bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5031: A humanized mouse model for translational assessment of targeted immune checkpoint blockade
Authors: Baia Gilson , Vasquez-Dunddel David , Ciznadija Daniel , Sidransky David , Katz Amanda , Paz Keren 
Published: August 2015

Abstract
The blockade of immune checkpoints is a promising therapeutic avenue for cancer therapy, with durable objective responses observed in patients with a variety of solid tumors. Despite these successes, current animal models do not reliably identify targets with the greatest clinical potential, due in part to differences between human and murine immune systems. Hence, robust preclinical tools to test these drugs directly against human cancers in the context of a human immune system are required. Champions Oncology has now developed the ImmunoGraft, whereby two innovative technologies, the patient-derived xenograft and humanized mice (immunodeficient mice reconstituted with a human immune system), are combined in a single platform.
Immune-compromised NOG (PrkdcscidIl2rgtm1Sug) mice were reconstituted (humanized) with human CD34+ cells and twelve weeks after humanization, mature human CD45+ cells comprised close to 50% of the leukocytes detected in the circulation and secondary lymphoid tissues of the now humanized animals. Growth of NSCLC tumors implanted into humanized NOG animals was comparable to those in non-humanized counterparts, and when humanized animals harboring NSCLC tumor implants were treated with ipilimumab, tumor growth was slowed, exhibiting marked regression. Systemic immune activation was observed in humanized mice following treatment with ipilimumab, characterized by robust proliferation of huCD3+ T cells and activated huCD4+ Th1 cells, as well as an increase in tumor-infiltrating huCD8+ cytotoxic T lymphocytes (all relative to vehicle controls).
We have developed an innovative new preclinical cancer model, the ImmunoGraft, which will enable novel immunotherapeutic agents to be accurately evaluated for efficacy against virtually any cancer indication that can be engrafted. As a proof-of-concept of the utility of the ImmunoGraft, we demonstrated how effectively ipilimumab restricted the growth of NSCLC implants engrafted in humanized animals. This translational platform is, therefore, more reflective of the human tumor microenvironment (both immune and non-immune cell-based) and is the most clinically-relevant model for screening immune system-targeting therapies, as single agents or in combination with standard-of-care drugs and other immuno-modulators. The ImmunoGraft has strong potential to revolutionize the application of immunotherapy to both personalized oncology and translational drug discovery.
Citation Format: Gilson Baia, David Vasquez-Dunddel, Daniel Ciznadija, David Sidransky, Amanda Katz, Keren Paz. A humanized mouse model for translational assessment of targeted immune checkpoint blockade. [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 5031. doi:10.1158/1538-7445.AM2015-5031
Abstract 5036: Tumor-induced activation of the Wnt/β-catenin/TCF4 pathway in dendritic cells promotes immune tolerance
Authors: Hong Yuan , Manoharan Indumathi , Suryawanshi Amol , Manicassamy Santhakumar 
Published: August 2015

Abstract
Tumors actively suppress host antitumor immune response and this represents a fundamental barrier to successful cancer immunotherapy. However, the molecular mechanisms underlying tumor-induced immune tolerance are largely unknown. In the present study, we show that Wnt ligands in the tumor microenvironment activate the β-catenin/TCF4 pathway within dendritic cells (DCs) rendering them tolerogenic and able to suppress host antitumor immunity against melanoma. This was because Wnt/β-catenin/TCF4 signaling in DCs induced retinoic acid synthesizing enzymes, which induced T regulatory responses and suppressed effector T cells. Consistent with this observation, DC-specific deletion of key downstream mediators of canonical Wnt signaling (Wnt co-receptors low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6), β-catenin and transcription factor 4 (TCF4)) in mice markedly delayed melanoma growth and enhanced host anti-tumor immunity. Likewise, pharmacological inhibition of the Wnt/β-catenin/TCF4 pathway in vivo had similar effects on tumor growth and effector T cell responses. Hence, Wnt/β-catenin/TCF4 pathway links together DCs, Tregs and the retionoic acid pathway, and is an important target for anticancer immunotherapy.
Note: This abstract was not presented at the meeting.
Citation Format: Yuan Hong, Indumathi Manoharan, Amol Suryawanshi, Santhakumar Manicassamy. Tumor-induced activation of the Wnt/β-catenin/TCF4 pathway in dendritic cells promotes immune tolerance. [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 5036. doi:10.1158/1538-7445.AM2015-5036
Abstract 5040: Calcium channels: Potential new therapeutic targets for hormone independent and resistant breast cancers
Authors: Cyrus Kedra , Kaushal Mudit , Sharawi Zeina , Noguchi Glyn , Chang Tiffany , Rydzewski William , Gibrel Fatima , Yeguech William , Haddad Bassam , Martin Mary Beth 
Published: August 2015

Abstract
Estrogen receptor alpha (ERα) is central to the growth and progression of a subset of breast cancers. As such, therapies that target ERα are a standard of care in the treatment of ERα -positive disease. Unfortunately, one-third of patients receiving hormonal therapies develop resistance. Several factors are believed to contribute to resistance including increased hormone independent activation of ERα by activated signal transduction pathways such as the epidermal growth factor (EGF) signaling pathway. We have shown that calcium mediates the cross talk between the EGF signaling pathway and ERα by directly binding to and activating the ligand binding domain of ERα suggesting a role for calcium in the development and progression of hormone independent and resistant breast cancer. Preliminary results from this study show that compared to normal (MCF10A) or hormone dependent (MCF-7) breast cells, hormone independent and resistant breast cancer cells (MCF7-2A, LCC-9, and MCF7-RR) have higher expression of the L-type and T-type calcium channels and higher concentrations of intracellular calcium. When hormone resistant (LCC-9) cells were treated with the intracellular calcium chelator BAPTA-AM, the L-type calcium channel blocker methoxyverapamil, or the T-type calcium channel blocker mibefradil, there was a significant decrease in the expression of the ERα regulated gene progesterone receptor that was reversed by the addition of estradiol. More importantly, when hormone independent (MCF7-2A) and hormone independent (LCC-9) cells were treated with the calcium channel blockers, there was in a significant decrease in growth and a re-sensitization of the antiestrogen resistant LCC-9 cells to tamoxifen and fulvestrant. Taken together, the preliminary results suggest that increased expression of calcium channels and intracellular calcium contribute to the hormone independent activation of ERα and point to a potential new therapeutic target for hormone independent and resistant breast cancer.
Citation Format: Kedra Cyrus, Mudit Kaushal, Zeina Sharawi, Glyn Noguchi, Tiffany Chang, William Rydzewski, Fatima Gibrel, William Yeguech, Bassam Haddad, Mary Beth Martin. Calcium channels: Potential new therapeutic targets for hormone independent and resistant breast 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 5040. doi:10.1158/1538-7445.AM2015-5040
Abstract 5048: The cholesterol metabolite, 27-hydroxycholesterol stimulates cell proliferation in prostate epithelial cell lines via estrogen receptor beta
Authors: Raza Shaneabbas , Schommer Jared , Meyer Megan , Guo Bin , Hammer Kimberly , Ghribi Othman 
Published: August 2015

Abstract
For every 6 men, 1 will be diagnosed with prostate cancer (PCa). Estrogen receptors are known to play a role in prostate carcinogenesis however, it is unclear whether the estrogenic effects are estrogen receptor α (ERα) or estrogen receptor β (ERβ) mediated. Although, it is speculated that ERα is associated with harmful effects on PCa while ERβ plays a more protective role on PCa, clinical trials using ERβ selective modulators have not shown improved clinical outcomes. Hence, the role of ERβ in PCa is yet to be understood.
Recently a cholesterol oxidized metabolite (oxysterol), 27- hydroxycholesterol (27-OHC), was found to bind to both estrogen receptors (ERs) and act as a selective ER modulator (SERM). 27-OHC is the most prevalent cholesterol metabolite present in the blood with levels increasing with oxidative stress and age, especially in men. Increased 27-OHC levels are also found in individuals with hypercholesterolemia, which is also a risk factor for PCa. The role of 27-OHC through its action on estrogen receptors in the context of PCa is yet to be determined.
We hypothesize that 27-OHC through ER activation has deleterious effect in PCa. We found that incubation with 27-OHC of RWPE-1, LNCaP and PC3 cells increased cell proliferation significantly. Using the ER inhibitor, Fulvestrant, we demonstrate that upon co-treatment with 27-OHC and fulvestrant, cell proliferation is reduced to basal levels, indicating the involvement of ERs. Interestingly, levels of ERβ, and to a lesser extent ERα, were increased following incubation of RWPE-1, LNCaP and PC3 with 27-OHC. Furthermore, in the presence of the ERβ specific inhibitor, PHTPP, we show that 27-OHC- induced proliferation is attenuated. Unexpectedly, while 27-OHC increases cell invasion in the moderately metastatic LNCaP, it decreases cell invasion in normal cells, RWPE-1 and highly metastatic, PC3.
Altogether, our results propose dysregulated levels of 27-OHC as a new risk factor for prostate cancers with low metastatic potential. This indicates a novel role for 27-OHC in the etiopathogenesis of in PCa.
Note: This abstract was not presented at the meeting.
Citation Format: Shaneabbas Raza, Jared Schommer, Megan Meyer, Bin Guo, Kimberly Hammer, Othman Ghribi. The cholesterol metabolite, 27-hydroxycholesterol stimulates cell proliferation in prostate epithelial cell lines via estrogen receptor beta. [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 5048. doi:10.1158/1538-7445.AM2015-5048
Abstract 5050: Proteome-based combined treatment strategies synergizing antagonism of androgen receptor function in prostate cancer
Authors: Lee Joo Hyoung , Mobley James A. , Ponnazhagan Selvarangan 
Published: August 2015

Abstract
Acquired resistance to second-generation androgen receptor (AR)-targeted therapies compels the development of novel therapeutic agents for castration-resistant prostate cancer (CRPC). We have recently reported a novel function of endostatin (ES) through direct binding and inhibition of AR in human prostate cancer (PCa) cells. Molecular characterization of the putative mechanisms of ES function on AR-positive PCa cells by global proteomic analysis revealed dramatic upregulation of CYP51A1 expression in LNCaP cells, suggesting that the increases in cholesterol biosynthesis and the resultant steroidogenesis may provide survival mechanism for PCa cells through the augmentation of androgen-AR axis. To validate this hypothesis, anti-proliferative effects of combined treatment of ES with Lovastatin or Fluconazole, inhibitor of HMG-CoA reductase or CYP5A1, were analyzed in vitro using AR-positive LNCaP cells. Results indicated a significantly enhanced ES-mediated growth inhibition on LNCaP cells by targeting both the ligand biosynthesis and receptor function. Proteomic profiling further indicated that ES significantly decreased the levels of AR, coactivator Ran (ARA24) and downregulated AR-driven expression of MCM complex 2, 3, 4 and 6, MDC1 and STMN1, suggesting that AR-targeted effects of ES include disruption of DNA replication, cell cycle propagation and cell division. We found that dual inhibition of AR nuclear transport and AR-mediated cell division by co-treatment of ES and Taxol greatly decreased PCa cell proliferation. Together, this interdisciplinary approach integrating proteomics with PCa cell function possibly suggests that antagonism of AR, which is the principal drug target for the PCa treatment, can be potentiated by the combination of ES with currently used chemotherapy agents and adjuvants. These findings further provide new insights into proteome-based approach as a useful tool to design and optimize effective therapeutic regimens for individual patients with CRPC.
Citation Format: Joo Hyoung Lee, James A. Mobley, Selvarangan Ponnazhagan. Proteome-based combined treatment strategies synergizing antagonism of androgen receptor function 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 5050. doi:10.1158/1538-7445.AM2015-5050
Abstract 5062: Ovarian cancer cells induce the microenvironment changes and subsequently promote disease propagation and dissemination through epithelial-mesenchymal transition and enrichment of tumorigenic cells
Authors: Huser Nanni , Yan Zhengming , Yuan Jing , Zhang Cathy C. 
Published: August 2015

Abstract
Ovarian cancer has the highest mortality rate of all gynecological cancers primarily due to the high incidence of metastatic spread prior to diagnosis. Understanding the biology of this malignancy and developing models that reflect the patient disease phenotype will create opportunities for testing targeted therapy. We used the Ovcar 3 cell line to establish a metastasis model through serial in vivo passage. After the treatment of docetaxel and carboplatin, the characteristics of minimal residual disease were assessed. Notably, the stromal environment and tumor initiating subpopulation play critical roles on the Ovcar 3MET disease invasiveness and progression. Compared to the molecular profile of the parental cells, these invasive Ovcar 3MET cells exhibited higher expressions of β-catenin, slug, N-cadherin and ZEB1, suggesting the epithelial-mesenchymal transition in these Ovcar 3MET cells. In addition, a higher fraction of the CD44+/CD24- subpopulation was found in the Ovcar 3MET cells, suggesting enrichment of the tumorigenic population. With the treatment of chemotherapeutic agents, we observed an enrichment of CD44+/CD24- subpopulation in the minimal residual disease. The self-renewal functional analysis demonstrated a higher tumorigenic potential of the MRD cells compared to the cells from vehicle treated mice. In contrast, treatment of the dual PI3K/mTOR inhibitor PF-04691502 resulted in significant anti-tumor and anti-metastatic activities without increasing the MRD self-renewal potential. These results warrant the combination assessment of chemotherapy with targeted agents to reduce or eradicate MRD, therefore to mitigate the risk of disease relapse.
Citation Format: Nanni Huser, Zhengming Yan, Jing Yuan, Cathy C. Zhang. Ovarian cancer cells induce the microenvironment changes and subsequently promote disease propagation and dissemination through epithelial-mesenchymal transition and enrichment of tumorigenic 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 5062. doi:10.1158/1538-7445.AM2015-5062
Abstract 5079: Parasympathetic signaling suppresses pancreatic cancer development
Authors: Renz Bernhard W. , Macchini Marina , Hayakawa Yoku , Westphalen C. Benedikt , Churchill Michael , Kar Suchetak , Chen Xiaowei , Nagar Karan , Tailor Yagnesh , Worthley Daniel L. , Iuga Alina C. , Olive Ken P. , Wang Timothy C. 
Published: August 2015

Abstract
Background/Aims: The parasympathetic nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. However, the exact role of the vagus nerve in pancreatic carcinogenesis is not well understood. Here we study the effects of muscarinic signaling on pancreatic tumorigenesis in a genetically engineered mouse model of pancreatic cancer (PDx1-Cre/KRasG12D (KC).
Methods: Mice were either vagotomized at 8 weeks or treated with a cholinergic agonist. Pancreatic tissue was collected and analyzed by immunohistochemistry and RT-PCR at 20 weeks of age; cells were isolated and assayed for colony and sphere forming assays. Different human (AsPC-1, BxPC-3, Mia PaCa-2, Panc-1) and murine (K-2548 and K-8282) pancreatic cancer cell lines were subjected to cholinergic and anti-cholinergic drugs and assayed by RT-PCR, Western blot and flow cytometry.
Results: In pancreatic organoid cultures derived from pancreata harboring an oncogenic KRas mutation, cholinergic agonists suppressed sphere formation significantly. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic M3 receptor abolished this effect in vitro. In human and murine pancreatic cancer cells, anchorage independent growth and tumor sphere forming capacity were reduced by pretreatment with cholinergic agonists. Further evaluation revealed that parasympathetic agonists decrease the CD44+CD24+EpCAM+ proved CSC's population. Vagotomy, when performed in KC mice at 8 weeks resulted in pancreatic cancer development in 20% of the animals at 20 week of age. Treatment with the direct muscarinic agonist bethanechol caused a significant delay of PanIN progression in KC mice.
Conclusions: Taken together, our findings suggest that vagal innervation has a regulatory role in pancreatic tumorigenesis via M3 receptor-mediated suppression of CSCs. Since current surgical approaches to resection of PDAC from the head of the pancreas are necessarily associated with a parasympathetic denervation of the pancreas, and thereby a loss of its suppressive effect, this fact may might partly explain the high local recurrence rate of this dismal disease. Additional treatment with cholinergic agonists should be considered in future regimen.
Citation Format: Bernhard W. Renz, Marina Macchini, Yoku Hayakawa, C. Benedikt Westphalen, Michael Churchill, Suchetak Kar, Xiaowei Chen, Karan Nagar, Yagnesh Tailor, Daniel L. Worthley, Alina C. Iuga, Ken P. Olive, Timothy C. Wang. Parasympathetic signaling suppresses pancreatic cancer development. [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 5079. doi:10.1158/1538-7445.AM2015-5079
Abstract 5094: Capsaicin inhibits invasion of human non-small cell lung cancer cells in a TRPV1 receptor independent manner
Authors: Eskew Matthew N. , Brown Kathleen C. , Dasgupta Piyali 
Published: August 2015

Abstract
Non-small cell lung cancer (NSCLC) comprises 85% of lung cancer cases and is characterized by aggressive clinical course and rapid metastasis. One of the challenges of NSCLCs is that the tumor has frequently metastasized to distant organs at the time of diagnosis. The invasion of tumor cells is a key step in the metastatic cascade. Dietary compounds like capsaicin have been known to cause apoptosis in human NSCLCs. However, the effect of capsaicin on the pro-invasive ability of NSCLC cells has not yet been studied. The present study investigates the impact of capsaicin on the invasion of human NSCLCs. Boyden chamber assays show that capsaicin inhibits the invasion of NSCLC in a concentration-dependent and time-dependent manner. The pro-invasive activity of capsaicin was verified by a second invasion assay, the spherical invasion assay, and similar results were obtained. The anti-invasive activity of capsaicin was independent of its growth-inhibitory activity and manifested at a lower concentration. The heat-sensation activity of capsaicin is mediated by the transient receptor potential vanilloid (TRPV) family of proteins. Capsaicin functions as an agonist of the TRPV1 receptor. However, the anti-invasive activity of capsaicin was not affected by the generalized TRPV receptor antagonist ruthenium red. Specific antagonists to TRPV1, namely capsazepine and SB36671, did not reverse the anti-invasive activity of capsaicin. Taken together, capsaicin potently suppresses invasion of human NSCLCs independent of the TRPV receptor family.
Citation Format: Matthew N. Eskew, Kathleen C. Brown, Piyali Dasgupta. Capsaicin inhibits invasion of human non-small cell lung cancer cells in a TRPV1 receptor independent manner. [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 5094. doi:10.1158/1538-7445.AM2015-5094
Abstract 5097: APE1/Ref-1 promotes cell adhesion and migration in cervical cancer cells
Authors: Kim Mihwa , You Ho Jin , Kim Dae Joon 
Published: August 2015

Abstract
Apurinic and apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 (Ref-1) is known to be involved in DNA base excision repair pathway and redox-dependent regulation of a number of transcription factors, such as AP1, p53, and Pax-8. It is expressed in numerous human cancers such as pancreatic cancer, prostate cancer, breast cancer, cervical cancer, and colon cancer. Our previous studies suggested APE1/Ref-1 can promote cancer progression through its involvement in cell proliferation, metastasis and angiogenesis; however, the molecular mechanism by which APE1/Ref-1 functions in these processes has not been characterized. In this study, we are the first to report that APE1/Ref-1 activates cell adhesion-related proteins to trigger cell migration. To investigate whether APE1/Ref-1 is involved in cell adhesion in normal fibroblasts, an adhesion assay was performed using GM00637 human fibroblast cell lines stably overexpressing APE1/Ref-1. Cell adhesion to vitronectin, a known ligand of the adhesion molecules integrin ανβ3 and integrin ανβ5, was significantly increased in APE1/Ref-1-overexpressing GM00637 cells compared to control fibroblast cells. FACS analysis showed APE1/Ref-1 induces the expression and activation of adhesion molecules including integrin αν and β3 in APE/Ref-1-overexpressing GM00637 cells. To evaluate whether APE1/Ref-1-mediated regulation of integrin ανβ3 is involved in cell migration in cervical cancer cells, a migration assay was performed using APE1/Ref-1-specific siRNA and an integrin ανβ3-specific antibody. Cell migration was significantly decreased in the absence of APE1/Ref-1 expression in cervical cancer cells, which was comparable with inhibition of integrin ανβ3. Consistent with these results, APE1/Ref-1 increased the activation and expression of integrin ανβ3 in both cervical cancer cells and cervical cancer patient tissue. Combined, these studies suggest that APE/Ref-1 can promote cell adhesion and migration through integrin ανβ3 signaling and thereby this signaling mechanism could contribute to cervical cancer progression.
Citation Format: Mihwa Kim, Ho Jin You, Dae Joon Kim. APE1/Ref-1 promotes cell adhesion and migration in cervical 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 5097. doi:10.1158/1538-7445.AM2015-5097