tbuckley/cabot-search huggingface dataset:
Abstract 2877: IKK-mediated signaling controls prostate tumor initiating cells
Authors: Sara E. Conard, Aaron Ebbs, Albert S. Baldwin
Journal: Cancer Research (2017)

Abstract The heterogeneous nature of prostate cancer tumors is thought to play an important role in the decreased effectiveness of existing therapies. Tumor initiating cells (TICs) are capable of self-renewal and comprise a subset of the tumor mass. These cells are proposed to drive the growth and metastasis of tumors, and are considered to be resistant to traditional cytotoxic and targeted therapies. Several studies have shown that NF-κB signaling is increased in recurrent prostate cancer and enriched in prostate TICs. We sought to determine the potential of an IKK/NF-κB-driven mechanism for inherent or acquired resistance by IKK-mediated control of a subset of prostate tumor initiating cells. These studies were performed by using established prostate cancer cell lines, murine prostate organoids, and a murine prostate cancer animal model. We have found that inhibition of IKKα and IKKβ, upstream regulators of noncanonical and canonical NF-κB signaling, block self-renewal of several PTEN-deficient prostate cancer cell lines. Furthermore, we have also found that IKK is important for tumorigenicity and stemness seen in prostate cancer cells as measured by colony formation and extreme limiting dilution assays. Loss of canonical NF-κB (p65/RelA) decreased stemness while loss of noncanonical did not alter tumorsphere formation. Interestingly, Pten-/- tumors with loss of Ikkα or Ikkβ displayed decreased levels of self-renewing cells as measured by CD49fhigh expression, a known prostate basal cell marker. Isolated murine Pten-/- cells were 2x more efficient than Pten-/-Ikkα-/- or Pten-/-Ikkβ-/- cells in forming prostate organoids suggesting that loss of Ikk decreased the number of self-renewing cells needed for formation. Taken together, we conclude that IKK-mediated signaling is important for maintenance of prostate tumor initiating cells and further studies will address whether IKK-mediated signaling provides a mechanism for evading current therapies. Note: This abstract was not presented at the meeting. Citation Format: Sara E. Conard, Aaron Ebbs, Albert S. Baldwin. IKK-mediated signaling controls prostate tumor initiating 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 2877. doi:10.1158/1538-7445.AM2017-2877
Abstract 3441: A novel lncRNA-mediated YAP1 signaling pathway activation in epithelial ovarian cancer
Authors: Xianzhi Lin, Rosario I. Corona, Simon A. Gayther, Dennis L. Hazelett, Kate Lawrenson
Journal: Cancer Research (2017)

Abstract Background: The long noncoding RNA (lncRNA) urothelial cancer associated 1 (UCA1) is upregulated in many cancer types, including ovarian cancer. In high grade serous ovarian cancers (HGSOCs), we had previously found that UCA1 expression negatively correlates with patients’ total survival and disease-free survival and that UCA1 knockout significantly impairs tumor growth in vivo. In addition, UCA1 promotes ovarian cancer cell growth via activating the YAP1 signaling pathway. Purpose: Our present study aims to dissect the molecular mechanisms underlying YAP1 signaling activation by UCA1. Methods: To characterize the UCA1 interactome, we utilized a modified in vivo RNA antisense purification method (UCA1-iRAP). This UCA1-iRAP method uses streptavidin-coupled magnetic beads to pull down biotin-labeled antisense probes which are complementary to the target RNA. In such a way, UCA1 RNA will be specifically enriched together with its in vivo-associated proteins, RNAs and/or genomic DNA, which can be profiled using mass spectrometry (MS) and next generation sequencing (NGS), respectively. Results: Using UCA1-iRAP RNA-Seq and UCA1-iRAP protein MS, we comprehensively annotated the UCA1-interacting RNAs as well as UCA1-associated proteins. Interestingly many of the proteins identified were not known to have RNA-binding potential. Integration of NGS and MS data with multilayered functional and molecular characterization of UCA1 knockout, knockdown and overexpression models identified a YAP1 modulator involved in UCA1-mediated regulation of YAP1 signaling. Through repressing this YAP1 modulator via direct RNA-protein interaction, UCA1 promotes nuclear translocation of YAP1, resulting in activation of YAP1 target genes expression. Conclusions: Our analyses indicate, for the first time, that UCA1 promotes ovarian cancer cell growth by activating YAP1 signaling via direct interaction with a YAP1 modulator. The interaction between UCA1 and this YAP1 modulator leads to activation of YAP1 signaling by nuclear translocation of YAP1. In summary, we characterize a novel UCA1-YAP1 signaling axis active in HGSOCs and also reveal that oncogenic lncRNA’s binding potential of cytoplasmic signaling proteins could be a common mechanism of post-translational control of signaling pathways deregulated in cancer. Note: This abstract was not presented at the meeting. Citation Format: Xianzhi Lin, Rosario I. Corona, Simon A. Gayther, Dennis L. Hazelett, Kate Lawrenson. A novel lncRNA-mediated YAP1 signaling pathway activation in epithelial 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 3441. doi:10.1158/1538-7445.AM2017-3441
Abstract 5733: Expression levels of UL16 binding protein 1 and natural killer group 2 member D in patients with gastric cancer
Authors: Kiyoshi Yoshimura, Moeko Inoue, Tetsuhiko Asao, Masanori Fuse, Satoshi Wada, Atsuo Kuramasu
Journal: Cancer Research (2017)

Abstract UL16 binding protein 1 (ULBP1) expressed on the tumor cell surface binds to the natural killer group 2 member D (NKG2D) receptor presenting on natural killer (NK), CD8+ T, and gamma delta T cells. However, the roles of ULBP1 and NKG2D expression and associated immune responses in gastric cancer are unclear. Here, we investigated the relationships between ULBP1 and NKG2D expression and clinical outcomes in patients with gastric cancer. The expression levels of ULBP1 and NKG2D were examined in human gastric cancer cell lines and gastric cancer tissues from 98 patients who underwent surgery from 2004 to 2008. MKN-72 cells expressed ULBP1 with ULBP2, -5, or -6. NKG2D was expressed at a higher level after activation on T cells and NK cells. Among tissue sections positive for NKG2D expression, six cases were positive for CD8 and CD56. In all tissues, NKG2D-expressing cells were typically aCD8+ T cells. Patients with NKG2D expression in tumors had significantly longer overall survival (OS) than patients without NKG2D expression in tumors (p = 0.0217). The longest OS was observed in patients positive for both ULBP1 and NKG2D, whereas the shortest OS was observed in patients negative for both ULBP1 and NKG2D. The interaction between ULBP1 and NKG2D may improve OS in patients with gastric cancer and may have applications in immunotherapy for induction of adaptive immunity in patients with cancer. Moreover, ULBP1 and NKG2D may be useful as prognostic biomarker in gastric cancer. Citation Format: Kiyoshi Yoshimura, Moeko Inoue, Tetsuhiko Asao, Masanori Fuse, Satoshi Wada, Atsuo Kuramasu. Expression levels of UL16 binding protein 1 and natural killer group 2 member D in patients with gastric 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 5733. doi:10.1158/1538-7445.AM2017-5733
Abstract 4043: Design of a novel MGMT inhibitor targeted to EGFR overexpressing tumor cells: a new approach to selectively potentiate temozolomide in refractory tumors
Authors: Martin Rupp, Bertrand J. Jean-Claude
Journal: Cancer Research (2017)

Abstract Temozolomide (TMZ) is an oral alkylating agent commonly used as a first-line chemotherapeutic agent for the treatment of high-grade gliomas and melanoma. Alkylation of the O6-position of guanine in DNA is mainly responsible for the antitumor effect of TMZ. The primary mechanism of chemoresistance to TMZ has been shown to be the overexpression of the DNA repair enzyme O6-methylguanine methyltransferase (MGMT) that specifically removes the methyl lesions from the O6-position of guanine. While O6-benzylguanine (O6-BG), a potent inhibitor of MGMT, was shown to sensitize tumor cells to TMZ in vitro and in vivo, the O6-BG+TMZ combination failed in clinical trial due to acute hematologic toxicity. To circumvent this problem, we wish to target O6-BG to the epidermal growth factor receptor (EGFR), a receptor that is not generally expressed in the hematological cells but overexpressed in many solid tumors. We have now successfully designed and synthesized one such molecule termed MR30 and showed that: 1) MR30 is capable of blocking EGFR and depleting MGMT levels in whole cells; 2) MR30 is a unique molecule capable of inducing stronger growth inhibition than the 2-drug combination involving clinical EGFR and MGMT inhibitors in a panel of melanoma, lung, prostate and ovarian cancer cell lines; 3) MR30 in vitro potentiated the effect of TMZ on MGMT positive cell lines; 4) its kinase inhibitory profiling over 25 different kinases demonstrated selectivity for EGFR, HER2 and EGFR mutant forms; 5) an isogenic model showed more than 70-fold selectivity towards EGFR expressing cells in growth inhibitory assay; 6) MR30 showed good cell penetration with distribution in the perinuclear region. The results in toto suggest that MR30 has the potential to be developed as a tumor selective potentiator of TMZ. Citation Format: Martin Rupp, Bertrand J. Jean-Claude. Design of a novel MGMT inhibitor targeted to EGFR overexpressing tumor cells: a new approach to selectively potentiate temozolomide in refractory tumors [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 4043. doi:10.1158/1538-7445.AM2017-4043
Abstract 3023: The antitumor activity of immunotoxins is enhanced by tofacitinib
Authors: Nathan Simon, Antonella Antignani, Stephen Hewitt, Massimo Gadina, Masanori Onda, Christine Alewine, David Joseph Fitzgerald
Journal: Cancer Research (2017)

Abstract Treatment outcomes of certain aggressive cancers have not improved significantly in the last decade, necessitating development of new therapies. Recombinant immunotoxins (IT) are fusion proteins consisting of the enzymatic domain of a cytotoxin linked to an antibody fragment targeting a cellular surface protein. While the combination of selective targeting and potent cell-killing make ITs well suited for targeted cancer therapy, clinical experience has indicated that patients can generate anti-toxin neutralizing antibodies after one cycle of treatment. Mice treated with the FDA-approved JAK inhibitor, tofacitinib, produced significantly lower anti-toxin antibody titers, suggesting that tofacitinib could be used in combination with immunotoxins to improve therapeutic efficacy. Accordingly, the combination of tofacitinib and IT was tested both in vitro and in vivo using two models of aggressive human cancers: pancreatic ductal adenocarcinoma and triple-negative breast cancer. In vitro combination studies examined the effects on oncogenic signaling pathways and looked for enhancement of cytotoxic potency. Results demonstrated some tofacitinib-mediated inhibition of key signaling pathways but no enhancement of immunotoxin killing. By contrast, when xenograft tumor models were challenged, immunotoxin activity was enhanced greatly by co-treating with tofacitinib. Tofacinib treatments alone did not demonstrate any antitumor activity. The combination of tofacitinib and immunotoxin decreased tumor growth and extended survival compared to either treatment alone. Examination of post-treatment tumor samples and sera from mice indicated that JAK inhibition resulted in alterations of the tumor microenvironment, including a decrease in cancer-promoting cytokine levels and reductions in recruitment of suppressive immune cells to tumor tissue. This study demonstrates that the inhibition of the JAK-STAT pathway can significantly enhance the ability of cytotoxin-based therapeutic agents to elicit anti-tumor effects through alteration of the tumor microenvironment. Citation Format: Nathan Simon, Antonella Antignani, Stephen Hewitt, Massimo Gadina, Masanori Onda, Christine Alewine, David Joseph Fitzgerald. The antitumor activity of immunotoxins is enhanced by tofacitinib [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 3023. doi:10.1158/1538-7445.AM2017-3023
Loss of Brain Aerobic Glycolysis in Normal Human Aging
Authors: Manu S. Goyal, Andrei G. Vlassenko, Tyler M. Blazey, Yi Su, Lars E. Couture, Tony J. Durbin, Randall J. Bateman, Tammie L.-S. Benzinger, John C. Morris, Marcus E. Raichle
Journal: Cell Metabolism (2017)
Abstract 2685: Modulating tumor microenvironments through inflammasome and IL-1 pathways
Authors: Beichu Guo, Jinyu Zhang, Shun-Jun Fu
Journal: Cancer Research (2017)

Abstract Chronic Inflammation has been shown to play important roles at all stages of tumor development including initiation, growth, invasion and metastasis. The inflammasome is an important innate immune pathway critical for the production of active IL-1β, a potent inflammatory cytokine. While extensive evidence indicates that inflammasomes are involved in infections and autoimmune diseases, the role of inflammasomes in tumor development remains controversial. To dissect the roles of the inflammasome and IL-1 pathway in tumor development, we utilized the MMTV-PyMT transgenic model, which develops mammary gland tumors with a high incidence of lung metastasis. Our results have demonstrated that inflammasome and IL-1β play a critical role in promoting tumor growth and metastasis. We found that tumor growth was associated with inflammasome activation and elevated levels of IL-1β in tumor microenvironments in mouse mammary tumor models and in human breast cancer tissues. Mice deficient for inflammasome components or IL-1R signaling exhibit significantly reduced lung metastasis. Our data also show that inflammasome activation led to the accumulation of myeloid cells, such as such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in tumor microenvironments. Furthermore, blocking IL-1R signaling with IL-1R antagonist (IL-Ra) or anti-IL-1R antibody inhibited tumor growth and metastasis. Our results suggest that targeting the tumor microenvironment through inflammasome and IL-1 blockade may provide a novel approach for the treatment of breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Beichu Guo, Jinyu Zhang, Shun-Jun Fu. Modulating tumor microenvironments through inflammasome and IL-1 pathways [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 2685. doi:10.1158/1538-7445.AM2017-2685
Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma
Authors: Jacob J Mandel, Shlomit Yust-Katz, Akash J Patel, David Cachia, Diane Liu, Minjeong Park, Ying Yuan, Thomas A Kent, John F de Groot
Journal: Neuro-Oncology (2017)

Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials.A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative.Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care.The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.
Time to Diagnostic Testing After a Positive Colorectal Cancer Screening Test
Authors: Chyke A. Doubeni, Douglas A. Corley, Theodore R. Levin
Journal: JAMA (2017)

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Abstract 4490: Post-transcriptional regulation on PIAS3 expression in malignant mesothelioma
Authors: Tian He, Karen McColl, Nneha Sakre, Gary Wildey, Afshin Dowlati
Journal: Cancer Research (2017)

Abstract Protein Inhibitor of Activated STAT3 (PIAS3) was originally identified as an endogenous suppressor of STAT3 activity which can specifically interact with activated STAT3 and block its downstream oncogenic effects. Previous studies from our lab have shown that low PIAS3 protein expression in mesothelioma tumors was associated with poor patient survival. Furthermore, low PIAS3 expression in mesothelioma cell lines correlated with higher STAT3 activity. Over-expression of PIAS3 decreased STAT3 activity and cell growth. These findings suggest that low PIAS3 expression may play an important role in mesothelioma tumorigenesis, thus understanding the regulatory mechanism(s) of PIAS3 expression may provide new therapeutic strategies in mesothelioma treatment. Initially, we examined PIAS3 expression by western blotting and RT-qPCR among six mesothelioma cell lines (H28, 211H, H2052, H2452, HAY, YOU) and found that while PIAS3 mRNA levels were relatively constant, PIAS3 protein expression was highly variable. This finding indicated a potential post-transcriptional regulation of PIAS3 expression in mesothelioma. To investigate this further, we first examined PIAS3 protein stability in the presence of proteasome inhibitors and cycloheximide (CHX). We observed no increase in PIAS3 protein levels during proteasome inhibition using either MG132 (10 μM) or bortezemib (1 μM) for up to 8 h in 211H, H2052 and H2452 cells, whereas TP53 protein expression was increased. Blocking translational protein synthesis with 50 or 100 μg/ml CHX for up to 24 h also produced little change in PIAS3 protein expression in mesothelioma cells, indicating that PIAS3 is a very stable protein. We next explored the PIAS3 3’UTR as a potential site for translational regulation. We initially utilized a miR microarray and computational analysis, followed by a PIAS3 3’UTR luciferase reporter assay, to screen miRNAs that are both increased in cells with low PIAS3 and have seed sequences targeting the PIAS3 3’UTR and identified miR-18a as our first candidate. Taken together, our study suggests that variable expression of PIAS3 protein in mesothelioma is regulated by translational control and not by protein stability. Citation Format: Tian He, Karen McColl, Nneha Sakre, Gary Wildey, Afshin Dowlati. Post-transcriptional regulation on PIAS3 expression in malignant mesothelioma [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 4490. doi:10.1158/1538-7445.AM2017-4490
Abstract 5380: Inactivation of endogenous genes in cancer cells using targeted promoter DNA methylation via CRISPR-DNMT3a fusion protein
Authors: Simon D. Spivack
Journal: Cancer Research (2017)

Abstract Background: Developing technologies for precise manipulation of individual DNA methylation loci is an attractive challenge in cancer and lung biology, because aberrant expression via hyper- or hypo-methylation is so common. Projects such as ENCODE and the Roadmap Epigenetics Project, have identified thousands of epigenetic marks from human genome. However, the functional evaluation of these marks has been largely limited to determining their associations with gene expression. Technologies for targeting manipulation of epigenetic marks would allow direct experimental testing of the impact of DNA methylation at specific residues, mechanisms of gene regulation, and potential use as interventions, for example to silence constitutively active oncogenes. Methods: Here, we developed a CRISPR Cas9-based tool for specific DNA methylation in which the catalytic domain of DNMT3a (DNMT3a-CD) is fused to the carboxy-terminus of Cas9 D10A-H840A mutant (dCas9). Both construct promoter strength and transfection strategies were optimized. Results: We demonstrated targeted and consistent CpG methylation in 30~100bp regions downstream of the PAM (binding) site of the gRNA guided fusion protein in HEK293 cells. The multiple guide RNAs could target the dCas9-DNMT3A to multiple sites consistently. DNA methylation activity was specific for the targeted region and was heritable across cell divisions. We also found directed promoter DNA methylation of DAL1, GATA5 and C-MYC could decrease the corresponding mRNA expression by up to 80%; different DNA methylation positions had consequently different effects on gene expression. We have now performed C-MYC methylation-mediated knockdown in A549 lung cancer cells and are evaluating resulting cell cycle and apoptosis phenotypes. Conclusion: We believe this new targeted epigenetic technology can be directed to cancer cells for the purpose of reprogramming lung cancer, and unregulated stromal and microenvironment cells, for preventive and therapeutic uses. Note: This abstract was not presented at the meeting. Citation Format: Simon D. Spivack. Inactivation of endogenous genes in cancer cells using targeted promoter DNA methylation via CRISPR-DNMT3a fusion protein [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 5380. doi:10.1158/1538-7445.AM2017-5380