bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1205: Circulating micro-RNAs can detect adaptive response to therapy and aggressive subset of prostate cancer.
Authors: Aparicio Ana M. , Gallichotte Emily , Cheng Heather , Yoo Suk-Young , Maity Sankar , Logothetis Christopher , Tewari Muneesh
Published: August 2014

Circulating markers that inform of the adaptive biology and the clinical virulence of prostate cancer do not exist. Small cell carcinoma of the prostate (SCPC) is an aggressive, androgen receptor (AR)-negative, morphological variant that arises often during the castration-resistant progression of typical adenocarcinoma. Its presence is associated with a poor response to hormonal therapies and predicts for a short survival. Micro-RNAs (miRNAs) regulate a range of processes, including establishment and maintenance of tissue differentiation, and are well-preserved in serum. Based on the observation that SCPC are characterized by a loss of prostate epithelial marker expression (such as AR and HOXB13) and an increase in the expression of proneural transcription factors (such as MYCN and ASCL1) we formulated the hypothesis that the SCPC display a miRNA profile distinct from that of typical AR-driven prostate carcinomas. We profiled the miR extracted from the serum samples of 13 men with biopsy-proven SCPC, and of 9 men with bone-predominant metastatic CRPC. Because SCPC is associated with large tumor burdens, we selected patients with bone-predominant CRPC that had abnormally high alkaline phosphatase levels and PSA > 20ng/mL. 322 miR were detected in at least one of the 22 samples. We identified two miR that were present in 10 and 11 of 13 (77% and 85%) patients with SCPC and 3 and 1 of 9 (33% and 11%) of men with unselected typical bone-predominant CRPC. Both of these miRs have been shown to control multiple genes regulating neuronal differentiation and to induce the conversion of human fibroblasts into neurons, a mechanism which may be shared by prostate adenocarcinoma cells in their transdifferentiation to small cell prostate cancer cells. Moreover, one of them was recently shown to silence AR expression. Therefore we conclude that two circulating miRs may serve to monitor adaptive responses and identify virulent subsets of prostate cancer, thus serving to guide therapy and selection of patients for clinical trials. Validation of these findings is ongoing in a larger cohort of patients.

Citation Format: Ana M. Aparicio, Emily Gallichotte, Heather Cheng, Suk-Young Yoo, Sankar Maity, Christopher Logothetis, Muneesh Tewari. Circulating micro-RNAs can detect adaptive response to therapy and aggressive subset of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1205. doi:10.1158/1538-7445.AM2013-1205
Abstract 1232: Immunomodulatory effects of a tyrosine kinase inhibitor and vascular remodeling properties of a cancer vaccine potentiate combinatorial immunotherapy.
Authors: Donahue Renee N. , Grenga Italia , Kim Peter S. , Coplin Michael A. , Hodge James W. , Schlom Jeffrey , Farsaci Benedetto P.
Published: August 2014

Many tyrosine kinase inhibitors (TKIs) that have antiangiogenic proprieties have also shown to have immunomodulatory proprieties by decreasing the number and function of immunosuppressive elements such as myeloid-derived suppressor cells and T-regulatory lymphocytes. These immunomodulatory properties make TKIs attractive candidates for combination with cancer immunotherapy. The aim of this study was to investigate the differential action of vaccine and the antiangiogenic TKI sunitinib on tumor architecture, to better define the mechanisms underlying the clinical benefit of this combination. Using a CEA+ colon carcinoma mouse model in CEA-transgenic mice, we show for the first time that vaccine and TKI exert differential effects on tumor architecture. Fluorescent immunohistochemistry (IHC) of 3 distinct types of tumor vessels (identified as CD31+, CD105+, and the monocytic marker CD11b+) demonstrated that vaccine decreased monocytic vasculature while sunitinib decreased the 3 types of vasculature and fenestrations. Immunoenzymatic IHC indicated that each single treatment and the combination affected tumor compactness and tight junctions. Each single treatment decreased hypoxia, as shown by hypoxyprobe IHC analysis, while combining sunitinib with vaccine resulted in the highest tumor oxygenation. Finally, vaccine plus sunitinib increased the tumor infiltration of antigen-specific T lymphocytes. These observations suggest that vaccine acted not only as an immune stimulant, but also as an angiogenic agent. These insights will assist in rationally developing and implementing such combination therapies.

Citation Format: Renee N. Donahue, Italia Grenga, Peter S. Kim, Michael A. Coplin, James W. Hodge, Jeffrey Schlom, Benedetto P. Farsaci. Immunomodulatory effects of a tyrosine kinase inhibitor and vascular remodeling properties of a cancer vaccine potentiate combinatorial immunotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1232. doi:10.1158/1538-7445.AM2013-1232
Abstract 1239: Characterization of the response of human T cells to an agonist human anti-CD27 mAb.
Authors: Sundarapandiyan Karuna , Vitale Laura , Zhao Biwei , O'Neill Thomas , Marsh Henry , Ramakrishna Venky , Keler Tibor
Published: August 2014

CD27, a member of the tumor necrosis factor receptor super family (TNFRSF), is constitutively expressed on the majority of mature T cells, memory B cells, and a portion of NK cells. Previously we have reported antitumor and immunological properties of the fully human anti-CD27 mAb 1F5 in huCD27 transgenic mouse models. Here we report the 1F5-induced immune modulation of isolated human T cells. In vitro activation of peripheral blood-derived T cells from different healthy volunteers with mAb 1F5 showed that crosslinking of CD27 in the presence of CD3 stimulation (OKT3 mAb) was essential to elicit proliferation and a broad spectrum of cytokine release. Analysis of this response on a multiplex cytokine array system revealed a Th1-biased cytokine profile (IFNγ, IL-2 and TNFα). Interestingly, IL-13 was the only major Th2 cytokine that was detected in large amounts. Furthermore, activation of isolated CD4+ and CD8+ T cells showed both subsets contributed to the IL-13 secretion with higher secretion amounts detected in the CD4+ T cell cultures. Altogether, the data suggest an agonistic role for 1F5 characterized predominantly by a defined antigen-receptor coupled Th1 effector response. IL-13, which appears later after stimulation may represent immune regulatory modulation as has been described in activation of the related 4-1BB co-stimulation pathway. Transcriptional profiling by microarray RNA hybridization is underway to map specific and global gene expression changes following 1F5 modulation of T cells.

Citation Format: Karuna Sundarapandiyan, Laura Vitale, Biwei Zhao, Thomas O'Neill, Henry Marsh, Venky Ramakrishna, Tibor Keler. Characterization of the response of human T cells to an agonist human anti-CD27 mAb. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1239. doi:10.1158/1538-7445.AM2013-1239
Abstract 1242: The association between treatment-related lymphopenia and survival in patients with solid tumors.
Authors: Grossman Stuart A. , Yovino Susannah , Campian Jian , Wild Aaron , Herman Joseph , Laheru Daniel , Brock Malcolm , Marur Shanthi , Balmanoukian Ani , Ye Xiaobu
Published: August 2014

Background: This retrospective review was conducted to determine: 1) the frequency and severity of treatment related lymphopenia (TRL) in solid tumors, 2) its association with survival accounting for prognostic variables, and 3) its relationship to radiation or chemotherapy.

Methods: Serial lymphocyte counts (pre-treatment and monthly for one year), prognostic factors, treatment details, and survival were retrospectively reviewed in 338 newly diagnosed patients with 1) high grade glioma, 2) resected pancreatic cancer, 3) unresectable pancreatic cancer, 4) stage III lung cancer, and 5) HPV- head and neck cancer in this IRB approved study. Severe TRL was defined as grade III-IV lymphopenia (<500 cells/mm3).

Results: The findings in each patient cohort are similar: 1) About 40% of patients develop severe TRL two months after initiating radiation and this persists for many months, 2) There is an association between TRL at two months and shorter survival from tumor progression, and 3) The hazard ratio for reduced survival is high after adjusting for known prognostic factors. Lung cancer patients treated with neoadjuvant chemotherapy did not experience TRL until after radiation was initiated.

Conclusions: Severe TRL is common, severe, long-lasting and associated with earlier death from tumor progression in patients with solid tumors receiving radiation and chemotherapy. These studies suggest that radiation likely plays a major role in the development of TRL and that novel approaches to protect and/or restore immunologic function in patients with solid tumors are critical.

NeoplasmTotal number patientsPatients developing grade III-IV TRLMedian Survival <500 vs >500 lymphocytes (months)Multivariate association with reduced survival:HR, (CI), pvalueHigh grade glioma9640%13 vs 19.7 (p = 0.002)OS: 1.66, (1.05–2.64), 0.03Pancreatic resected5345%14 vs 20 (p = 0.048)OS: 2.2, (1.17–4.12), 0.01Pancreatic unresectable12074%9.2 vs 14.6 (p = 0.013)OS: 1.34, (0.09–2.0), 0.15NSCLC Stage III4750%21.8 vs 28.3 (p = 0.38)OS: 1.7, (0.8–3.6), 0.17HEENT (HPV)2236%PFS onlyPFS: 6.2, (1.1–35.2), 0.04

Citation Format: Stuart A. Grossman, Susannah Yovino, Jian Campian, Aaron Wild, Joseph Herman, Daniel Laheru, Malcolm Brock, Shanthi Marur, Ani Balmanoukian, Xiaobu Ye. The association between treatment-related lymphopenia and survival in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2013-1242
Abstract 1247: Development of GRP78 scFv-Subtilase fusion proteins for sensitization of melanoma to chemotherapeutics.
Authors: Ray Rupa , de Ridder Gustaaf , Pizzo Salvatore V.
Published: August 2014

GRP78 is an important molecular chaperone in the endoplasmic reticulum (ER). However, GRP78 is aberrantly expressed on the surface of melanoma cells. Our objective is to characterize cell-surface GRP78 in melanoma and determine whether immunoconjugates against GRP78 are a viable treatment strategy. We have demonstrated that cleavage of ER GRP78 by Subtilase (SubAB), a GRP78-specific protease, sensitizes melanoma cell lines of different genotypes to melphalan, vemurafenib, and temozolomide. Our data indicate that SubAB cleavage of GRP78 sensitizes melanoma cells to melphalan and vemurafenib. We then coupled the catalytic domain of SubAB, SubA, to GRP78-single chain variable fragments derived from anti-GRP78 mouse monoclonal antibodies. We have previously published that these antibodies target GRP78+ mouse melanomas in a syngeneic mouse melanoma model. These GRP78 scFv-SubA fusion proteins are internalized by cell-surface GRP78 and the SubA moiety cleaves ER GRP78 inside the cell, leading to tumor cell sensitization to chemotherapeutics, and in some instances, tumor cell death. To determine the mechanism by which ER GRP78 cleavage sensitizes melanoma cells to chemotherapeutics, the NH2-terminal 28 kDa and COOH-terminal 50 kDa SubA cleavage products were overexpressed in melanoma cells, and pull-down experiments were performed to identify binding partners. Microarray analyses were also performed on chemotherapy-treated and GRP78 scFv-SubA fusion protein-treated melanoma cells to obtain a broad view of cellular events that occurred subsequent to ER GRP78 cleavage by SubAB or GRP78 scFv-SubA fusion proteins. These fusion proteins will then be tested in mouse melanoma models to determine whether they sensitize cancer cells to chemotherapeutics in vivo. These results of these studies may lead to the development of novel melanoma therapeutics.

Citation Format: Rupa Ray, Gustaaf de Ridder, Salvatore V. Pizzo. Development of GRP78 scFv-Subtilase fusion proteins for sensitization of melanoma to chemotherapeutics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1247. doi:10.1158/1538-7445.AM2013-1247
Abstract 1254: Tumor infiltrating M1 macrophages work side by side with T cells to prolong the survival in patients with cervical carcinoma.
Authors: Van Der Burg Sjoerd H. , de Vos van Steenwijk Peggy , van Hall Thorbald , Jordanova Ekaterina S.
Published: August 2014

One of the hallmarks of cancer is the influx of myeloid cells. In this study we exploited a cohort of 86 patients with cervical carcinoma to investigate the constitution of cervical cancer infiltrating myeloid cells and their relationship to other tumor infiltrating immune cells, tumor characteristics and the survival of patients. Triple color immunofluorescent confocal microscopy was used to locate, identify and quantify macrophages (CD14), their maturation status (CD33) and their polarization (CD163). Quantification of the numbers of populations of myeloid cells based on the expression of these three markers revealed that a strong intraepithelial infiltration of CD14+ cells, more specifically the population of CD14+CD33-CD163- M1 macrophages, is associated with a large general influx of intraepithelial T lymphocytes (p=0.008) and improved survival (p=0.007) as well as forms an independent prognostic factor for survival (p=0.033). The ratio of intraepithelial CD8+ T-cells / Tregs also formed an independent prognostic factor (p=0.010). Combination of these two factors revealed a dramatic difference in survival between the group of patients whose tumor was well infiltrated with intraepithelial M1 macrophages and relatively high numbers of CD8+ T-cells compared to Tregs (100%) and the group of patients whose tumor displayed a low infiltration with M1 macrophages and a low CD8+ T-cell / Treg ratio (50%), indicating that these two populations of immune cells work side by side to improve survival. Our data suggests that reinforcement and activation of the intratumoral M1 macrophages may form an attractive immunotherapeutic option in cervical cancer.

Citation Format: Sjoerd H. Van Der Burg, Peggy de Vos van Steenwijk, Thorbald van Hall, Ekaterina S. Jordanova. Tumor infiltrating M1 macrophages work side by side with T cells to prolong the survival in patients with cervical carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1254. doi:10.1158/1538-7445.AM2013-1254
Abstract 1269: Activation of the NKG2D receptor differentially activates mTOR and NFκB signaling pathways in CD8+ T cells.
Authors: Barber Amorette E. , Bedsworth Taylor , Spence Jasmine , Whitman Emily
Published: August 2014

To induce strong anti-tumor immune responses, CD8+ T cells require stimulation through the TCR and costimulatory receptors. Each costimulatory molecule can have a unique effect on the function of T cells due to differential activation of downstream signaling pathways and gene expression. One costimulation molecule that is likely to be engaged in the tumor microenvironment is NKG2D since the ligands for this receptor are expressed in over 80% of tumors. In order to determine how activation of costimulatory receptors in the tumor microenvironment affects CD8+ T cell functions, previous studies have compared the activation of CD8+ T cells through CD3 in combination with either CD28 or NKG2D and showed that CD3 and NKG2D stimulated cells secreted less anti-inflammatory cytokines. Both costimulatory receptors activated AKT, however the altered cytokine secretion was due to the unique activation of β-catenin in NKG2D stimulated cells. This study aimed to further investigate the differences in the signaling pathways downstream of AKT that are activated by CD3 /CD28 and CD3/NKG2D. Specifically, this study focused on the activation of mammalian target of rapamycin complex 1 and 2 (mTORC1 and mTORC2) along with nuclear factor kappa B (NFκB), all of which have been shown to have important roles in the CD8+ T cell anti-tumor functions. Activation of the mTORC1, mTORC2 and NFκB pathways were compared in murine CD8+ effector T cells stimulated through CD3 alone, CD3 and CD28 or CD3 and NKG2D. The activation of mTORC1was measured through phosphorylation of its downstream effectors including 4-EBP1, P70SK6 and HIF-1, while mTORC2 measured activation of AKT, SGK1 and NFkβ. Activation of CD8+ T cells through CD3 and NKG2D decreased activation of mTORC1 while increasing activation of mTORC2. Together this shows that activation through NKG2D leads to the differential activation of signaling pathways, thus likely altering the anti-tumor effector functions of the CD8+ T cells.

Citation Format: Amorette E. Barber, Taylor Bedsworth, Jasmine Spence, Emily Whitman. Activation of the NKG2D receptor differentially activates mTOR and NFκB signaling pathways in CD8+ T cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1269. doi:10.1158/1538-7445.AM2013-1269
Abstract 1274: SLITRK6, the target of a novel antibody drug conjugate AGS15E, is expressed in bladder and other cancers.
Authors: YANG Peng , Coleman Jeffrey , Li Ying , Zhang Yi , Junge Candice , Morrison Kendall , Donate Fernando , Stover David , Morrison Karen
Published: August 2014

SLITRK6, a member of the SLITRK family of neuronal transmembrane proteins, was discovered by Agensys using suppressive subtractive hybridization on biopsies from bladder cancer patients. Immunohistochemical (IHC) analysis of SLITRK6 expression was evaluated in various human cancers including bladder, using a SLITRK6-specific antibody M15-68(2)22. This mouse monoclonal antibody was raised to a peptide contained within the extracellular domain of SLITRK6 and was selected as a suitable IHC reagent by screening on RNA positive and negative cell lines and xenografts. Subsequent analysis of SLITRK6 expression in human cancer tissue microarray samples, utilizing M15-68(2)22, showed positive staining in 90% of 452 cases of bladder transitional cell carcinoma, including in situ, advanced primary and metastatic tumors. A subset of lung primary and metastatic cancers, breast cancers and glioblastomas also expressed SLITRK6. In normal tissues SLTRK6 expression is highly restricted to limited epithelia, including transitional epithelium, and some mast cells. In view of the restricted expression in normal tissues and the high expression in bladder transitional cell carcinoma, SLITRK6 constitutes an excellent target for antibody drug conjugate therapy for bladder transitional cell carcinoma and, potentially, for other cancer indications.

Citation Format: Peng YANG, Jeffrey Coleman, Ying Li, Yi Zhang, Candice Junge, Kendall Morrison, Fernando Donate, David Stover, Karen Morrison. SLITRK6, the target of a novel antibody drug conjugate AGS15E, is expressed in bladder and other cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1274. doi:10.1158/1538-7445.AM2013-1274
Abstract 1291: Identification of penfluridol as potential treatment for pancreatic cancer cells.
Authors: Chien Wenwen , Lee Kian Leong , Sun Qiaoyang , Wuensche Peer , Sudo Makoto , Poellinger Lorenz , Tyner Jeffrey W. , Yang Henry , Koeffler H. Phillip
Published: August 2014

Tyrosine kinase inhibitors (TKIs) have provided promising anti-cancer activities, but intrinsic or acquired resistance to these drugs is a major problem. To overcome this resistance, we have used microarray analysis to identify a signature of intrinsic drug resistance in human pancreatic cancer cells, and applied this gene expression profile to silico drug screening for potential drugs for pancreatic cancer therapy. The potency of dasatinib (a multiple family TKI) was assessed against a panel of 14 human pancreatic cancer cell lines. This drug is undergoing clinical trials for pancreatic cancers. Nine of fourteen pancreatic cell lines were growth inhibited by dasatinib. Three dasatinib-resistant (MiaPaCa2, Panc1, SU8686) and three -sensitive (Panc0504, Panc1005, Panc0403) pancreatic cancer cell lines were used in microarray analysis to compare the gene expression profiles. A total of 598 genes were differentially expressed in dasatinib-resistant cell lines compared to the sensitive cell lines. To discover therapeutic drugs that sensitize pancreatic cancer cells to dasatinib, we performed in silico drug screening using the Connectivity Map database (CMAP). The gene signature induced by thioridazine in CMAP showed a “glove in hand” pattern to that found in dasatinib-resistant versus -sensitive pancreatic cancer cell lines. Thioridazine belongs to the phenothiazine family including chlorpromazine, perphenazine, penfluridol, and pimethixene. Each was examined. Assays of cell proliferaton, cell cycle, and Annexin V showed that each was effective at inhibiting the cell cycle and inducing apoptosis. Penfluridol (a calcium channel inhibitor) was the most potent against both the dasatinib-resistant and -sensitive pancreatic cancer cell lines. Drug combination studies of penfluridol and either dasatinib or gemcitabine (FDA-approved for pancreatic cancer) showed synergistic enhancement of cytotoxicity. Mechanistic investigations suggested that multiple signaling pathways were suppressed by penfluridol. These studies suggest a potential novel class of drugs for treatment of pancreatic cancers.

Citation Format: Wenwen Chien, Kian Leong Lee, Qiaoyang Sun, Peer Wuensche, Makoto Sudo, Lorenz Poellinger, Jeffrey W. Tyner, Henry Yang, H. Phillip Koeffler. Identification of penfluridol as potential treatment for pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1291. doi:10.1158/1538-7445.AM2013-1291
Abstract 1299: KEAP1-NRF2-ARE signaling interacts with the SWI/SNF chromatin remodeling complex in non-small cell lung cancer.
Authors: Song Shujie , Orvis Tess , Zheng Yanfang , Major Michael B. , Weissman Bernard E.
Published: August 2014

NF-E2-related factor 2 (NRF2), negatively regulated by KEAP1, modulates induction of a battery of cytoprotective genes against oxidative stress via binding to the antioxidant responsive element (ARE) sequence. Recent NGS studies have shown a significant number of mutations in the KEAP1-NRF2-ARE signaling pathway, implicating aberrant activation of this pathway in lung cancer carcinogenesis and chemoresistance. The SWI/SNF chromatin-remodeling complex, employing either

BRG1 or BRM as a catalytic subunit, regulates gene expression and alters chromatin structures in an ATP-dependent manner. Loss of complex function often occurs in lung cancers, via mutations in complex subunits. Since KEAP1/NRF2 mutations and BRG1/BRM loss occur frequently in non-small cell lung cancers (NSCLCs) in a mutually exclusive fashion, we hypothesized that BRG1 and/or BRM play(s) a role in the regulation of NRF2 target genes. To test this hypothesis, we developed a series of isogenic H358 NSCLC lines with reduced BRG1 and/or BRM expression using shRNA technology. We observed a significant increase in the levels of HMOX1 (heme oxygenase1) and GSTM4 (Glutathione

S-transferase Mu 4) with a concomitant decrease in NQO1 (NAD(P)H dehydrogenase, quinone 1) in the BRG1-deficient H358 cell lines. However, GCLM (Glutamate–cysteine ligase regulatory subunit) was elevated only in the BRM-reduced H358 cells. Interestingly, BRG1 loss, either alone or combined with BRM loss, promoted SDS-resistant KEAP1 dimerization. We are currently examining whether BRG1 and/or BRM loss increases ROS levels. Chromatin immunoprecipitation (ChIP) showed that NRF2 were enriched at NRF2 downstream genes in both H358 parental and vector control cells, whereas BRG1 knockdown led to a moderate increase (HMOX1) or decrease (NQO1) in NRF2 binding. These results provide evidence that loss of

SWI/SNF chromatin remodeling complex activity alters the NRF2 pathway in NSCLC.

Furthermore, novel drugs targeting NRF2 downstream genes might provide a therapeutic approach for BRG1 deficient NSCLC patients.

Citation Format: Shujie Song, Tess Orvis, Yanfang Zheng, Michael B. Major, Bernard E. Weissman. KEAP1-NRF2-ARE signaling interacts with the SWI/SNF chromatin remodeling complex in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1299. doi:10.1158/1538-7445.AM2013-1299
Abstract 1309: ERβ1 induces apoptosis in lung cancer cells by regulating growth factor signaling.
Authors: Thomas Christoforos , Nikolos Fotis , Rajapaksa Gayani , Bado Igor , Gustafsson Jan-Ake
Published: August 2014

Estrogens have recently been associated with the clinical outcome of patients with non-small cell lung cancer (NSCLC). The wild-type estrogen receptor β (ERβ1) one of the mediators of the estrogen signaling in cells is expressed in lung cancer. However, the role of ERβ1 in NSCLC cell growth has not been fully elucidated. Here we show that induction of ERβ1 expression inhibited cell growth in H1299 and A549 NSCLC cells. Treatment of these cells with the ERβ agonists 17β-estradiol or 3β-Adiol further decreased cell proliferation and induced apoptosis. ERβ1 was found to induce apoptosis through stimulation of the intrinsic apoptotic pathway that involves upregulation of the proapoptotic protein Bim. Inactivation of the extracellular-signal-regulated kinases ERK1/2 was found to be involved in the ERβ1-mediated induction of apoptosis since treatment with EGF that activates ERK1/2 abolished the ability of ERβ1 to sustain the apoptotic phenotype. These results suggest that, by regulating NSCLC cell growth, ERβ1 could be an important factor in biology of lung cancer and a potentially useful component in the clinical management of the disease.

Citation Format: Christoforos Thomas, Fotis Nikolos, Gayani Rajapaksa, Igor Bado, Jan-Ake Gustafsson. ERβ1 induces apoptosis in lung cancer cells by regulating growth factor signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1309. doi:10.1158/1538-7445.AM2013-1309
Abstract 1324: PMEPA1 enhances the prostate cancer cell growth inhibitory effect of MDV3100 and bicalutamide.
Authors: Li Hua E. , Heidenberg Daniel , Dobi Albert , Srivastava Shiv
Published: August 2014

Introduction and Objective: PMEPA1 is a highly androgen-inducible gene in prostate cancer cells, recruits the NEDD4-1, an E3 ubiquitin ligase, to degrade AR. We hypothesize that the frequently (65%) observed decrease or loss of PMPEA1 expression in human prostate tumors may lead to enhanced AR functions and accelerated prostate tumorigenesis. Therefore, we investigated the growth and survival of prostate cancer cells in the presence of AR inhibitors in response to PMEPA1 knockdown.

Methods: PMEPA1 was silenced by PMEPA1 Mission shRNA lentivirus infection and puromycin selection in LNCaP and VCaP cells respectively. The PMEPA1 deficient LNCaP and VCaP cells were treated with the AR inhibitors (MDV3100 and bicalutamide), as well as the artificial synthesized androgen R1881. Ectopic NEDD4-1 was expressed by pCMV-XL4-NEDD4-1 eukaryotic expression vector. Cell growth was monitored by cell counting assay, BrdU incorporation assay and colony plating efficiency assay. Cell cycle was analyzed with propidium iodide staining based flowcytometry assay. Protein levels of AR, PMEPA1, PSA and NEDD4-1 were assessed by immunoblot assays.

Results: PMEPA1 silenced LNCaP and VCaP cells had higher AR, PSA protein levels, suggesting activated AR signaling. Consistent with this observation, inhibition of PMEPA1-1 by shRNA resulted in increased cell growth, stronger BrdU incorporation ability and higher colony plating efficiency in both LNCaP and VCaP cells. Cell cycle assay showed more S-phase cells in PMEPA1 deficient LNCaP and VCaP cells in regular medium or R1881 supplemented charcoal-striped medium. Ectopic expression of NEDD4-1 could not inhibit cell growth in PMEPA1 silenced LNCaP cells. More interestingly, the PMEPA1 deficient CaP cells (both LNCaP and VCaP cells) demonstrated more resistance to the growth inhibitory effects of MDV3100 and bicalutamide.

Conclusions: The frequently observed decreased expression of PMEPA1 results in elevated AR protein levels and activated AR signaling, which in turn promotes cell growth in androgen responsive prostate cancer cells. The PMEPA1 deficient cells develop more resistance to AR inhibitors. Our findings further suggest the important role of decreased PMEPA1 in AR related prostate tumorigenesis. These data highlight that PMEPA1 deficiency may confer resistance to AR inhibitors during CaP progression.

This study is supported by the NIH grant (R01CA106653) to SS.

Citation Format: Hua E. Li, Daniel Heidenberg, Albert Dobi, Shiv Srivastava. PMEPA1 enhances the prostate cancer cell growth inhibitory effect of MDV3100 and bicalutamide. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1324. doi:10.1158/1538-7445.AM2013-1324
Abstract 1335: Association between polymorphisms of APE1 and OGG1 genes and risk of colorectal cancer in Taiwan.
Authors: Yeh Chih-Ching , Hsieh Ling-Ling , Tang Reiping
Published: August 2014

Background: Colorectal cancer (CRC) is the third leading cause of cancer death in Taiwan. Previous studies indicated that oxidative damages resulting from reactive oxygen species (ROS) generation participate in all stages of the cancer process. Mutagenic 8-hydroxy-2’-deoxyguanosine, one of the major DNA lesions generated by ROS, is preferentially repaired by 8-oxoguanine glycosylase I (OGG1) and apurinic-apyrimidinic endonuclease 1 (APE1). Since polymorphisms of OGG1 S326C, R154H and APE1 D148E, T-656G were associated with the enzyme activities, this study was designed to evaluate the roles of the OGG1 and APE1 polymorphisms in CRC risk.

Method: We recruited 727 newly diagnosed colorectal adenocarcinoma cases and 736 age- and sex-matched healthy controls in a medical center. Genomic DNA isolated from buffy coat was used for genotyping by PCR methods. Because the frequency of the sequence variants of OGG1 R154H was too low (H allele was 0.14%), this polymorphism was excluded in further data analysis. Unconditional logistic regressions were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Subjects with OGG1 326 Ser/Cys genotype had an increased CRC risk (OR = 1.47; 95% CI = 1.06-2.04) compared to those carrying the Ser/Ser genotype, particularly among individuals aged more than 60 years (OR = 1.60, 95% CI = 1.02-2.05). However, there was no significant association between APE1 polymorphisms and CRC risk.

Conclusion: Our results indicated that OGG1 S326C polymorphism may associate with CRC risk in Taiwanese population, whereas APE1 polymorphisms may not modulate this disease risk.

Citation Format: Chih-Ching Yeh, Ling-Ling Hsieh, Reiping Tang. Association between polymorphisms of APE1 and OGG1 genes and risk of colorectal cancer in Taiwan. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1335. doi:10.1158/1538-7445.AM2013-1335
Abstract 134: Smoking duration before first childbirth: An emerging risk factor for breast cancer? Results from the Norwegian National Health Service Cohort (NHHS).
Authors: Bjerkaas Eivind , Parajuli Ranjan , Engeland Anders , Mascarinec Gertraud , Selmer Randi , Weiderpass Elisabete , Gram Inger Torhild
Published: August 2014

Purpose - Recent studies suggest that the period before the first childbirth is important in the relation between smoking and risk of breast cancer. We wanted to examine this association with focus on smoking duration before the first childbirth.

Methods - We followed 302,865 Norwegian women born between 1899 -1975 and identified 7,490 cases of primary invasive breast cancer cases during > 4.1 million person years of observation (mean 14 person years). We used Cox proportional hazard models to find hazard ratios (HR) with 95 % confidence intervals (CIs) adjusting for age, education, parity, age at first childbirth, BMI and physical activity. Information came from a questionnaire and a physical examination at enrolment, and from linkages to national registries.

Results - Compared with women who had never smoked, current smokers had a 14% [HR= 1.14 (95% CI 1.08-1.20)] and former smokers a 17% [HR=1.17 (95% CI 1.10-1.24)] increased risk of breast cancer. Ever smokers who started to smoke after their first childbirth did not have an increased risk [HR=0.93 (95% CI 0.86-1.02)], compared with never smokers. Those who had smoked for more than 20 years, and who had smoked 11 or more of those years before the first childbirth, showed a doubling in risk [HR=1.97 (95% CI 1.33-2.93)] compared with those starting to smoke after the first childbirth.

Conclusions - Our study suggests that duration of smoking before the first childbirth is a key factor in the relationship between smoking and breast cancer.

Citation Format: Eivind Bjerkaas, Ranjan Parajuli, Anders Engeland, Gertraud Mascarinec, Randi Selmer, Elisabete Weiderpass, Inger Torhild Gram. Smoking duration before first childbirth: An emerging risk factor for breast cancer? Results from the Norwegian National Health Service Cohort (NHHS). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 134. doi:10.1158/1538-7445.AM2013-134
Abstract 1347: CXCR4 pathway associated with family history of melanoma.
Authors: LI Wenqing , Han Jiali , Widlund Hans , Correll Mick , Wang Yaoyu , Quackenbush John , Mihm Martin , Laga Canales Alvaro , Golub Todd , Hoshida Yujin , Hunter David , Murphy George , Kupper Thomas , Qureshi Abrar
Published: August 2014

Background & Aims: Inherited genetic variants involved in the etiology of melanoma predispose towards elevated risk of disease, but known allele variants only account for a limited fraction of family history-associated melanoma cases. Hence, there is a need to determine contributing allele variants associated with augmented risk and surrogate biomarkers, which can be used to discern family history-associated melanoma.

Methods: Using data from the Nurses’ Health Study cohort, family history was defined as having one or more immediate family members diagnosed with melanoma. Secondary confirmation of melanoma cases were reviewed by pathology reports and tumor blocks collected by mail from across the United States. Genomic interrogation was accomplished through evaluating formalin-fixed paraffin-embedded tissues from 78 primary cutaneous invasive melanoma cases, using expression profiling on either a 6K or whole-genome (24K) Illumina gene chip. Gene Set Enrichment Analysis was performed separately for each batch to determine the differentially enriched pathways and key contributing genes.

Results: The CXC chemokine receptor 4 (CXCR4) pathway was consistently up-regulated within cases of familial melanoma in both platforms. Leading edge analysis showed four genes from the CXCR4 pathway, including MAPK1, PLCG1, CRK, and PTK2, were among the core members that contributed to the enrichment of this pathway. There was no association between the enrichment of CXCR4 pathway and NRAS, BRAF status, or Breslow thickness of the primary melanoma cases.

Conclusion: We found that the CXCR4 pathway may constitute a novel susceptibility pathway associated with family history of melanoma in first-degree relatives.

Citation Format: Wenqing LI, Jiali Han, Hans Widlund, Mick Correll, Yaoyu Wang, John Quackenbush, Martin Mihm, Alvaro Laga Canales, Todd Golub, Yujin Hoshida, David Hunter, George Murphy, Thomas Kupper, Abrar Qureshi. CXCR4 pathway associated with family history of melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1347. doi:10.1158/1538-7445.AM2013-1347
Abstract 1350: Genetic variations in apoptosis pathway are associated with survival in late stage non-small cell lung cancer.
Authors: Shu Xiang , Lu Charles , Chang Joe Y. , Roth Jack A. , Wu Xifeng
Published: August 2014

Dysregulation of apoptosis pathway plays an essential role in carcinogenesis, tumor progression, and resistance to chemotherapy. We hypothesized that genetic variations in genes involved in the apoptosis pathway may affect the survival in late stage non-small cell lung cancer (NSCLC) patients. To test this hypothesis, we genotyped 583 tagging SNPs in 598 late stage NSCLC patients and analyzed their associations with survival individually and jointly. Seven SNPs were statistically significantly associated with overall survival after correction for multiple comparisons (q<0.1). The most significant SNP was rs17592236 on FOXO1 gene under the dominant model (OR: 2.54, 95%CI: 1.71-3.78, p=4.15x10−6). We also observed a significant cumulative effect. Compared to the reference group (patients with no more than two risk alleles), those having five or more risk alleles were much more likely to die within seven months (HR: 3.58, 95% CI: 2.55-5.04, p<0.001). Notably, the median survival time (MST) was significantly reduced by up to 15 months in high risk patients when compared to the reference group (MST: 22.2 months, p<0.001). Survival tree analysis revealed potential higher order gene-gene interactions among these SNPs. Our results provided evidence that genetic variations in the apoptosis pathway modulate NSCLC survival and may serve as biomarkers to differentiate NSCLC patients with different prognosis.

Citation Format: Xiang Shu, Charles Lu, Joe Y. Chang, Jack A. Roth, Xifeng Wu. Genetic variations in apoptosis pathway are associated with survival in late stage non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1350. doi:10.1158/1538-7445.AM2013-1350
Abstract 1354: Chronic social stress in a mouse model of triple-negative breast cancer is associated with oncogenic changes in mammary fat.
Authors: Volden Paul A. , Wonder Erin , Skor Maxwell , Patel Feenalie , McClintock Martha , Brady Matthew , Conzen Suzanne
Published: August 2014

Chronic social isolation is linked to increased mammary tumor growth in rodent models of breast cancer. In the C3(1)/SV40 T-antigen (Tag) FVB/N mouse model of “triple-negative” breast cancer, the heightened stress response elicited by social isolation has been associated with increased expression of metabolic genes in the mammary gland before invasive tumors develop (i.e. during the in situ carcinoma stage). To further understand how underlying accelerated mammary tumor growth is associated with social isolation, we separated the mammary gland adipose tissue from adjacent ductal epithelial cells and analyzed individual cell types for changes in metabolic gene expression. Specifically, increased expression of the key metabolic genes Acaca, Hk2 and Acly was found primarily in the adipocyte, rather than epithelial fraction. Increased metabolic gene expression in the mammary adipocytes of socially isolated mice coincided with increased glucose metabolism, lipid synthesis, and leptin expression. Furthermore, culture media from isolated mouse mammary adipose tissue resulted in relatively increased proliferation and decreased apoptosis of mammary epithelial cancer cells derived from the same mouse strain. Additional gene expression analyses identified significant upregulation of the novel carbohydrate response element binding protein beta isoform (CHREBP-β) in socially isolated mammary fat. We hypothesize that the response to social isolation induces metabolic changes in mammary fat that are coordinated through CHREBP-β and are pro-oncogenic. We are currently performing global lipidomic and metabolomic analyses of mammary adipose tissue and secreted culture media to identify bioactive molecules involved in tumor growth.

Citation Format: Paul A. Volden, Erin Wonder, Maxwell Skor, Feenalie Patel, Martha McClintock, Matthew Brady, Suzanne Conzen. Chronic social stress in a mouse model of triple-negative breast cancer is associated with oncogenic changes in mammary fat. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1354. doi:10.1158/1538-7445.AM2013-1354
Abstract 1409: Genetic ablation of lymphoma development inp53 knockout mice reveals a novel model of osteosarcoma and hemangiosarcoma.
Authors: Landuzzi Lorena , Nicoletti Giordano , Palladini Arianna , Ianzano Marianna , Grosso Valentina , Ranieri Dario , De Giovanni Carla , Lollini Pier-Luigi , Nanni Patrizia
Published: August 2014

Homozygous knockout of p53 in mice leads to early mortality from lymphoma, with almost complete penetrance, thus hampering the study of other tumor histotypes related to p53. To ablate lymphoma development, we crossed p53 knockout mice with Rag2-/-;Il2rg-/- (RGKO) mice, which lack T, B and NK cells. We then compared the tumor spectrum of homozygous (p53-/-) and heterozygous (p53+/-) mice with those of mice lacking lymphocytes (RGKO-p53-/- and RGKO-p53+/-, respectively). All mice were of BALB/c genetic background. Lymphoma incidence in p53-/- mice exceeded 80%, whereas in RGKO-p53-/- it was near zero. The prevalent tumor of RGKO-p53-/- mice was hemangiosarcoma (incidence was about 60%in both sexes, median latency 19 weeks), other tumors included soft tissue sarcomas (incidence ∼10%), osteosarcomas and mammary carcinomas. Changes in tumor spectrum occurred also in p53 heterozygotes, in which lymphomas were relatively rare (<20%). Male RGKO-p53+/- had an increased incidence of hemangiosarcomas, reaching ∼25%, whereas females had an increased incidence of osteosarcomas, reaching ∼20%. The latter shared with human osteosarcoma the involvement of limbs and a high metastatic ability, in particular to the lungs. Molecular studies of tumors, in vitro cultured tumor cells and established cell lines showed specific alterations in the expression of p53-related genes (p16Ink4a, p19Arf, p15Ink4b, p21Cip1) and high expression levels of insulin-like growth factors and their receptors. In conclusion, genetic ablation of lymphoma in p53 knockout mice led to the development of new models of sarcoma development that can be now explored to study the development and metastatic spread of hemangiosarcoma and osteosarcoma.

Citation Format: Lorena Landuzzi, Giordano Nicoletti, Arianna Palladini, Marianna Ianzano, Valentina Grosso, Dario Ranieri, Carla De Giovanni, Pier-Luigi Lollini, Patrizia Nanni. Genetic ablation of lymphoma development inp53 knockout mice reveals a novel model of osteosarcoma and hemangiosarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1409. doi:10.1158/1538-7445.AM2013-1409
Abstract 1411: Pathogenesis and treatment of rhabdomyosarcoma in a susceptible murine model.
Authors: Zaid-Kaylani Samer , Pressey Joseph G. , Kelly David R. , Athar Mohammad
Published: August 2014

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. While the establishment of standard multi-modal therapy has led to improved survival, new therapeutic approaches are desperately needed to improve outcomes in patients with metastatic and recurrent disease. Our objective was to develop a highly penetrant mouse model of RMS to study the molecular pathways of the disease and to evaluate novel anticancer agents for the treatment of RMS. The hedgehog (Hh) pathway has been demonstrated to be activated in embryonal RMS. Communication between Hh and PI3K/AKT/mTOR pathways provides a rationale for the study of mTOR inhibitors such as rapamycin in RMS therapy. We developed a novel RMS mouse model by breeding Ptch6-7 knockouts onto a tumor susceptible SKH1 genetic background. We employed these animals (n=20/group) to study the effects of mTOR inhibitor, rapamycin, on the growth and progression of RMS tumors. We found that 42% of the Ptch1+/−SKH1 mice receiving no treatment developed RMS. These tumors were confirmed to have embryonal RMS morphology. These animals spontaneously develop RMS with embryonal histology predominantly in the hind limbs. The tumors developed at approximately 20 weeks of age; thereafter they grew very prolifically. Molecular studies demonstrated high expression of both Myogenin and Myf5. The tumors also manifested Hh pathway activation. The RMS bearing animals were divided into two groups with a third group of Ptch+/+ mice acting as a wild-type control group. Group-I animals receiving no treatment served as positive controls. The increase in tumor size in these animals was compared with the tumor growth of animals treated with rapamycin. The treatment resulted in a significant decrease in the rate of tumor growth as compared to the control group (p<0.05). This treatment also reduced the expression of AKT and Hh pathways, which was consistent with the tumor inhibitory response seen on a gross level. Decreases in markers of tumor invasiveness and VEGF expression were also noted. We conclude that the Ptch1+/− Skh1 mouse represents a novel murine model for aggressive embryonal RMS that recapitulates the pathobiology of human disease. Rapamycin effectively inhibits the growth of Ptch1+/− Skh1 RMS tumors providing insight into the mechanism underlying RMS tumorigenesis. mTOR inhibition with possible Hh pathway cross talk inhibition represents a promising target in the treatment of RMS in this murine model.

Citation Format: Samer Zaid-Kaylani, Joseph G. Pressey, David R. Kelly, Mohammad Athar. Pathogenesis and treatment of rhabdomyosarcoma in a susceptible murine model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1411. doi:10.1158/1538-7445.AM2013-1411