bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5037: Immunotherapy meets epigenetics: GP96-Ig cellular vaccine genetic signature is modulated by the inhibition of histone modifications
Authors: Fromm George J. , Schilling Neal , Schreiber Taylor H. 
Published: August 2015

Abstract
A number of novel cancer treatment strategies have been identified and developed over the last decade with hopes of eradicating a diverse range of cancers, however the molecular mechanisms behind patient immune responses and tumor microenvironment signaling are complex, and have often hindered the translation of these ideas into successful patient treatments. Two modalities at the forefront of these potential blockbuster strategies are combinatorial immunotherapy and epigenetic manipulation. These approaches are supported by compelling clinical data, but have been encumbered by a number of factors including: adverse event profiles, complicated manufacturing and regulatory issues, toxicity due to non-specific small molecule interactions, limited overlap in patient/therapy antigen presentation, and exorbitant cost of biological treatments. To circumvent a number of these limitations, we have taken a novel approach by engineering allogeneic cellular vaccines tailored to specific cancers, that secrete heat-shock protein gp96-Ig and achieve high-frequency polyclonal CD8+ T cell responses to femto-molar concentrations of tumor antigens through antigen cross-priming in vivo. Using genomics (RNA-sequencing) we identified differential mRNA expression levels genome-wide between normal bladder tissue, our proprietary bladder cancer cellular vaccine Vesigenurtacel-L or HS410, and patient bladder tumor biopsy samples, to generate a genomic signature of Bladder Cancer Altered Genes, or BCAGs. Next, we examined a number of small molecule inhibitors of epigenetic modifications (i.e. histone deacetylases or HDACs), and determined their effect on BCAG expression and antigen secretion in HS410 cells. We find that the inhibition of certain HDACs results in decreased proliferation, dampened secretion of gp96-Ig, and attenuated expression of tumor specific genes. Together our work has defined the pattern of gene dysregulation genome-wide in bladder cancer and shown that epigenetic modifiers are capable of modulating the expression of many of these genes, which may be important for the efficacy of our cancer vaccine strategy. Therefore, epigenetic manipulation may present an attractive means to fine-tune gene expression programs and maximize antigen secretion thereby increasing vaccine potency and the ability of a single vaccine to target a variety of cancer types.
Citation Format: George J. Fromm, Neal Schilling, Taylor H. Schreiber. Immunotherapy meets epigenetics: GP96-Ig cellular vaccine genetic signature is modulated by the inhibition of histone modifications. [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 5037. doi:10.1158/1538-7445.AM2015-5037
Abstract 504: Glutamine metabolic inhibitors suppress growth and tumorigenicity in MYC and MYCN-driven pediatric malignancies
Authors: Hanaford Allison , Guerra Catherine , Eberhart Charles , Raabe Eric , Price Antoinette 
Published: August 2015

Abstract
The MYC family of oncogenes is associated with aggressive pediatric cancers such as medulloblastoma and neuroblastoma. These transcription factors promote oncogenesis in part by altering cellular metabolism. In multiple types of cancer, high-level MYC expression drives increased glutamine metabolism. We hypothesized that MYC-driven medulloblastoma and MYCN amplified neuroblastoma would be sensitive to the glutamine metabolic inhibitors 6-diazo-5-oxo-l-norleucine (DON) and Acivicin. These drugs have previously be used in pediatric clinical trials, but never extensively clinically tested in MYC-driven malignancies. The high MYC medulloblastoma cell lines D425Med and D283Med experienced an 82% decrease in growth as measured by MTS assay when treated with Acivicin or DON (p&lt;0.004). DON and Acivicin treatment also caused a 400% increase in apoptosis as measured by cleaved caspase-3 immunofluorescence (p&lt;0.03). In human neural stem cells transformed with MYC, Acivicin treatment decreased proliferation by 50% as measured by BrdU incorporation (p&lt;0.003) and increased apoptosis by over 100% as measured by cleaved caspase-3 immunofluoresence (p&lt;0.0001). Human neural stem cells immortalized with SV40 were unaffected by Acivicin and DON treatment (p = 0.1). In mice with D283Med flank xenografts, Acivicin decreased the size of tumors by 70%. DON treatment decreased the volume of flank tumors by 94% in animals with D425Med xenografts (p = 0.001). In mice with D425Med cerebellar xenografts (p = 0.0018), DON tripled median survival from 26 to 90 days in animals with. The MYCN amplified neuroblastoma cell lines LAN5 and IMR32 were also sensitive to treatment with DON and Acivicin. DON and acivicin treatment significantly decreased proliferation as measured by BrdU incorporation (p&lt;0.03) and significantly increased apoptosis as measured by cleaved caspase-3 immunofluroescence (p&lt;0.003). The non-MYCN amplified neuroblastoma cell line SKNAS was resistant to treatment with both DON and Acivicin, suggesting that expression confers sensitivity to glutamine analogs. These data suggest glutamine metabolism is a therapeutic target in medulloblastoma and neuroblastoma with elevated MYC or MYCN levels, and potentially other pediatric cancer types associated with MYC oncogenes.
Citation Format: Allison Hanaford, Catherine Guerra, Charles Eberhart, Eric Raabe, Antoinette Price. Glutamine metabolic inhibitors suppress growth and tumorigenicity in MYC and MYCN-driven pediatric malignancies. [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 504. doi:10.1158/1538-7445.AM2015-504
Abstract 5044: Reducing breast cancer risk with hormone replacement therapy
Authors: Dembo Anna , Greene Geoffrey 
Published: August 2015

Abstract
Menopause occurs in women between the ages of 45 and 55 and often results in symptoms that can be alleviated with hormone replacement therapy (HRT). HRT improves the symptoms associated with menopause that negatively affect quality of life, such as hot flashes, difficulty sleeping, fatigue, and vaginal atrophy. HRT also prevents osteoporosis. A current HRT formulation, which includes conjugated equine estrogens (CE) and medroxyprogesterone acetate, unfortunately increases the risk of breast cancer. Over the years, the number of women taking HRT has decreased due to this perceived increased risk. A new form of HRT, which contains CE and bazedoxifene (BZA), a selective estrogen receptor modulator, has recently been approved by the FDA for treatment of moderate to severe hot flashes and for the reduction of osteoporosis development. The CE/BZA mixture has been shown to not only relieve symptoms associated with menopause, but also does not stimulate the breast or uterus. Various studies show that CE/BZA may be protective in the breast. Currently, the mechanism of action of this new combination therapy is not known. Our goal is to identify the molecular mechanism of action of CE/BZA through transcriptome and whole genome occupancy analysis in breast cancer cell lines. In addition, we are determining the effects of the combination therapy on breast cancer progression in a transgenic mouse model. The overall hypothesis of our project is that the ability of CE/BZA to delay the onset of mammary tumors and decrease the number of lesions in the polyoma middle T antigen transgenic mouse model is due to its action as an estrogen receptor α antagonist in the mammary gland. We have determined that CE stimulates gene expression in MCF7 cells at a similar rate to 17β-estradiol, and that BZA is able to decrease this stimulation. Similarly, we have found that CE increases ERα occupancy at promoters of some estrogen target genes, while a combination of CE and BZA decreases this occupancy. Through understanding the molecular mechanism of CE/BZA and by determining whether it reduces the incidence of invasive breast cancer in a transgenic mouse model, we will be able to improve quality of life for many women by relieving menopausal symptoms in a safe manner.
Citation Format: Anna Dembo, Geoffrey Greene. Reducing breast cancer risk with hormone replacement therapy. [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 5044. doi:10.1158/1538-7445.AM2015-5044
Abstract 5045: Characterization of estrogen receptor alpha phosphorylation sites as a marker for tamoxifen resistant breast cancer
Authors: Speckmann Wayne A. , Brockett Robert , Yang Chun , Mohan Chandra , Long Kevin , Hatler Michele , Xu Xiaoyi 
Published: August 2015

Abstract
A major focus of breast cancer research is to understand the mechanisms responsible for disease progression and drug resistance. Most treatment options target endocrine therapy, however, the processes that modulate these signaling pathways are poorly understood. Here, we seek to gain additional understanding about the phosphorylation status of the estrogen receptor as it relates to tamoxifin drug treatment. Tamoxifen, a selective ER inhibitor, was the first targeted breast cancer therapy developed. Unfortunately, tamoxifen therapy was shown to be ineffective for certain kinds of cancers and even in affected tumors an acquired resistance was eventually seen. Previous research has shown that the estrogen receptor protein is phosphorylated at more than 20 different sites and some of these sites are linked with poor prognosis in tamoxifen treated patients. For example, phosphorylation at the S305 site may lead to an activation of ERα and to transcription of ERα-responsive gene after tamoxifen treatment, leading to tamoxifen resistance. In addition, other phosphorylation sites have also been found to correlate with poor prognosis of tamoxifen treated patients. Thus, differential phosphorylation of ERα may serve as a biomarker to identify patients unlikely to respond to tamoxifen treatment. Here, utilizing a newly developed medium throughput IHC test system we have interrogated multiple sites of ERα for phosphorylation status by screening an extensive panel of different breast cancer patient samples and other non-breast cancer tissue microarray (TMA) samples. These patient samples were classified according to their clinical grade (ER positive or negative, Her2, progesterone positive or negative, and Ki67 index) and tamoxifen treatment and then screened for their ERα phosphorylation status. The results show unique staining patterns depending upon the tumor classification and conclusions about the utilization of this information as a potential for diagnostic applications will be discussed.
Citation Format: Wayne A. Speckmann, Robert Brockett, Chun Yang, Chandra Mohan, Kevin Long, Michele Hatler, Xiaoyi Xu. Characterization of estrogen receptor alpha phosphorylation sites as a marker for tamoxifen resistant breast 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 5045. doi:10.1158/1538-7445.AM2015-5045
Abstract 5047: Role of estrogen receptors alpha and beta in the balance between proliferation and surveillance
Authors: Jerry D. Joseph , Dunphy Karen A. , Roberts Amy L. , Brown Margarita 
Published: August 2015

Abstract
Estrogens have paradoxical effects in both promoting and preventing breast cancer. The proliferative actions of estrogens promote the expansion of both normal mammary epithelium and breast cancer. But estrogen also activates p53-mediated surveillance and apoptotic pathways to eliminate cells with potential oncogenic mutations. This is exemplified by tumor regression in response to high dose estrogen-treatment in postmenopausal breast cancer. Estrogens mediate their effects through the activation of two estrogen receptor subtypes: Estrogen Receptor alpha (ERα)and Estrogen Receptor beta (ERβ). Our objective is to examine the contribution of these receptors in mediating surveillance as opposed to proliferation by comparing selective estrogen receptor agonists with 17β-estradiol (E2) for induction of proliferation and surveillance in three model systems: (1) in vivo mouse model, (2) in vitro MCF7-tet-off-ERβ model, and (3) an ex-vivo human mammary explant model. Selective activation of ERβ with the agonist diarylpropionitrile (DPN) in vivo enhances p53-mediated apoptosis in the mouse mammary epithelium without stimulating proliferation. In addition, radiation-induced apoptosis is significantly reduced in mice lacking ERβ (βERKO). E2 or the ERα selective agonist pyrazole triol (PPT) induced the expression of estrogen response genes including progesterone receptor and amphiregulin in all three models. DPN-mediated activation of ERβ failed to induce the expression of these genes. The ERβ agonist DPN selectively induced the expression of genes that repress proliferation including TGFβ and inhibitors of canonical WNT signaling, WNT5a and AXIN2. DPN was also more potent in stimulating EGR1, a modulator of p53 activity, and CEBPd, a pro-apoptotic gene. Conclusions: The ability of DPN and ERβ to potentiate surveillance pathways while limiting proliferation suggests that ERβ agonists may provide a new approach for chemoprevention of breast cancer.
Citation Format: D. Joseph Jerry, Karen A. Dunphy, Amy L. Roberts, Margarita Brown. Role of estrogen receptors alpha and beta in the balance between proliferation and surveillance. [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 5047. doi:10.1158/1538-7445.AM2015-5047
Abstract 5054: Discerning the PARP-dependent AR cistrome/transcriptome in prostate cancer
Authors: Schiewer Matthew J. , Han Sumin , Evans Joseph , Augello Michael A. , Berman-Booty Lisa , Parsons Theodore , Birbe Ruth , Dicker Adam P. , Kelly William Kevin , Gomella Leonard G. , Feng Felix , Knudsen Karen E. 
Published: August 2015

Abstract
Poly (ADP-ribose) polymerase 1 (PARP-1) is an abundant nuclear enzyme that modifies substrates by poly (ADP-ribose)-ylation. Although PARP-1 has a number of well-described roles in the response to and repair of DNA damage (especially as associated with base excision repair), significant studies have demonstrated that PARP-1 functions in transcriptional regulation in multiple contexts. In the context of prostatic adenocarcinoma (PCa), our group recently discovered that PARP-1 enzymatic activity is a critical effector of androgen receptor (AR) function, and is recruited to regulatory sites of select AR target genes. Pharmacological inhibition of PARP-1 enzymatic activity results in diminished AR and PARP-1 residency at AR target gene regulatory loci, reduced AR target gene expression, and reduced AR-driven, PCa-associated phenotypes, including castrate-resistant PCa (CRPC) AR function, tumor cell growth, and transition to CRPC. Accordingly, to gain further mechanistic insight in to the PARP-1-dependent AR cistrome/transcriptome, unbiased genome-wide analyses were undertaken in both hormone therapy-sensitive PCa and CRPC model systems. Data to be discussed provide essential insight into the mechanisms by which PARP-1 modulates gene regulation and AR function, but also identifies new and unexpected functions of PARP-1 in human malignancies.
Citation Format: Matthew J. Schiewer, Sumin Han, Joseph Evans, Michael A. Augello, Lisa Berman-Booty, Theodore Parsons, Ruth Birbe, Adam P. Dicker, William Kevin Kelly, Leonard G. Gomella, Felix Feng, Karen E. Knudsen. Discerning the PARP-dependent AR cistrome/transcriptome 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 5054. doi:10.1158/1538-7445.AM2015-5054
Abstract 5061: Astrocytes promote medulloblastoma tumorigenesis via sonic hedgehog secretion
Authors: Yuelling Larra Walling , Du Fang , Lee Eric , Muradimova Renata , Li Peng , Yang Zeng-jie 
Published: August 2015

Abstract
Tumor development is a complex process that involves interactions between tumor cells and the surrounding cells (the microenvironment). However, in medulloblastoma (MB), the most common malignant pediatric brain tumor, the contribution of the tumor microenvironment in tumorigenesis still remains elusive. Using MB mouse models, we have recently found that astrocytes represent the major component of the MB microenvironment. Astrocytes significantly enhance MB cell proliferation in vitro and genetic ablation of astrocytes dramatically prevents MB cell proliferation and inhibits MB growth in tumor-bearing mice. These results indicate the critical role of astrocytes during MB development. Our studies have further revealed that astrocytes stimulate proliferation of MB cells by secretion of sonic hedgehog (Shh), a mitogen required for neuronal proliferation during normal development. It is well established that Shh triggers canonical hedgehog signaling via activation of the Gli1 transcription factor. Interestingly, astrocyte-derived Shh stimulates MB cell proliferation independent of Gli1 activation, suggesting that astrocytes promote MB tumorigenesis through a novel Shh signaling pathway. Together, our studies shed light on the important function of the tumor microenvironment in MB initiation and progression, and pave the road to develop therapeutic approaches to treat MB by targeting Shh secretion in astrocytes.
Note: This abstract was not presented at the meeting.
Citation Format: Larra Walling Yuelling, Fang Du, Eric Lee, Renata Muradimova, Peng Li, Zeng-jie Yang. Astrocytes promote medulloblastoma tumorigenesis via sonic hedgehog secretion. [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 5061. doi:10.1158/1538-7445.AM2015-5061
Abstract 5068: Treatment with regorafenib inhibits the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic nude mice model of colon cancer
Authors: Shinagawa Kei , Kitadai Yasuhiko , Yuge Ryo , Onoyama Mieko , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: August 2015

Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to migrate to tumor stroma as well as injured tissue. We reported that, in an orthotopic nude mice model of colon cancer, MSCs travel to tumor stroma and differentiate into carcinoma-associated fibroblasts (CAFs), and then, they promote growth and metastasis of colon cancer. We also found that CAFs express platelet-derived growth factor receptor-beta (PDGFR-β), at a high level and that imatinib therapy targeting PDGFR in CAFs combined with administration of a cytotoxic drug significantly inhibits growth and metastasis of human colon cancer. A novel oral multi-kinase inhibitor, regorafenib not only inhibits oncogenic receptor tyrosine kinases such as c-KIT, RET, and B-RAF, but also inhibits stromal cells which express VEGFR1-3, TIE2, PDGFR-β, and fibroblast growth factor receptor 1 (FGFR1). These cell surface receptor tyrosine kinases are known to be involved in tumor neovascularization, vessel stabilization, lymphatic vessel formation as well as activation of stroma. We examined whether the effect of MSCs on tumor growth and metastasis was inhibited by regorafenib. KM12SM human colon cancer cells alone or KM12SM cells mixed with MSCs in a 1:2 ratio were transplanted into the cecal wall of nude mice. Orthotopic transplantation of KM12SM cells + MSCs, in comparison to transplantation of KM12SM cells alone, resulted in tumors of greater weight and volume, and higher rate of lymphatic metastasis. Co-injection of MSCs with tumor cells promoted tumor growth and metastasis of colon cancer by enhancing angiogenesis, lymphangiogenesis, and tumor cell proliferation and by inhibiting tumor cell apoptosis. When CRC tumor + MSCs bearing animals were treated with regorafenib (by oral gavage once daily at 10 mg/kg for 35 days), primary tumor size or the number of lymph node metastases were significantly decreased compared to those treated with vehicle, and reached to the level with no significant difference from KM12SM tumor cells alone. Our data suggest that targeting tumor microenvironmental signaling pathways by regorafenib influences the interaction between bone marrow-derived MSCs and tumor cells and, hence, inhibits the progressive growth of colon cancer.
Citation Format: Kei Shinagawa, Yasuhiko Kitadai, Ryo Yuge, Mieko Onoyama, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Treatment with regorafenib inhibits the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic nude mice model of colon 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 5068. doi:10.1158/1538-7445.AM2015-5068
Abstract 507: Ionizing radiation regulates mutant p53-mediated cancer cell invasiveness through targeting cyclin D1
Authors: Lee Shin-Hee , Craigmile Phillip , Wu Shiyong 
Published: August 2015

Abstract
Ionizing radiation (IR) is widely used as a main treatment for solid tumors, however, its potential influence and its role in the invasion and metastasis of cancer still remain unknown. In this study, we found that IR showed an inhibitory effect on the invasion of mutant p53 expressing cancer cells through targeting cyclin D1, which has been known as implicated in invasion and metastasis. Our data showed that gamma-irradiation (5 Gy) decreased trans-well migration of mutant p53 expressing cancer cells. It has been reported that following exposure to IR cyclin D1 is rapidly degraded via the ubiquitin pathway. We showed that IR-induced cyclin D1 degradation is restored after 24 hr in H1299 p53 negative cells. In contrast, cyclin D1 depletion was not recovered in H1299 mutant p53 cells, suggesting its inhibiting effect on cyclin D1 regulation. In addition, the levels of matrix metalloproteinase 9 were decreased in mutant p53 expressing cancer cells, indicating the reduction of cell migration and invasion. These data indicate that IR suppresses the restoration of cyclin D1 via the mutant p53, thus inhibiting the invasion of cancer cells expressing mutant p53.
Citation Format: Shin-Hee Lee, Phillip Craigmile, Shiyong Wu. Ionizing radiation regulates mutant p53-mediated cancer cell invasiveness through targeting cyclin D1. [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 507. doi:10.1158/1538-7445.AM2015-507