tbuckley/cabot-search huggingface dataset:
Abstract LB-140: Inhibition of cancer stemness sensitizes colorectal cancer to immune checkpoint inhibitors
Authors: Yuan Gao, Youzhi Li, Eric Hsu, Yuxin Wang, Janet Huang, Emily Brooks, Chiang J. Li
Journal: Cancer Research (2017)

Abstract Cancer stem cells (CSCs), a highly malignant tumor cell subpopulation capable of self-renewal, are considered to be fundamentally responsible for malignant growth and tumor recurrence. Emerging evidences indicate that CSCs and CSC pathways, such as STAT3, beta-Catenin, CD44 and Nanog pathway, are involved in the immune evasion in cancers. With the exception of a small percentage of colorectal cancers (CRC) patients that display microsatellite instability (MSI), the vast majority of CRC patients have been found to be resistant to immune checkpoint therapies. BBI-608 (napabucasin) is an orally-administered first-in-class cancer stemness inhibitor that works by targeting STAT3, which lead to inhibition of multiple cancer stemness pathways, including Stat3 and β-catenin pathways. In this study, we investigate the effect of cancer stemness inhibition on sensitizing CRC to immune checkpoint inhibitors in preclinical models. In the syngeneic tumor model, anti-PD-1 antibody monotherapy produced low level and temporary antitumor activity with rapid development of complete resistance to anti-PD1 in the MSS CT26 CRC model. The anti-PD-1 antibody treated CT26 tumors exhibited increased p-STAT3 activation and overexpression of a variety of stemness factors, including Nanog, CD44 and CD133, as well as enrichment of sphere-forming stemness-high cancer cells. BBI-608 was able to reduce basal as well as anti-PD1-induced STAT3 activation and other CSC features within CT26 tumors. Combination of stemness inhibitor BBI-608 with anti-PD-1 antibody to treat CT26 tumors led to tumor complete response (CR) virtually in all treated CT26 tumors with 40% of the mice remain tumor-free for 30 days following treatment termination. This combination also had a synergistic effect on the influx of tumor infiltrating CD8+ T cells, which likely contributed to the rapid tumor regression. Finally, mice CR-induced by BBI-608 and anti-PD-1 antibody were able to reject CT26 tumors upon rechallenge, but not the unrelated breast cancer 4T1 tumors. Our data suggests cancer stemness pathways contribute to immunotherapy resistance in MSS CRC and inhibition of cancer stemness by BBI-608 sensitizes colorectal cancer to immune checkpoint inhibition. This study provides compelling preclinical evidence to support the investigation of the combination of BBI608 with immune checkpoint inhibitors in CRC. Citation Format: Yuan Gao, Youzhi Li, Eric Hsu, Yuxin Wang, Janet Huang, Emily Brooks, Chiang J. Li. Inhibition of cancer stemness sensitizes colorectal cancer to immune checkpoint inhibitors [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 LB-140. doi:10.1158/1538-7445.AM2017-LB-140
Abstract 5502: Functional evaluation of superenhancers as mediators of epithelial ovarian cancer risk
Authors: Kevin C. Vavra, Simon Coetzee, Janet M. Lee, Paul Pharoah, Dennis J. Hazelett, Kate Lawrenson, Simon A. Gayther
Journal: Cancer Research (2017)

Abstract Superenhancers are master regulators of genes involved in cellular differentiation and tumorigenesis. While it is now well established that typical enhancers are key mediators of alleles associated with a mild risk of polygenic diseases, including cancer, the role of superenhancers is less understood. We evaluated the role of superenhancers in mediating risk of epithelial ovarian cancer (EOC). Using FunciVar software and superenhancers defined using H3K27ac chromatin immunoprecipitation followed by next generation sequencing, performed in cell lines and tissues, we characterized the superenhancer-risk SNP intersect and identified a series of risk-associated loci where multiple candidate causal alleles overlap with ovarian superenhancers. In particular, locus 3q25, the locus most associated with epithelial ovarian cancer (EOC) risk from GWAS studies, has &amp;gt;70 candidate causal risk SNPs, all of which coincide with superenhancers detected in ovarian cancer precursor cells (ovarian and fallopian tube epithelia) but not in ovarian cancers. We are proposing that the presence of one or more SNPs occurring at this locus leads to a higher expression of one or more genes by modulating activation of the superenhancer region. We tested the effect of decreasing the binding affinity of BRD4, a protein that binds superenhancer regions, using a small molecule inhibitor on the expression of genes in this locus. We identified three candidate genes—LEKR1, SSR3, and TiPARP—that demonstrated a decrease expression level as a result of BRD4 binding inhibition. Preliminary results show that partial knockdown of either SSR3 or TiPARP decreases normal ovarian and fallopian cell proliferation, and knocking down both SSR3 and TiPARP simultaneously shows an enhanced proliferation decrease compared with knockdown of a single gene. We then created stable knockout (KO) models using the CRISPR-Cas9 system to fully KO one, two or all three of our candidate causal genes: LEKR1, SSR3, and TiPARP. Functional evaluation of these KO models is currently underway to test the hypothesis that risk SNPs may regulate more than one gene at this locus. In all we identify a potential role for superenhancers at a subset of EOC risk loci, and present a functional pipeline for identification of the target gene/genes and evaluation of their role in neoplastic transformation. Citation Format: Kevin C. Vavra, Simon Coetzee, Janet M. Lee, Paul Pharoah, Dennis J. Hazelett, Kate Lawrenson, Simon A. Gayther. Functional evaluation of superenhancers as mediators of epithelial ovarian cancer risk [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 5502. doi:10.1158/1538-7445.AM2017-5502
Abstract 3665: Tumor Treating Fields (TTFields) plus anti-PD-1 therapy induce immunogenic cell death resulting in enhanced antitumor efficacy
Authors: Tali Voloshin, Orna Tal-Yitzhaki, Noa Kaynan, Moshe Giladi, Anna Shteingauz, Mijal Munster, Roni Blat, Yaara Porat, Rosa S. Schneiderman, Shay Cahal, Aviran Itzhaki, Eilon D. Kirson, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2017)

Abstract Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. TTFields is approved for the treatment of both newly diagnosed and recurrent glioblastoma. TTFields interrupt cancer cell mitosis by disrupting microtubules and septin filaments, which play key roles in mitosis. The mitotic effects of TTFields include abnormal chromosome segregation and ER stress, which trigger different forms of cell death. We evaluated the in vitro and in vivo effects of TTFields combined with an immune checkpoint inhibitor (anti-PD1) on immunogenic cell death. Murine Lewis lung carcinoma (LLC) and ovarian surface epithelial (MOSE) cells were treated with TTFields using the inovitroTM system. Levels of calreticulin (CRT) on the surface of treated cells and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured using an ELISA assay. Mice were implanted with LLC cells were treated with TTFields, anti-PD-1, or a combination of the two modalities. Tumor volume was monitored; flow cytometry analysis was performed for phenotypic characterization of infiltrating immune cells. TTFields induced elevated cell surface expression of CRT, decreased intracellular ATP levels, and promoted HMGB1 secretion. In vivo, the combined treatment of lung tumor-bearing mice with TTFields plus anti-PD-1 led to a significant decrease in tumor volume compared to anti-PD-1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD-1 group. Infiltrating cells demonstrated a significant upregulation of surface PD-L1 expression. Both F4/80+CD11b+ cells and CS11c+ cells exhibited higher tumor infiltration and elevated PD-L1 expression as compared to infiltrating immune cell in the control group. Our results demonstrate that TTFields treatment potentiates immunogenic cell death in cancer cells. Combining TTFields with specific immunotherapies such as anti-PD-1 may enhance antitumor immunity and result in increased tumor control. Citation Format: Tali Voloshin, Orna Tal-Yitzhaki, Noa Kaynan, Moshe Giladi, Anna Shteingauz, Mijal Munster, Roni Blat, Yaara Porat, Rosa S. Schneiderman, Shay Cahal, Aviran Itzhaki, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Tumor Treating Fields (TTFields) plus anti-PD-1 therapy induce immunogenic cell death resulting in enhanced antitumor efficacy [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 3665. doi:10.1158/1538-7445.AM2017-3665
Abstract 790: Regulation of tumor angiogenesis by low dose Aspirin
Authors: Jinia Chakraborty, Gargi Maity, Snigdha Banerjee, Sushanta K. Banerjee
Journal: Cancer Research (2017)

Abstract Background and Objective: Tumor angiogenesis is a pathophysiological process in which new blood vessels are formed in the primary tumor site or distant organs for the nourishment of cancer cells and metastatic growth. Thereby, targeting tumor angiogenesis is an important area of research for cancer therapy. Abnormal structure of blood vessels (i.e. leakiness due to abnormal lining of pericytes on the microvessels) is one of the critical features of tumor angiogenesis that sensitizes vascular cells to cytokines and helps circulating tumor cells to metastasize to distant organs. Our long term goal is to repurpose the drugs that may prevent tumor angiogenesis or normalize the vessels by repairing leakiness via recruiting pericytes or both. Our recent studies found that Aspirin (ASA) has the potency to inhibit breast cancer growth and metastasis, as well as reprogram the mesenchymal to epithelial transition (MET). Given the importance of ASA, we tested whether ASA may be able to regulate tumor angiogenesis. Methods: To do so, we determined the effect of low dose ASA (1mM, which is equivalent to 80mg human dose), ASA-treated (2.5mM) conditioned media (231-CMASA) or vehicle-treated conditioned media (231-CMVT) of MDA-MB-231 cells on different endothelial cell physiology. These include endothelial cells’ migration towards serum using 3D modified Boyden chamber assay, in vitro capillary-like structure formation on Matrigel, cell permeability using in vitro endothelial permeability assay and interactions of pericytes-endothelial cells. We also determined the effect of ASA on various angiogenic factors associated with tumor angiogenesis. Finally, we determined the effect of ASA on in vivo tumor angiogenesis using in vivo Angiogenesis Assay (Trevigen) Results and Conclusions: We found that 231-CMASA significantly blocks in vitro migration, the formation of in vitro capillary-like structures parallel with leakiness via incomplete interaction of pericytes and endothelial cells as compared to 231-CMASA. The antiangiogenic effect of ASA was also documented in in vivo assays. Mechanistically, ASA treatment blocks several angiogenic factors including VEGF-A that are associated with these three events, implicating a low dose of Aspirin is potentially therapeutic for breast cancer via blocking and normalizing tumor angiogenesis. Citation Format: Jinia Chakraborty, Gargi Maity, Snigdha Banerjee, Sushanta K. Banerjee. Regulation of tumor angiogenesis by low dose Aspirin [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 790. doi:10.1158/1538-7445.AM2017-790
Abstract 918: Cdc42 is crucial for intestinal stem cells survival by regulating Wnt and YAP signaling
Authors: Xiao Zhang, Nan Gao
Journal: Cancer Research (2017)

Abstract Strictly defined architecture of intestinal epithelial cells and the gradient of signaling cues along the villus-crypt axis ensure the maintenance of adult intestinal stem cells, as well as proper regeneration and differentiation of all intestinal epithelial cell types. The Rho family small GTPase Cdc42 controls the polarized division of intestinal stem cells, and affects subsequent fate-determination of the progenitor cells. As we previously described in Cdc42 Villin-Cre knockout mice, loss of Paneth cells from crypt bottom and emergence of Goblet cell-like intermediate cells at the villus indicate possible compromise of the canonical Wnt signaling during Paneth cell differentiation. Here we further characterized the underlying molecular mechanism of Cdc42 regulating intestinal stem cell survival, proliferation, and differentiation. IHC of the intestinal tissue in Cdc42 Villin-Cre knockout mice suggests greatly reduced Olfm4 level in the stem cells, which are abnormally positioned in the crypts, along with a reduction of both transcription co-factors beta-Catenin and YAP. However, the Notch signaling, which is required for stem cells and the differentiation of absorptive linage, seems intact. The autonomous regulation of Cdc42 on Yap signaling is probably through its specific role in stabilizing cell-cell junction and actin filaments in the epithelium, both of which are known regulatory inputs of the Hippo-YAP pathway. Both Wnt/beta-Catenin and Yap signaling are required for the initiation and progression of colorectal cancer, and the regeneration of stem cells post radiation. Given that Cdc42 is overexpressed in multiple types of cancers, especially colorectal cancer, our finding that Cdc42 regulates both Wnt and YAP pathways in the homeostasis of adult intestinal tissue sheds new light on the molecular mechanism of its pathological involvement, and potential therapeutic target. Citation Format: Xiao Zhang, Nan Gao. Cdc42 is crucial for intestinal stem cells survival by regulating Wnt and YAP signaling [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 918. doi:10.1158/1538-7445.AM2017-918
Abstract 580: Nivolumab treatment of metastatic renal cancer patients impairs Tregs and potentiates NK function: The role of CXCR4 inhibition (“REVOLUTION Trial”)
Authors: Sara Santagata, Anna Maria Trotta, Maria Napolitano, Luigi Portella, Sabrina Rossetti, Sisto Perdona, Sandro Pignata, Stefania Scala
Journal: Cancer Research (2017)

Abstract Despite encouraging results, Nivolumab response is not as wide as expected in renal cancer ( RCC). Among mechanisms of immunoresistance T-regulatory cells(Tregs) activity plays a central role. We previously showed that tumoral Tregs in RCC patients are more suppressive than healthy donors Tregs. Since tumoral Tregs express high level of CXCR4, the receptor antagonism was evaluated on patients Tregs revealing that CXCR4 antagonism reverted Treg suppressive activity( Santagata et al, submitted manuscript). To identify biomarkers informative and predictive of nivolumab efficacy Treg function, tumoral access and NK interactions was determined in nivolumab treated mRCC patients (“ Revolution” trial). At today eleven patients were analyzed for Tregs and NKs function at time 0-2-4 weeks-3-6 months of treatment. 2 patients died for unrelated causes, 5 Patients showed PR, 4 SD and 1 PD at six months. At time 0 Tregs function, evaluated as inhibition of T-effector (Teff) proliferation, varied among patients; two patients showed anergy reversed by Nivolumab treatment. Overall, increase in Teff proliferation, compatible with a decreased Tregs activity, was revealed during nivolumab treatment and, while the total peripheral Tregs was unaffected, a decrease in CD4+CD25+127lowFOXp3 highCD45RA - (suppressive Tregs) was detected. NK activity, evaluated as CD107a exposure, increased with nivolumab treatment with a concomitant reduction in the inhibitory receptors CD158a, PD-1 and CXCR4. Moreover patients Tregs and NKs were evaluated in vitro for the efficacy of CXCR4 inhibition in affecting cell function. CXCR4 antagonists suppressed the Treg mediated inhibition of Teff proliferation. In conclusion the evaluation of 11 patients enrolled in the REVOLUTION study revealed detectable variations on Tregs and NKs function relatively to Nivolumab treatment to be correlated with clinical outcome. Tregs suppressive function was impaired by inhibition of CXCR4 receptor. Citation Format: Sara Santagata, Anna Maria Trotta, Maria Napolitano, Luigi Portella, Sabrina Rossetti, Sisto Perdona, Sandro Pignata, Stefania Scala. Nivolumab treatment of metastatic renal cancer patients impairs Tregs and potentiates NK function: The role of CXCR4 inhibition (“REVOLUTION Trial”) [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 580. doi:10.1158/1538-7445.AM2017-580
Progression in Patients with with Low- and Intermediate-1 Risk Del(5q) MDS Is Predicted By a Limited Subset of Mutations
Authors: Christian Scharenberg, Petter S. Woll, Valentina Giai, Andrea Pellagatti, Leonie Saft, Marios Dimitriou, Martin Jädersten, Monika Jansson, Iyadh Douagi, Donna S. Neuberg, Mohsen Karimi, Katarina Le Blanc, Jacqueline Boultwood, Sten Eirik Jacobsen, Eva Hellstrom-Lindberg
Journal: Blood (2016)
Approximate number sense theory or approximate theory of magnitude?
Authors: Alain Content, Michael Vande Velde, Andrea Adriano
Journal: Behavioral and Brain Sciences (2017)

Leibovich et al. argue that the evidence in favor of a perceptual mechanism devoted to the extraction of numerosity from visual collections is unsatisfactory and propose to replace it with an unspecific mechanism capturing approximate magnitudes from continuous dimensions. We argue that their representation of the evidence is incomplete and that their theoretical proposal is too vague to be useful.
Abstract 2412: Monitoring small molecules and macromolecules methyltransferase activities using homogenous luminescent assay
Authors: Said A. Goueli, Kevin Hsiao
Journal: Cancer Research (2017)

Abstract It is well recognized that methylation/demethylation of not only DNA, RNA, Proteins but also methylation of small molecules play major roles in modulation of the epigenome, transcriptome, neurotransmitter uptake and metabolic regulation. Recent biochemicval and biological data suggest that the activity of these enzymes and their expression level are under very strict regulation and any abnormal alteration in either one or both results in a wide varieties of pathogenic conditions such as cancer, inflammation, and neurodegenerative diseases. In addition to chromatin modulation, altered methylation of DNA and more recently mRNA have been recognized to regulate the transcriptome and the rate of message translation and stability. Furthermore, methylation of small molecules such as catechols and nicotinamide play critical roles in neurotransmitters uptake and function, and metabolic regulation, respectively. Thus, pharmacological modulation of these enzymes by small molecules will be beneficial in developing novel therapeutics for multiple unmet medical needs. Towards this goal of searching for activators/inhibitors of these enzymes for the development of next generation of drugs, screening assays for these modulators are urgently needed. To address these unmet needs, we have developed a novel assay that monitors the activities of these enzymes and their modulation by small molecules. The assay is bioluminescent based, HTS formatted and highly sensitive. A unique feature of this assay is its universality since it is based on monitoring the formation of the universal product S-adenosylhomocysteine (SAH), i.e., capable of detecting changes in activity of a broad range of methyltransferases such as DNA, RNA, protein, and small molecules. In addition, the assay has been validated for all classes of protein methyltransferases (Lysine and Arginine), and with different types of substrates (small peptides, large proteins, or even nucleosomes). This enables determining the specificity of these enzymes and their substrate requirements. The assay has high signal to background, low C.V., robust (Z’ value &amp;gt; 0.7), and has been validated using various plate densities such as 96-, 384, and 1536-well plates. A strong feature of this assay is its utility with broad range of substrates concentrations or the composition of the substrates (short vs. long peptides), thus enabling the generation of kinetic data and determining the mechanism of action of various modulators of methyltransferases of interest. Citation Format: Said A. Goueli, Kevin Hsiao. Monitoring small molecules and macromolecules methyltransferase activities using homogenous luminescent assay [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 2412. doi:10.1158/1538-7445.AM2017-2412
Iron oxide nanoclusters for T 1 magnetic resonance imaging of non-human primates
Authors: Yang Lu, Yun-Jun Xu, Guo-bing Zhang, Daishun Ling, Ming-quan Wang, Yong Zhou, Ya-Dong Wu, Tao Wu, Michael J. Hackett, Byung Hyo Kim, Hogeun Chang, Jonghoon Kim, Xin-Tian Hu, Liang Dong, Nohyun Lee, Fangyuan Li, Jia-Cai He, Li Zhang, Hui-Qin Wen, Bo Yang, Seung Hong Choi, Taeghwan Hyeon, Duo-Hong Zou
Journal: Nature Biomedical Engineering (2017)