lines, similarly to immunization with a rec. NY-BR-1 encoding adenovirus as observed in parallel experiments.
Results and conclusions: Transplanted EL4 and EO771 derived transfectant clones stably expressing NY-BR-1 gave rise to subcutaneous tumors in H2-compatible, HLA-DR4 transgenic mice. In addition, a NY-BR-1-specific CTL line recognizing EL-4/NY-BR-1 expressing transfectants in vitro was successfully generated upon peptide immunization as described above. Studies to investigate the cooperative effect between the aforementioned CTL line and HLA-DR3- and HLA-DR4-restricted NY-BR-1-specifc CD4+ T cell lines, upon joint adoptive transfer into tumor bearing HLA-transgenic mice are currently ongoing. The results presented here demonstrate the first NY-BR-1 expressing mouse tumor model, allowing the investigation of NY-BR-1-specific immune responses in vivo.
Citation Format: Krishna Das, Adriane Gardyan, Mathias Vormehr, Karin Mueller-Decker, Inka Zörnig, Dirk Jäger, Wolfram Osen, Stefan B. Eichmüller. Establishment of a transplantable, NY-BR-1 expressing breast cancer model in HLA-transgenic mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5012. doi:10.1158/1538-7445.AM2015-5012
Abstract 5017: The discovery of novel therapeutics that restore antigen processing pathways in immune-edited metastatic cancers
Authors: Nohara Lilian , Gabathuler Reinhard , Ahn Paul , Cheng Ping , Williams David , Andersen Raymond , Jefferies Wilfred A. 
Published: August 2015

Abstract
Cancer immune-editing resulting in immune escape where Major Histocompatibility Complex I (MHC I) molecules and the endogenous Antigen Processing Pathway (APP) leading to MHC I expression are down regulated, are prevalent in metastatic forms of cancer. In the absence of MHC I, these tumors subvert host immune surveillance mechanisms and are thus resistant to many of the immunotherapies approaches that evoke adaptive immunity to eradicate tumors in humans.
Previously, we showed that by restoring TAP-1 expression in metastatic disease it is possible to restore the APP and the CTL recognition of tumor specific antigen loaded MHC-I molecules in carcinomas. We continued to investigate this mechanism of TAP deficiencies leading to APP defects and were the first to discover that this phenotype is not regulated by defects or mutations in the TAP-1 gene, but it is epigenetically regulated and can be restored by treatment with Histone Deacetylase Inhibitors (HDACi).
Here, we describe a novel mechanism of action of compounds in promoting immune responses against tumors. We have developed a high-throughput screening assay to identify compounds that induce antigen presentation in metastatic prostate and lung carcinomas. We have used this system to screen a pharmacological library made from deep-sea sponge extracts, as it has been found that marine invertebrates are a diverse source of pharmaceutical leads and also of chemical diversity. Our results exploiting this system indicate several extracts isolated from amongst 500 sea sponges result in an increase a significant increase in surface MHC I expression, while at the same time exhibiting low cytotoxicity. The chemical structures of several of the active components of these extracts have been determined and one particularly promising candidate has been synthesized and produced in sufficient quantities to commence animal testing. Initial studies indicate the compound is well tolerated and there is no toxicity in animals at the doses that were studied. Results will be presented regarding the activity of the compound against subcutaneously implanted metastatic tumors.
The work described herein will provide new therapeutic candidates for harnessing the power of the immune system to recognize and destroy metastatic cancers.
Citation Format: Lilian Nohara, Reinhard Gabathuler, Paul Ahn, Ping Cheng, David Williams, Raymond Andersen, Wilfred A. Jefferies. The discovery of novel therapeutics that restore antigen processing pathways in immune-edited metastatic cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5017. doi:10.1158/1538-7445.AM2015-5017
Abstract 5019: Characterization of sentinel node-derived antibodies from breast cancer patients
Authors: Shukla Girja S. , Pero Stephanie C. , Sun Yu-Jing , Carman Chelsea L. , Krag David N. 
Published: August 2015

Abstract
Lymph nodes are one of the important sites in the body where immune responses to antigens are initiated. The tumor-draining lymph node or sentinel node is the first site where cancer cells and cancer-related antigens are most likely to spread. In response to antigen exposure and immune activation, the lymph node B cells undergo clonal expansion and somatic hypermutation, leading to the affinity-matured populations of effector B cells secreting antibodies that bind to the tumor. The cancer-draining node is therefore an ideal source of B cells that produce anticancer antibodies. In the present investigation, we have characterized the antibodies derived from immortalization of sentinel node B cells from 29 breast cancer patients. The antibodies were screened for their isotypes and for binding to breast cancers classified as luminal A, luminal B, HER2, and basal/normal subtypes, based on the expressions of estrogen, progesterone and HER2 receptors. The isotype analysis showed a higher percentages of antibodies belong to IgG (48%) and IgM (34%) isotypes along with a smaller share of IgA (18%). The cell-binding studies were conducted using ELISA, immunofluorescence microscopy, and flow cytometry techniques. Of the studied antibodies, about 28% showed binding to the tumor cells. The comparative studies of antibody-binding to breast tumor cells and non-cancer breast cells identified several antibodies showing differential binding profile. The binding analyses also demonstrated that all of the tumor-binding antibodies belonged to IgM isotype. It is evident from the results that the tumor-reactive antibodies are generated in the sentinel nodes of breast cancer patients; however, the absence of class-switched anti-tumor antibodies in the repertoire raises a possibility of tumor-induced node suppression leading to an inefficient humoral immune response towards tumor antigens. The results are important in assessing the tumor immune response/lymph node suppression, and the possible role of the autoantibodies in diagnosis and therapy of breast cancer.
Citation Format: Girja S. Shukla, Stephanie C. Pero, Yu-Jing Sun, Chelsea L. Carman, David N. Krag. Characterization of sentinel node-derived antibodies from breast cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5019. doi:10.1158/1538-7445.AM2015-5019
Abstract 5024: Implications of MAPK pathway inhibition on monocytes and tumor-associated macrophages in melanoma
Authors: Gremel Gabriela , Girotti Maria Romina , Viros Amaya , Ashton Garry , Bradley Helen , Galvani Elena , Lee Rebecca , Fusi Alberto , Lorigan Paul , Marais Richard 
Published: August 2015

Abstract
Plasticity in T-cell populations during response and onset of resistance to targeted therapy has been well documented. More recently, macrophage-derived tumor necrosis factor has been described to drive resistance to MAPK pathway inhibition, yet little is known on the adaptation of tumor-associated macrophage populations to treatment and disease progression in human melanoma.
To test for alterations in macrophage abundance following resistance to MAPK pathway inhibition, we applied a fluorescence-based co-staining strategy on melanoma specimens, representing tissue collected from patients before treatment and at relapse. In addition, we established in vitro co-culture systems to study the paracrine effects of melanoma cells on various aspects of monocyte differentiation and macrophage activation in the background of MAPK inhibition and resistance.
Resistance to targeted therapy was found to be associated with an increase in the number of tumor-resident macrophages. In vitro co-culture of melanoma cell lines with monocytes isolated from the peripheral blood of healthy donors or with CSF1-differentiated macrophages in the presence or absence of MAPK inhibition led to profound changes in monocyte/macrophage marker expression, indicating a direct interplay between the two cell populations upon MAPK pathway inhibition. Our data show that macrophages play an integral role in the changing immune-microenvironment during the course of MAPK pathway inhibition. Elucidation of mechanisms driving these processes will result in strategies to optimize treatment combinations and consecutive treatment outcomes for melanoma patients.
Note: This abstract was not presented at the meeting.
Citation Format: Gabriela Gremel, Maria Romina Girotti, Amaya Viros, Garry Ashton, Helen Bradley, Elena Galvani, Rebecca Lee, Alberto Fusi, Paul Lorigan, Richard Marais. Implications of MAPK pathway inhibition on monocytes and tumor-associated macrophages in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5024. doi:10.1158/1538-7445.AM2015-5024
Abstract 5025: Immune expression profiling of MAPK inhibitor resistant tumors based upon mechanisms of resistance
Authors: Wilmott James S. , Kakavand Hojabr , Menzies Alexander M. , Vilain Ricardo , Pupo Gulietta M. , Thompson John F. , Kefford Richard F. , Carlino Matteo S. , Rizos Helen , Long Georgina V. , Scolyer Richard A. 
Published: August 2015

Abstract
Purpose: To evaluate the association between the immunoreactivity of the immune inhibitory ligand PD-L1 with tumour infiltrating lymphocytes (TILs) and known mechanisms of MAPK inhibitor (MAPKi) resistance in tumor biopsies resected at the time of MAPKi disease progression.
Experimental Design: 23 patients with disease progression on MAPKi (vemurafenib, dabrafenib, and combination dabrafenib and trametinib) each had a progressing tumor biospied. All tumors underwent MAPKi resistance screening including RNA expression profiling. Morphological features, PD-L1 immunohistochemical immunoreactivity, and RNA expression profile were correlated with mechanisms of resistance (including mutations in NRAS and MEK, and amplification and aberrant splicing of BRAF).
Results: PD-L1 immunoreactivity was significantly higher in tumors that harbored an aberrant BRAF splicing variant (n = 8) or MEK mutations (n = 5) than those with BRAF amplification (n = 4), NRAS mutations (n = 2) or those with unknown resistance mechanisms (n = 4) (mean 27% vs 1%, p = 0.049). Additionally, the PD-L1 immunoreactivity in tumors with known MAPK-reactivating mechanisms (n = 19) tended to be higher than those with unknown resistance mechanisms (n = 4) (mean 17% vs 0%, p = 0.283). The immunoreactivity of PDL1 in progressed lesions was independent of BRAFV600 genotype, RECIST response and type of MAPK inhibitor. Correlations with TIL subsets, RNA expression, and response to subsequent anti-PD-1 therapy are underway.
Conclusions: The induction of PD-L1 immunoreactivity following MAPKi treatment in human melanoma is variable, however specific mechanisms of MAPKi resistance may confer increased expression of the inhibitory ligand. Further study is underway examining the association of the above with TIL infiltration, the RNA expression profile, and the response to subsequent anti-PD1 therapy.
Citation Format: James S. Wilmott, Hojabr Kakavand, Alexander M. Menzies, Ricardo Vilain, Gulietta M. Pupo, John F. Thompson, Richard F. Kefford, Matteo S. Carlino, Helen Rizos, Georgina V. Long, Richard A. Scolyer. Immune expression profiling of MAPK inhibitor resistant tumors based upon mechanisms of resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5025. doi:10.1158/1538-7445.AM2015-5025
Abstract 5028: CXCL10 within the tumor microenvironment induces gemcitabine resistance in pancreatic cancer cells
Authors: Delitto Daniel , Perez Chelsey , Black Brian S. , Sorenson Heather L. , Knowlton Andrea E. , Han Song , Zhang Dongyu , Sarosi George A. , Moldawer Lyle L. , Behrns Kevin E. , Liu Chen , George Thomas J. , Thomas Ryan M. , Trevino Jose G. , Wallet Shannon M. , Hughes Steven J. 
Published: August 2015

Abstract
Background: The systemic treatment of pancreatic cancer (PC) is hindered by the rapid development of chemoresistance to current cytotoxic therapies. Mechanisms governing the development of chemoresistance remain poorly characterized, particularly with respect to contributions from the tumor microenvironment. Thus, the goal of this study was to identify novel mechanisms acting within the tumor microenvironment which lead to PC chemoresistance.
Methods: Intratumoral soluble mediator concentrations from resected PC specimens (n = 26) as well as supernatants from co-cultures of primary tumor-associated pancreatic stellate cells (PSCs) and PC cells (n = 12) were evaluated using a panel of 41 growth factors, chemokines and cytokines. The effect of CXCL10, a highly expressed soluble mediator during co-culture, on viability, proliferation, and apoptosis of PC cells was evaluated with and without gemcitabine treatment. In addition, the contribution of CXCL10 on migration patterns of peripheral blood mononuclear cells (PBMCs) was assessed.
Results: Co-culture of tumor-associated PSCs with PC cells revealed increased CXCL10 levels compared to either cell type cultured alone. In addition, high intratumoral CXCL10 concentrations correlated with reduced overall survival (HR 6.9; P = .006). While CXCL10 treatment had a small effect on the viability of PC cells, it led to significantly increased PC cell viability in the presence of gemcitabine. Further, gemcitabine treatment induced the expression of the CXCL10 receptor, CXCR3, and this induction of CXCR3 was associated with the absence of apoptotic markers in PC cells. Finally, constitutive expression of CXCL10 by PC cells preferentially led to the migration of regulatory immune cell subsets.
Conclusion: Paracrine CXCL10 signaling between stromal, PC and immune cells may be responsible not only for chemoresistance to gemcitabine, but also the recruitment and potential polarization of regulatory immune cell subsets in the pancreatic cancer microenvironment.
Citation Format: Daniel Delitto, Chelsey Perez, Brian S. Black, Heather L. Sorenson, Andrea E. Knowlton, Song Han, Dongyu Zhang, George A. Sarosi, Lyle L. Moldawer, Kevin E. Behrns, Chen Liu, Thomas J. George, Ryan M. Thomas, Jose G. Trevino, Shannon M. Wallet, Steven J. Hughes. CXCL10 within the tumor microenvironment induces gemcitabine resistance in pancreatic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5028. doi:10.1158/1538-7445.AM2015-5028
Abstract 5030: Polarizing tumor associated macrophages (TAMs) towards an anti-tumor phenotype with a novel compound reveals a new subset of TAMs within breast tumors which facilitate tumor regression
Authors: Sotayo Alaba O. , Guerriero Jennnifer L. , Ponichtera Holly E. , Letai Anthony G. 
Published: August 2015

Abstract
Manipulation of the innate immune system is a relatively understudied strategy for anti-cancer immunotherapy. The current focus on immunotherapy is centered on the adaptive immune system. However, there is growing evidence that manipulation of the innate immune system, including macrophages, is also a promising method to combat cancer.
Tumor associated macrophages (TAMs) are one of the major infiltrating leukocyte populations associated with solid tumors. There are two major types of macrophages: classically activated macrophages, which can kill bacteria, pathogens, and similarly tumor cells; and alternatively activated macrophages which facilitate wound repair and are generally found in the tumor microenvironment. TAMs are generally alternatively activated cells with immunosuppressive properties that have been shown to enhance tumorogenesis by facilitating metastasis, angiogenesis, and inhibiting a protecting adaptive immune response. The presence of macrophages in the tumor microenvironment correlates with poor prognosis. Here we describe a novel, first in class compound that activates macrophages to an anti-tumor phenotype. While this compound has no direct cytotoxic activity, we show in the PyMT mouse model of breast cancer that breast tumors regress in response to therapy in a manner dependent on myeloid cells. Through the use of flow cytometry, we have been able to identify different subpopulations of TAMs using the markers CD45, MHCII, and CD11b. Correlating with tumor regression, we see an increase in PARP and cleaved caspase 3, indicating apoptotic cell death. Here we show that a novel compound effectively polarize macrophages to an anti-tumor phenotype to induce tumor regression. This strategy may have great therapeutic promise.
Citation Format: Alaba O. Sotayo, Jennnifer L. Guerriero, Holly E. Ponichtera, Anthony G. Letai. Polarizing tumor associated macrophages (TAMs) towards an anti-tumor phenotype with a novel compound reveals a new subset of TAMs within breast tumors which facilitate tumor regression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5030. doi:10.1158/1538-7445.AM2015-5030