bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5513: Targeting brain tumor initiating cells in atypical teratoid/rhabdoid tumors: Aldehyde dehydrogenase inhibition with disulfiram
Authors: Choi Seung A. , Choi Jung Won , Wang Kyu-Chang , Phi Ji Hoon , Lee Ji Yeoun , Kim Yong Hwy , Kim Young-Hoon , Park Sung-Hye , Kim Seung-Ki 
Published: May 2015

Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are one of the most malignant pediatric brain tumors with a dismal prognosis. Cells with high aldehyde dehydrogenase (ALDH) activity from brain tumors have a number of characteristics that are expected of brain tumor initiating cells (BTICs). This study aimed to evaluate the therapeutic potential of ALDH inhibition using disulfiram (DSF) against BTICs from AT/RT.
Primary cultured BTICs from AT/RT were stained with Aldefluor and isolated by fluorescence activated cell sorting. Therapeutic effect of DSF against BTICs from AT/RT was confirmed using in vitro and in vivo studies.
AT/RT showed high expression of ALDH. DSF significantly inhibited ALDH enzyme activity of AT/RT cells. DSF decreased self-renewal ability, cell viability, proliferation potential and induced apoptosis and cell cycle arrest on ALDH+ AT/RT cells. DSF showed more potent cytotoxic effect to ALDH+ AT/RT cells compared to standard anti-cancer agents including ifosfamide, carboplatin and etoposide. Importantly, DSF reduced metabolite (metabolism?) of ALDH+ AT/RT cells by increasing NAD+ ratio and regulating SIRT1, NF-κB, Lin28A/B and miRNA let-7g. Notably, treatment with DSF did not have considerable effect on the normal neural stem cells and fibroblasts. Animals in the DSF-treated group demonstrated a significant survival benefit (105 days of median survival in the DSF-treated group versus 91 days in the control group, p = 0.0219).
Our study demonstrated the therapeutic potential of DSF against BTICs from AT/RT and suggested the possibility of ALDH inhibition for clinical application.
Note: This abstract was not presented at the meeting.
Citation Format: Seung Ah Choi, Jung Won Choi, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Yong Hwy Kim, Young-Hoon Kim, Sung-Hye Park, Seung-Ki Kim. Targeting brain tumor initiating cells in atypical teratoid/rhabdoid tumors: Aldehyde dehydrogenase inhibition with disulfiram. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5513. doi:10.1158/1538-7445.AM2014-5513
Abstract 5570: Laminin-5 gamma-2 (LAMC2) is highly expressed in anaplastic thyroid carcinoma and is associated with tumor progression, migration and invasion by modulating signaling of EGFR
Authors: Garg Manoj , Kanojia Deepika , Okamoto Ryoko , Madan Vikas , Chien Wenwen , Sampath Abhishek , Ding Ling-Wen , Xuan Meng , Said Jonathan W , Doan Ngan , Liu Li-Zhen , Yang Henry , Gery Sigal , Braunstein Gleen D , Koeffler H.Phillip 
Published: May 2015

Abstract
Context: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy having no effective treatment. Laminin subunit gamma-2 (LAMC2) is an epithelial basement membrane protein involved in cell migration and tumour invasion and might represent an ideal target for the development of novel therapeutic approaches for ATC.
Objective: Study the role of LAMC2 in ATC tumorigenesis.
Design: LAMC2 expression was evaluated by RT-PCR, western blotting and immunohistochemistry in tumor specimens, adjacent non-cancerous tissues and cell lines. shRNA approach was used to investigate the effect of LAMC2 knockdown on tumorigenesis of ATC.
Results: LAMC2 was highly expressed in ATC samples and cell lines compared to normal thyroid tissues. Silencing LAMC2 by shRNA in ATC cells moderately inhibited cell growth in liquid culture and dramatically decreased growth in soft agar and in xenografts growing in immunodeficient mice. Silencing LAMC2 caused cell cycle arrest and significantly suppressed migration, invasion and wound healing of ATC cells. Rescue experiments by overexpressing LAMC2 in LAMC2 knockdown cells, reversed the inhibitory effects as shown by increased cell proliferation and colony formation. Microarray data demonstrated that LAMC2 shRNA significantly altered expression of genes associated with migration, invasion, proliferation and survival. Immunoprecipitation and co-localization experiments showed that LAMC2 bound to EGFR in ATC cells. Silencing LAMC2 partially blocked EGF-mediated activation of EGFR and its downstream pathway. Interestingly, cetuximab (EGFR blocking antibody) or EGFR siRNA additively enhanced the anti-proliferative activity of the LAMC2 knockdown ATC cells compared to control cells.
Conclusions: To our knowledge, this is the first report investigating the effect of LAMC2 on cell growth, cell cycle, migration, invasion and EGFR signaling in ATC cells, suggesting that LAMC2 may be a potential therapeutic target for treatment of ATC.
Citation Format: Manoj Garg, Deepika Kanojia, Ryoko Okamoto, Vikas Madan, Wenwen Chien, Abhishek Sampath, Ling-Wen Ding, Meng Xuan, Jonathan W Said, Ngan Doan, Li-Zhen Liu, Henry Yang, Sigal Gery, Gleen D Braunstein, H.Phillip Koeffler. Laminin-5 gamma-2 (LAMC2) is highly expressed in anaplastic thyroid carcinoma and is associated with tumor progression, migration and invasion by modulating signaling of EGFR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5570. doi:10.1158/1538-7445.AM2014-5570
Abstract 5577: ERG enhances prostate cancer growth by upregulating neurotransmitter receptors
Authors: On Seungtae 
Published: May 2015

Abstract
Almost 50% of prostate cancer (PCa) cases exhibit a gene fusion between TMPRSS2 and the ETS transcription factor ERG. ERG is suspected to promote the acceleration and progression of prostate cancer. However, the mechanisms whereby ERG exerts its affects growth and development of the prostate cancer cell is are poorly understood. We aimed to identify and characterize ERG-related changes using a prostate tumor cell as a model. We profiled the transcription and metabolomics of cell lines induced to express ERG, and used RT-PCR, calcium influx, proliferation and phosphorylation assays to test our in silico observations. Genome-wide gene expression and metabolite profiling revealed a significantly increased representation of neuronal receptors and metabolites in the ERG+ cells. Specifically, ERG+ cells overexpressed several nicotinic, adrenergic and glutamate receptors. Out of all three receptors, nicotinic receptors were predominently upregulated compared to others. To test the function of these receptors, cells expressing ERG were treated with neuronal receptor agonists nicotin, epinephrine and glutamate. Interestingly, ERG+ cells responded with increased calcium influx, and phosphorylation of pAKT and GSK3b. Nicotine increased cellular growth in ERG+ cells, but had no effect on the ERG- cells. Similar expression of these receptors was found in human PCa samples. Furtheremore, our analysis using the EDRN tissue bank identified a positive correlation between smoking and tumor size among TMRPSS2:ERG expressing PCa patients. Collectively, our findings suggest a correlation between neurotransmitter receptors and cellular proliferation of ERG-expressing Pca, and identify GSK3b and pAKT as the possible underlying signaling mediators.
Citation Format: Seungtae On. ERG enhances prostate cancer growth by upregulating neurotransmitter receptors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5577. doi:10.1158/1538-7445.AM2014-5577
Abstract 623: BIG3-PHB2 interaction is a key therapeutic target in luminal-type of breast cancer
Authors: Katagiri Toyomasa , Yoshimaru Tesuro , Komatsu Masato , Matsuo Taisuke 
Published: May 2015

Abstract
More than 70% of primary breast tumors are estrogen receptor alpha (ERα)-positive, and the interactions between estrogen (E2) and ERα dramatically enhance the proliferative and metastatic activity of breast tumor cells. The selective estrogen receptor modulator tamoxifen directly inhibits E2 and ERα interactions and is a standard treatment offered to patients with ERα-positive breast cancer. The acquisition of endocrine resistance is a common obstacle in endocrine therapy for ERα-positive breast tumors. Therefore, identifying the factors and pathways responsible for resistance and defining ways to overcome it represent important therapeutic challenges in breast cancer research. Prohibitin 2 (PHB2) is known to function as a co-repressor of ERα because it regulates ERα transcriptional activity via its direct binding to ERα. However, it remains unclear how endogenous PHB2 is inactivated in ERα-positive breast cancer cells, despite its abundant expression and the lack of genomic mutations or methylations in breast cancer clinical specimens or cell lines. Here we report that brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) protein interacts PP1α, and dephosphorylates the E2-dependent phosphorylation of PHB2, which is indispensable for its tumor suppressive ability, thereby causing an apparent “loss-of-function” of PHB2 protein, resulting in the constitutive activation of ERα signaling pathways. These findings demonstrate for the first time the novel mechanism for the inactivation of tumor suppressor protein. From a therapeutic perspective, intrinsic PHB2 released from BIG3 by the cell-permeable peptide inhibitor directly binds to both nuclear- and membrane-associated ERα, which leads to the inhibition of multiple ERα-signaling pathways, and the growth of ERα-positive breast cancer cells both in vitro and in vivo. More importantly, this peptide inhibitor treatment suppressed tamoxifen resistance and enhanced tamoxifen responsiveness in ERα-positive breast cancer cells. These findings mark the first step toward uncovering a new E2/ ERα signaling network in breast cancer and shed light on novel therapeutic strategies utilizing PHB2 protein functions for E2/ ERα-positive breast cancer.
Citation Format: Toyomasa Katagiri, Tesuro Yoshimaru, Masato Komatsu, Taisuke Matsuo. BIG3-PHB2 interaction is a key therapeutic target in luminal-type of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 623. doi:10.1158/1538-7445.AM2014-623
Abstract 633: Inhibition of TGFβ as a strategy to convert the irradiated tumor into in situ individualized vaccine
Authors: Vanpouille-Box Claire I. , Diamond Julie M. , Zavadil Jiri , Babb James , Schaue Dörthe , Barcellos-Hoff Mary Helen , McBride William H. , Formenti Silvia C. , Demaria Sandra 
Published: May 2015

Abstract
Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in two pre-clinical models of metastatic breast cancer and analyzed in patients with metastatic breast cancer treated with local radiotherapy and the TGFβ-neutralizing antibody Fresolimumab.
Mice bearing established 4T1 and TSA mouse mammary carcinomas treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Likewise, HLA-A2.1+ metastatic breast cancer patients (n=8) enrolled in NCT01401062 trial of local RT and fresolimumab were examined for CD8+ T cells specific for the tumor antigen survivin by tetramer staining. Three patients developed increased frequencies of survivin-specific CD8+ T cells in the blood during treatment, while two patients negative at baseline became positive.
Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade.
These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity.
Supported by DOD BCRP Multi-Team Award BC100481.
Citation Format: Claire I. Vanpouille-Box, Julie M. Diamond, Jiri Zavadil, James Babb, Dörthe Schaue, Mary Helen Barcellos-Hoff, William H. McBride, Silvia C. Formenti, Sandra Demaria. Inhibition of TGFβ as a strategy to convert the irradiated tumor into in situ individualized vaccine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 633. doi:10.1158/1538-7445.AM2014-633
Abstract CT207: Pharmacokinetic analysis of the HDAC inhibitor belinostat (PXD-101) and metabolites in patients with hepatic dysfunction
Authors: Kiesel Brian , Parise Robert , Lin Yan , Allen Deborah , Reddy Guru , Chawla Shanta , Piekarz Richard , Ivy Percy , Kumar Shivaani , Beumer Jan H. 
Published: May 2015

Abstract
Introduction: Histone deacetylases (HDAC) are frequently deregulated in human cancers and their inhibition allows re-expression of silenced genes. Belinostat is an HDAC inhibitor with in vitro and in vivo activity in multiple malignancies, currently in phase II trials. We report the pharmacokinetics of belinostat and metabolites in patients enrolled in a phase I liver dysfunction trial currently being conducted and led by the NCI.
Methods: Patients enrolled into the study were assigned to varying cohorts depending on their level of hepatic dysfunction (normal=N, mild=H1, moderate=H2, and severe=H3). All patients were given a 30 minute infusion at 400 mg/m2 on cycle 1 day -7. Heparinized plasma samples were collected prior to infusion, 15 and 25 min after start, and 5, 10, 15, 30, 60, 90, 120, 240, 360, 480 and 1440 minutes after infusion. Patients from the NCIDTC had samples collected and these were quantitated by a previously validated assay for belinostat, belinostat-glucuronide, methyl-belinostat, M21, M24, and M26. Pharmacokinetic parameters were derived non-compartmentally with PK Solutions. Metabolic ratios were calculated as a measure of metabolic fate.
Results: 15 patients (N=2, H1=10, H2=2, H3=1) had useable pharmacokinetic data. Observed belinostat Cmax (N=21.1±4.9, H1=55.8±78.0, H2=23.0±7.2, H3=23.1 µg/mL) and belinostat AUC0-inf (N=806±294, H1=1308±996, H2=702±82, H3=780 µg/mL•min) did not reveal any trends with dysfunction cohort. Metabolic AUC0-inf ratios of belinostat to the various metabolites also did not appear to change with dysfunction cohort.
Conclusion: Liver function does not appear to affect the pharmacokinetics or metabolic fate of belinostat. Analysis of additional subjects is ongoing. The results of this study will facilitate optimal dosing for patients with liver dysfunction.
Citation Format: Brian Kiesel, Robert Parise, Yan Lin, Deborah Allen, Guru Reddy, Shanta Chawla, Richard Piekarz, Percy Ivy, Shivaani Kumar, Jan H. Beumer. Pharmacokinetic analysis of the HDAC inhibitor belinostat (PXD-101) and metabolites in patients with hepatic dysfunction. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT207. doi:10.1158/1538-7445.AM2014-CT207
Abstract CT304: Anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 plus low-dose interleukin-2 (IL-2) in patients with recurrent prostate cancer (PC)
Authors: Khagi Yulian , Kaur Gurveen , Christos Paul , Akhtar Naveed H. , Nanus David M. , Bander Neil H. , Tagawa Scott T. 
Published: May 2015

Abstract
Purpose
J591 is a deimmunized monoclonal antibody that recognizes the extracellular domain of prostate specific membrane antigen and was engineered to induce antibody-dependent cellular cytotoxicity (ADCC). Low dose IL-2 may enhance ADCC by the clonal expansion of natural killer (NK) cells. Immunotherapy may result in survival benefits independent of immediate response. This study was designed to evaluate the efficacy of J591 plus low-dose IL-2 in men with recurrent PC.
Experimental Design
Men with non-castrate PSA relapse or progressive metastatic castration-resistant PC (mCRPC) received low-dose subcutaneous IL-2 (1.2 x 106 IU/m2/day) daily for 8 weeks with weekly intravenous infusions of J591 (25 mg/m2) on weeks 4-6 (considered 1 cycle). A maximum of 3 cycles of therapy was delivered. Flow cytometry was used to assess NK cell fraction and PSA changes and survival were assessed.
Results
Seventeen men were treated between 2001-03 with at least 1 cycle (11 PSA relapse, 6 mCRPC) with 1 mCRPC patient invaluable for PSA response due to a protocol violation (9 received 2 cycles, 2 received 3 cycles). Toxicity was mild, mainly limited to fatigue and injection site reactions. PSA declined following therapy in 7 of 16 evaluable men (2 of 5 mCRPC). Flow cytometry revealed an average increase in absolute NK cell count of 107% at week 4 and 117% at the end of cycle 1. NK cell percent change had an inverse relationship with PSA (2-tailed Pearson correlation coefficient r = -0.46; P= 0.13). The actual vs. predicted survival for 5 of the 6 men with mCRPC disease was greater than predicted by the Halabi nomogram (Spearman correlation analysis r=0.29; P=0.57, i.e. nomogram did not predict survival).
Conclusions
The combination of J591 with low-dose IL-2 was well tolerated in patients with biochemical relapse and mCRPC. In addition, combination therapy expanded NK cell fraction which correlated with PSA decline. Interestingly, long term follow up reveals that 83% of the mCRPC group lived significantly longer than predicted, mostly in an era prior to the approval of life-prolonging therapy. These data support further testing of the hypothesis that PSMA-directed immunotherapy influences outcome in men with advanced PC.
Citation Format: Yulian Khagi, Gurveen Kaur, Paul Christos, Naveed H. Akhtar, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 plus low-dose interleukin-2 (IL-2) in patients with recurrent prostate cancer (PC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT304. doi:10.1158/1538-7445.AM2014-CT304
Abstract CT414: Efficient induction of cellular and humoral immune responses by heterologous prime-boost therapeutic vaccination, involving plasmid DNA and adenoviral vector, in subjects with HER2-expressing breast cancer: Results from a phase Ib study
Authors: KIM SUNGBAE , Jung KyungHae , Ahn JinHee , Kim Jeongeun 
Published: May 2015

Abstract
A phase I clinical trial was conducted to assess safety, tolerability and preliminary efficacy of a heterologous prime-boost strategy, involving a plasmid DNA (pHM-GM-CSF, expressing truncated HER2 and GM-CSF as a bicistronic message) and an adenoviral vector (Ad-HM, containing the same modified HER2 sequence only), in subjects with stage III-IV metastatic breast cancer expressing HER2 (1+∼3+ by immunohistochemistry). Nine eligible subjects were divided into three cohorts based on three different DNA doses (2, 4 and 8 mg) of pHM-GM-CSF, which were intramuscularly injected three times on weeks 0, 2, and 4 (i.e. 6, 12, and 24mg in total), followed by a single injection of Ad-HM (3x109 viral particle) on week 6. Relevant parameters were measured during the 6-month follow-up period. Seven minor grade 1 toxicities were found in four of nine patients, while no drug-related serious adverse event was reported. HER2-specific cell-mediated or humoral immunities were produced in all (100 %) or three patients (33 %), respectively. One patient showed a partial response, and seven subjects had stable diseases. No clear correlation was observed between DNA dosages and induction of immunogenicity and clinical tumor response. Our data showed that intramuscular injection of pHM-GM-CSF 24mg and Ad-HM 3x109 VP were well tolerated and safe. To our knowledge, this is the first clinical study demonstrating an efficient induction of HER2-specific cellular and humoral responses in patients with metastatic breast cancer expressing HER2.
Citation Format: SUNGBAE KIM, KyungHae Jung, JinHee Ahn, Jeongeun Kim. Efficient induction of cellular and humoral immune responses by heterologous prime-boost therapeutic vaccination, involving plasmid DNA and adenoviral vector, in subjects with HER2-expressing breast cancer: Results from a phase Ib study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT414. doi:10.1158/1538-7445.AM2014-CT414