tbuckley/cabot-search huggingface dataset:
Abstract 4653: Genomics of regulatory crosstalk between PPAR gamma &amp; 14-3-3 genes in breast cancer cells
Authors: Ashraf A. Khalil, Nihal F. Kabapy, Fouad N. Sharabi
Journal: Cancer Research (2017)

Abstract PPARγ, a ligand-stimulated transcription factor with differentiation promoting activity is overexpressed in a variety of cancers. Perturbation of PPAR-γ signaling is now believed to be a strategy for treatment of several cancers, including breast cancer. A set of genes regulated by PPAR-γ ligands is expected to mediate the antiproliferative and prodifferentiation effects in cancer cells. Because 14-3-3 family of proteins shows a debatable activity and varying expression levels in different tumors, in the studies presented here we explored the transcriptional regulatory role of Pioglitazone on the seven 14-3-3 isoforms presenting in MCF-7 breast cancer cells. This study demonstrated that the potent PPAR-γ agonist, Pioglitazone exerted a regulatory role on expression of 14-3-3 genes where it upregulated 14-3-3 gamma, epsilon, zeta and tau by 3.8, 5.2, 2.7 and 739 folds, respectively. However, it had a negative regulatory effect on 14-3-3 beta, sigma and Eta by 16.94, 4.58 and 2.12 folds, respectively compared with control cells. These results correlated with growth arrest and a great increase in BRCA1 gene expression by 1076 folds. In summary, these findings are the first time showing that PPAR-γ regulates 14-3-3 genes and raises question whether PPAR-γ ligands mediate their anticancer effects via regulation of 14-3-3 proteins. Selected References: 1. Bridges, D. and G.B. Moorhead. 2005. 14-3-3 proteins: a number of functions for a numbered protein. Sci. STKE 2005(296):re10. 2. Chearwae, W. and J. Bright. 2008. PPARγ agonists inhibit growth and expansion of CD133+; brain tumour stem cells. Brit. J. Cancer 99(12): 2044-2053 Citation Format: Ashraf A. Khalil, Nihal F. Kabapy, Fouad N. Sharabi. Genomics of regulatory crosstalk between PPAR gamma &amp; 14-3-3 genes in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4653. doi:10.1158/1538-7445.AM2017-4653
Abstract 4196: Anti-tumor activity of a TAM kinase-targeting compound in CT-26 syngeneic mouse model
Authors: Shenshen Lai, Hong Zhang, Jun Yan, Zaihui Zhang
Journal: Cancer Research (2017)

Abstract Aberrant expression of TAM family receptor tyrosine kinases, comprising Tyro3, Axl and Mer, is found in virtually every type of human cancer. The expression levels correlate positively with disease staging and prognostic outcome, attributing to metastasis and drug resistance. The TAM kinases have recently emerged as a dual oncological therapeutic target, owing to their immunosuppressive activity. Apart from targeting tumor-survival/growth pathways their inhibition also unleash the anti-tumor immunity in the tumor microenvironment. In our efforts to develop small-molecule inhibitors targeting the TAM kinases, we identified SLC-391 as one of the most promising preclinical candidates with potent activity towards both Axl and Mer, which play roles in maintaining tumor survival and immunosuppressive tumor microenvironment, respectively. Pharmacodynamic studies of SLC-391 in CT26 syngeneic mouse model revealed increase in the number of NK cells and the ratio of M1/M2-polarized macrophages in the treatment group relative to the vehicle control, followed by the rise of CD8+ T/Treg ratio and reduction in immunosuppressive myeloid cells. This is indicative of sequential engagement and stimulation of pro-inflammatory innate immune response and adaptive immune response. In addition, a synergistic anti-tumor effect was observed when the anti-PD-1 insensitive CT-26 model was treated with a combination of SLC-391 and an anti-PD-1 antibody, suggesting that blocking the Axl/Mer-mediated immunosuppressive pathway may significantly enhance the therapeutic efficacy of immune checkpoint inhibitors. In summary, the anti-tumor activity of SLC-391 is mediated by directly inhibiting tumor cell growth as well as reversing the immunosuppressive tumor microenvironment. Citation Format: Shenshen Lai, Hong Zhang, Jun Yan, Zaihui Zhang. Anti-tumor activity of a TAM kinase-targeting compound in CT-26 syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4196. doi:10.1158/1538-7445.AM2017-4196
Abstract 1528: Forecasting novel therapies by understanding the role BRD4 in regulating the Notch3 signaling in ovarian cancer
Authors: Alejandro Villar-Prados, Sherry Y. Wu, Jason Roszik, Anil K. Sood, Margaret I. Engelhardt
Journal: Cancer Research (2017)

Abstract Advances in cancer research have led to the rapid development of novel drug therapies designed for optimal personalized patient care. Despite this surge of treatments, there is still a challenge in accurately predicting the most effective targeted therapy for a specific cancer. Additionally, the potential of systematically identifying and re-purposing currently existing therapeutics designed for one specific cancer to treat other malignancies remains understudied. To address this problem, our group has developed an integrative computational therapy-forecasting algorithm. This algorithm incorporates data from The Cancer Genome Atlas (TCGA) as well as molecular and survival correlations to identify candidate anti-tumor drugs that can be re-purposed for other malignancies by targeting novel pathways. Our computational analysis predicted that bromodomain inhibitors, which inhibit bromodomain-containing proteins such as BRD4, would target the Notch3 pathway in high-grade serous ovarian carcinoma (HGSC). Upregulation of Notch3 plays a crucial role in HGSC tumorigenesis and is associated with worse patient survival. Current Notch3 targeted therapies are not effective, thus designing therapeutic strategies to target Notch3 are critical for HGSC. We hypothesize that inhibition of BRD4 is an effective therapeutic target in HGSC by downregulating the Notch3 pathway. Current in vitro results demonstrated that BRD4 inhibition either by using chemical inhibitors or siRNA results in a decrease in HGSC cell viability by both MTT and 2-D colony formation assays. Furthermore, inhibition of BRD4 resulted in a decrease in both Notch3 transcription and protein levels. Given that BRD4 regulates gene transcription, we performed chromatin immunoprecipitation (ChIP) and observed that BRD4 was present in the Notch3 gene promoter. These findings suggest that by inhibiting BRD4 in HGSC, we can target Notch3 and biologically validates our initial in sillico analysis. The successful completion of this project could have major implications for development of personalized therapies not only for HGSC but for other cancers as well. Note: This abstract was not presented at the meeting. Citation Format: Alejandro Villar-Prados, Sherry Y. Wu, Jason Roszik, Anil K. Sood, Margaret I. Engelhardt. Forecasting novel therapies by understanding the role BRD4 in regulating the Notch3 signaling in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1528. doi:10.1158/1538-7445.AM2017-1528
Abstract 2222: Sildenafil suppresses inflammation-driven colorectal cancer in mice
Authors: Bianca N. Islam, Sarah K. Sharman, Yali Hou, Allison Bridges, Ravindra Kolhe, JImena Trillo-Tinoco, Nagendra Singh, Sangmi Kim, Subbaramiah Sridhar, Frankin G. Berger, Darren D. Browning
Journal: Cancer Research (2017)

Abstract Intestinal cyclic guanosine monophosphate (cGMP) signaling regulates epithelial homeostasis, and has been implicated in the suppression of colitis and colorectal cancer (CRC). In this study, we investigated the cGMP-specific phosphodiesterase-5 (PDE5) inhibitor sildenafil to prevent tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) inflammation-driven colorectal cancer model. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against DSS-induced barrier dysfunction. In mice treated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared to untreated controls. Polyps formed in sildenafil-treated mice showed less proliferation and were more differentiated compared to polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil-treated mice were also less inflamed; they exhibited reduced myeloid-cell infiltration, and reduced expression of iNOS, IFNγ and IL-6 compared to untreated controls. Most of the protection was observed when sildenafil was added during the initiation stage of carcinogenesis (40% reduction in multiplicity), whereas administration of sildenafil later during the promotion stages did not affect polyp number. While later treatment with sildenafil did not affect multiplicity, it did have a similar effect on polyp phenotype, including increased mucus production, reduced proliferation and inflammation. In summary, our results demonstrate that oral administration of sildenafil suppresses inflammation and polyp formation in mice treated with AOM/DSS. This suggests that PDE5 inhibitors could have therapeutic value for the prevention of CRC in inflammatory bowel disease patients. Citation Format: Bianca N. Islam, Sarah K. Sharman, Yali Hou, Allison Bridges, Ravindra Kolhe, JImena Trillo-Tinoco, Nagendra Singh, Sangmi Kim, Subbaramiah Sridhar, Frankin G. Berger, Darren D. Browning. Sildenafil suppresses inflammation-driven colorectal cancer in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2222. doi:10.1158/1538-7445.AM2017-2222
Erratum to: Long non-coding RNA ANRIL is upregulated in hepatocellular carcinoma and regulates cell proliferation by epigenetic silencing of KLF2
Authors: Ming-de Huang, Wen-ming Chen, Fu-zhen Qi, Rui Xia, Ming Sun, Tong-peng Xu, Li Yin, Er-bao Zhang, Wei De, Yong-qian Shu
Journal: Journal of Hematology & Oncology (2017)
Abstract 4165: <i>SOX2</i> promotes lineage plasticity and antiandrogen resistance in <i>TP53</i> and <i>RB1</i> deficient prostate cancer
Authors: Ping Mu, Zeda Zhang, Matteo Benelli, Wouter Karthaus, Elizebeth Hoover, Chi-Chao Chen, John Wongvipat, Sheng-Yu Ku, Dong Gao, Zhen Cao, Neel Shah, Elizabeth Adams, Wassim Abida, Philip Watson, Davide Prandi, Chun-Hao Huang, Elisa de Stanchina, Scott Lowe, Leigh Ellis, Himisha Beltran, Mark Rubin, David Goodrich, Francesca Demichelis, Charles L. Sawyers
Journal: Cancer Research (2017)

Abstract Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. Here we show, using in vitro and in vivo prostate cancer models, that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR) dependent luminal epithelial cells to AR independent basal-like cells. This lineage plasticity is enabled by loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2 and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching. Citation Format: Ping Mu, Zeda Zhang, Matteo Benelli, Wouter Karthaus, Elizebeth Hoover, Chi-Chao Chen, John Wongvipat, Sheng-Yu Ku, Dong Gao, Zhen Cao, Neel Shah, Elizabeth Adams, Wassim Abida, Philip Watson, Davide Prandi, Chun-Hao Huang, Elisa de Stanchina, Scott Lowe, Leigh Ellis, Himisha Beltran, Mark Rubin, David Goodrich, Francesca Demichelis, Charles L. Sawyers. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53 and RB1 deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4165. doi:10.1158/1538-7445.AM2017-4165
Abstract 249: Dietary supplementation with methylseleninic acid reduces male mammary tumorigenesis in MMTV-PyMT mice
Authors: Sneha Sundaram
Journal: Cancer Research (2017)

Abstract Male breast cancer makes up approximately 1% of all breast cancers and less than 1% of all cancers in men in the United States. However, it is an aggressive disease with poor prognosis and the incidence of male breast cancer is on the rise. The present study investigated the effects of dietary supplementation of selenium on male breast carcinogenesis in MMTV-PyMT mice (FVB/N background). Three-week-old male mice were weaned onto the AIN93G diet with or without supplementation of selenium in the form of methylseleninic acid (2.5 mg Se/kg). Mice were euthanized 10 weeks after the first palpable mammary tumor was detected. There were no differences in food intake and body weight between the groups. The median latency (the age at which the first palpable tumor was detected) was 14.1 and 13.9 weeks and the incidence of palpable mammary tumor was 71% and 70% for the control and the selenium group, respectively. Selenium supplementation compared to the control diet reduced mammary tumor progression by 258% and tumor weight by 84%, respectively. Tumor progression was defined as the change in tumor volume from detection of the first palpable mammary tumor to termination 10 weeks later. Incidence of lung metastasis was 74% and 50% in control and selenium group, respectively. In mice bearing lung metastases, selenium supplementation significantly reduced the number of metastases by 83% compared to the control group. In conclusion, dietary supplementation with selenium in the form of methylseleninic acid reduces male breast carcinogenesis and its metastasis in mice. It indicates that selenium may be useful in male breast cancer prevention. Citation Format: Sneha Sundaram. Dietary supplementation with methylseleninic acid reduces male mammary tumorigenesis in MMTV-PyMT mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 249. doi:10.1158/1538-7445.AM2017-249
Abstract 2532: High expression of MiR-432-3p is associated with the chemoresistance by NRF2 stabilization via directly targeting KEAP1
Authors: Burak Akdemir, Jun Inoue, Tatsuyuki Kawano, Johji Inazawa
Journal: Cancer Research (2017)

Abstract NF-E2-related factor 2 (NRF2) is a master transcriptional regulator that integrates cellular stress responses and is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1) at the post-translational level. In human cancers, aberrantly stabilized NRF2, either by mutation of NRF2 or KEAP1, plays a vital role in chemoresistance through the activation of target genes, suggesting that targeted inhibition of NRF2 is a potential therapy for NRF2-stabilized tumors. MicroRNAs (miRNA) are endogenous small noncoding RNAs that can negatively regulate gene expression by interfering with the translation or stability of target transcripts. Previously, we identified miRNAs negatively regulating NRF2 pathway via directly targeting NRF2 itself by a reporter-coupled miRNA library screening and demonstrated the potential of miRNA-based therapy against NRF2-stabilized tumors in esophageal squamous cell carcinoma (ESCC) (Mol. Cancer Res 2014, Cancer Res 2015). In the present study, we further identified miR-432-3p as a miRNA positively regulating NRF2 pathway. MiR-432-3p could directly targeted KEAP1 via binding to its seed sequence within the cording region. Overexpression of miR-432-3p resulted in enhanced resistance to cisplatin via activation of NRF2 in ESCC cell lines. Furthermore, miR-432-3p was overexpressed in 55 of 84 primary ESCC tumors, compared with that of corresponding non-cancerous esophageal mucosa (65.5%). Importantly, we showed the negative correlation between the expression level of KEAP1 and miR-432-3p in primary ESCC tumors. Taken together, these findings suggest that the high expression of miR-432-3p may contribute to the chemoresistance by NRF2 stabilization via down-regulation of KEAP1 expression in ESCC. Citation Format: Burak Akdemir, Jun Inoue, Tatsuyuki Kawano, Johji Inazawa. High expression of MiR-432-3p is associated with the chemoresistance by NRF2 stabilization via directly targeting KEAP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2532. doi:10.1158/1538-7445.AM2017-2532
Abstract 633: Induction of ADCC resistance profoundly alters tumor cell phenotype and stress response
Authors: Dalal S. Aldeghaither, Joseph C. Murray, Sarah M. Roth, Elana J. Fertig, Shaojun Tang, Sandra A. Jablonski, Louis M. Weiner
Journal: Cancer Research (2017)

Abstract Antibody dependent cellular cytotoxicity (ADCC) is one mechanism by which monoclonal antibodies (mAb) work. In addition to ADCC, mAbs act on their target by causing signal perturbation and complement activation. Cetuximab is an EGFR targeting mAb used to target EGFR overexpression and amplification seen in many types of cancer. While mechanisms of resistance to EGFR targeted therapy have been extensively studied, resistance to ADCC has not, mainly due to the lack of ADCC-resistance models for study. To address this limitation we established a model system for anti-EGFR ADCC using NK92-CD16V effector cells, cetuximab, and the high EGFR-expressing squamous cell carcinoma cell line A431. Continuous A431 exposure to ADCC yielded an ADCC resistant phenotype (ADCCr) that exhibits a stable phenotype in the absence of continued ADCC selection. We have explored: ADCCr cell gene expression profile, NK cell activation, metabolic signature and subsequent RPPA analysis to further understand the causes and properties associated with this resistance. This ADCCr cell line has a distinctive transcriptional profile highlighted by overexpression of histone- and interferon-related genes, reduced sensitivity to antimetabolites, DNA-intercalating and ABC transporter-regulated cytotoxic agents. Intense ADCC selection causes epigenetic modification and stress response characterized by the transcriptional overexpression of PCAF (KAT2B), which initiates histone hyper-acetylation and epigenetic changes, inducing DNA replication arrest, DNA damage and stress responses that activate checkpoint signaling in the cell cycle. The pharmacologic inhibition of KAT2B reverses the ADCCr phenotype. Immune checkpoints such as PD-L1 do not modulate ADCC in this model system. These results shed light on new mechanisms of ADCC resistance and inform future combinatorial treatments for mAb therapy. We are exploring the possibility that stress response mechanisms are responsible for resistance for diverse selection pressures imposed by immune synapse-mediated cytotoxic attack. Citation Format: Dalal S. Aldeghaither, Joseph C. Murray, Sarah M. Roth, Elana J. Fertig, Shaojun Tang, Sandra A. Jablonski, Louis M. Weiner. Induction of ADCC resistance profoundly alters tumor cell phenotype and stress response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 633. doi:10.1158/1538-7445.AM2017-633
Abstract 4208: Inhibition of proliferation and induction of apoptosis by a novel phytobiological mixture against breast cancer cell lines
Authors: Afnan A. Alqarni, Aliaa A. Alamoudi, Ghada M. Ajabnoor, Ahmed M. Al-Abd, Aleksandra Niedwiecki, Matthias Rath, Steve Harakeh
Journal: Cancer Research (2017)

Abstract Breast cancer remains a leading cause of women’s death worldwide with progressive emergence of resistance towards approved chemotherapies. For this reason, new complementarytreatments have been sought. One of those includethe use of a phytobiological mixture against different types of malignancies, including but not limited to breast cancer. Herein, we investigated the anti-proliferative effects of a novel phytobiological mixture (PB)against two breast cancer cell lines :MDA-MB-231 and MCF-7.The PB mixture is composed of the following: quercetin, resveratrol, cruciferex, epigallocatechin-3-gallate and curcumin at different proportions. Theanti-proliferative and pro-apoptotic effects of PB were evaluated at non-cytotoxic concentrations as determined usingthe Sulfa-Rhodamine B assay (SRB).The effects of PB on the induction of apoptosis were valuated using Annexin-V and flow cytometry to measure the resultingDNA fragments. The results showed that at 72hrs, PB had cytotoxic effects against MDA-MB-231 and MCF-7 cells with an IC50’s of 25.8±5.4 µg/ml and 56.9±4.2 µg/ml, respectively. Exposure of MDA-MB-231 to PB for 72hrs resulted in the induction of apoptosis in a dose-dependent manner. PB concentrations of 10 µg/ml and 30 µg/ml, resulted in early programmed cell death of 9.1±1.5% and 22.1±1.8% respectively. Exposure to PB (10 µg/ml for 24 hrs) resulted in mild cell cycle arrest at the G2/M phase20.3±0.3% ;while higher dosesshowed a significant cell cyclearrest at theS-phaseas compared to the control untreated cells (p&amp;lt;0.001). However, exposure to PB for 48 hrs at both doses,10 µg/ml and30 µg/ml,resulted in a significant cell cycle arrest at the S-phase 25.3±1.6% and 20.5± 0.4%respectivelyas compared to the control untreated cells 12.4±1.5% (p&amp;lt;0.001). In conclusion, PB was found to have a promising anti-proliferative and pro-apoptotic effect in breast cancer cell lines. Further studies are needed to address the underlying mechanism of action of PB against breast cancer cell lines. Citation Format: Afnan A. Alqarni, Aliaa A. Alamoudi, Ghada M. Ajabnoor, Ahmed M. Al-Abd, Aleksandra Niedwiecki, Matthias Rath, Steve Harakeh. Inhibition of proliferation and induction of apoptosis by a novel phytobiological mixture against breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4208. doi:10.1158/1538-7445.AM2017-4208