tbuckley/cabot-search huggingface dataset:
Abstract 4709: Cell-specific gene program-based small-molecule immunomodulators targeting solid-tumor microenvironments
Authors: Erin Kischuk, Joydeb Majumder, Jonathan A. Fine, Travis C. Lantz, Deepika Dhawan, Deborah W. Knapp, Timothy L. Ratliff, Gaurav Chopra
Journal: Cancer Research (2018)

Abstract Cancer immunotherapy includes promising strategies based on immune checkpoint blockade (e.g., anti-PD-1/PD-L1, anti-CTLA-4). A limitation of such therapies for solid tumors stems from other immune-suppressive mechanisms mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages. We hypothesize that molecules that target specific suppressive immune cells in the tumor microenvironment can reprogram the pro-tumor microenvironment towards antitumor immunity. Using our proteome-scale target/antitarget network-based lead optimization method (CANDESIGN), we designed and synthesized cell-specific nontoxic chemical libraries with modular functions for anticancer potency and immunomodulation. We used machine learning iteratively on experimental data to identify cell-specific target/anti-target networks (gene programs) as well as designed and synthesized compound libraries targeting cell-specific programs for desired cancer and immune cell function ex vivo. Specifically, we altered suppressive function of MDSCs by targeting upregulated genes in activated monocytic MDSCs in the tumor microenvironment compared to cells in spleen. We synthesized a potent nontoxic compound that specifically modulates activated MDSC function and corresponding changes in CD4+ and CD8+ T-cell activity in a mouse bladder cancer model. We observed a significant reduction in tumor mass following treatment by oral gavage. Interestingly, the bladder cancer cells used in our mouse model (as well as human and dog bladder cancer cells) are insensitive to our lead compound in vitro, suggesting in vivo antitumor activity via immunomodulation. Our lead decreased frequency of monocytic and granulocytic MDSCs in the ascites and the tumor. Moreover, a decreased frequency of MDSC expressing suppressive functional markers (e.g., Arg1, iNOS, PD-L1) and increased IFNγ+CD8+ T cells were observed in the tumor microenvironment after compound treatment. Finally, we performed a small clinical trial on pet dogs with bladder tumors treated with our compound tablets for 4-5 weeks that resulted in ~50% reduction in tumor volume. We conclude that designing cell-specific compounds perturbing the tumor microenvironment to combat immune suppression gives a selective advantage to the immune system to combat solid tumors via single and combination drug/cell therapies. Citation Format: Erin Kischuk, Joydeb Majumder, Jonathan A. Fine, Travis C. Lantz, Deepika Dhawan, Deborah W. Knapp, Timothy L. Ratliff, Gaurav Chopra. Cell-specific gene program-based small-molecule immunomodulators targeting solid-tumor microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4709.
Abstract 162: UBE2T: A molecular regulator for cancer stemness and drug resistance in hepatocellular carcinoma
Authors: Pui Yu Ho, Kin Wah Lee
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is one of the common cancers worldwide. Poor prognosis of HCC patients is attributed to high frequency of tumor relapse and chemoresistant nature of this disease. Increasing evidence showed the critical role of cancer stem cells (CSCs) on tumor relapse and therapeutic resistance. Since normal stem cells and CSCs share high similarity, we would like to identify the molecules/pathways crucial in liver CSCs by determining what molecules involved in normal liver stem cells during liver regeneration. Comparison of expression profiles between early regenerating liver and intact liver revealed the upregulation of DNA Damage Response pathways in the self-renewing liver, in which Ubiquitin Conjugating Enzyme E2 T (UBE2T) was the most significantly upregulated. This, together with the publicly available dataset (GSE5975) shows upregulation of UBE2T in EpCAM-enriched liver CSC populations, suggest the potential role of UBE2T on regulation of cancer stemness. By qPCR analysis UBE2T mRNA level was overexpressed in 91% of the clinical HCC specimens (n=56) and associated with aggressive tumor behavior and poorer patients' survival. The overexpression of UBE2T was further confirmed by western blot and immunohistochemical analysis. By lentiviral based knock-down approach, we demonstrated the role of UBE2T in regulation of liver CSC properties, including self-renewal, tumorigenicity, drug resistance and expression of liver CSC markers. In orthotopic HCC model, UBE2T was found to play pivotal role in lung metastasis in vivo. Mechanistically, UBE2T is found to interact directly with E3 ligase Mule and regulate its protein expression via ubiquitination. Since Mule is found to directly degrade β-catenin protein, we are examining whether UBE2T mediates liver T-IC function through direct regulation of Mule-mediated β-catenin degradation. In conclusion, we have uncovered the novel role of UBE2T signaling cascade in regulation liver CSCs, which provides attractive therapeutic target for potential treatment of HCC. Citation Format: Pui Yu Ho, Kin Wah Lee. UBE2T: A molecular regulator for cancer stemness and drug resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 162.
AB1154 Increase generation but defects of secreting ifn-Α play a role in the pathogenesis of igg4-rd
Authors: P. Zhang, W. Zhang
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> IgG4 related disease (IgG4-RD) is a multi-organ involvement, fibro-inflammatory disease of unknown etiology. Both innate and adaptive immunity played vital roles in the pathogenesis of IgG4-RD. Plasmacytoid dendritic cells (pDC) had major roles in antigen presentation and secreting IFN-a upon infection. However, the characteristics and relevant function of this cell population in IgG4-RD was poorly understood. So we aim to study the expression and function of pDC in IgG4-RD. <h3>Objectives</h3> To study the expression and function of Plasmacytoid dendritic cells (pDCs) in IgG4-RD <h3>Methods</h3> Flow cytometry was performed to analyse the expression of pDC cells in untreated IgG4-RD patients (n=12) and healthy controls (n=12). The immunehistochemeistry technique was used to assess the location of pDC in the involved tissues of IgG4-RD patients. Furthermore, by cells culture <i>in vitro</i>, the abilities of pDC secreting INF-α and the activation of NF-kB signal in IgG4-RD were explored. <h3>Results</h3> The frequencies of pDC in the IgG4-RD patients were significantly higher in the peripheral blood and involved tissues compared with healthy controls. The cell surface marker of CCR7 in pDC was lower in untreated IgG4-RD patients, but after treatment, the expression of CCR7 increased. There was on significance of the expression of pDC maturation marker (CD83), activation marker (CD80, CD86), CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR8, CCR9, CCR10, CXCR2, CXCR3 and CX3CR1 compared with healthy controls. Interestingly, the frequencies of CD123hiCD303+cells were also higher in untreated patients, and reduced after treatment, and the cell surface marker CD83 was also elevated. By cell culture <i>in vitro</i>, pDC had defects in secreting INF-α of IgG4-RD patients than healthy controls. <h3>Conclusions</h3> The excessive infiltration of pDC in peripheral blood and tissue but less CCR7 Defects of secreting INF-α of pDC in IgG4-RD may indicate less function of eliminating infection which may induce constant infection. pDC may played vital roles in the pathogenesis of IgG4-RD, <h3>Disclosure of Interest</h3> None declared
Additive Effects of Combined Angiotensin-Converting Enzyme Inhibition and Angiotensin II Antagonism on Blood Pressure and Renin Release in Sodium-Depleted Normotensives
Authors: MichelAzizi, GillesChatellier, Thanh-TamGuyene, DaliaMurieta-Geoffroy, JoëlMénard
Journal: Circulation (1995)

Background Angiotensin-converting enzyme (ACE) inhibitors do not decrease plasma angiotensin (Ang) II levels 24 hours after drug intake to the same extent as at peak. This intermittent partial “escape” is explained either by a renin-mediated reactive rise in plasma Ang I or by non–ACE-dependent Ang II generation. We therefore tested the hypothesis that a combination of ACE inhibition and Ang II blockade may have additive biological and hemodynamic effects. Methods and Results In a single-dose, double-blind, randomized, four-way, crossover study, an Ang II antagonist (losartan 50 mg), an ACE inhibitor (captopril 50 mg), their combination, and matched placebos were orally administered to 12 normotensive male volunteers maintained in mild sodium depletion. When captopril 50 mg and losartan 50 mg were given alone, the magnitude of their effects on blood pressure, plasma active renin, Ang I, and aldosterone was similar, whereas the kinetics of their effects were different, reflecting differences in drug pharma...
Abstract 4329: Enhancer mapping in triple-negative breast cancer as a tool for novel biomarker and oncogene discovery
Authors: Ryan Raisner, Russ Bainer, Karen Gascoigne
Journal: Cancer Research (2018)

Abstract Breast cancer is the most commonly diagnosed cancer in women, affecting ~8% of women in the U.S. in their lifetime. Triple-negative breast cancer (TNBC) represents a heterogeneous class of aggressive cancers that comprise 15-20% of all breast cancers. TNBCs characteristically do not have significant levels of estrogen receptor (ER), progesterone receptor (PR), or overexpression of human epidermal growth factor 2 (HER-2). Consequently, there is a lack of proven drug therapies and biomarkers for TNBC. Here we have used ChIP-SEQ combined with RNA-SEQ to profile TNBC cell lines for their super-enhancer patterns. These noncoding, trans-acting elements control gene expression and play an essential role in the establishment and maintenance of cell states. It has been suggested that a wide range of cancers arise in part due to enhancer dysregulation, and key oncogenes genes coming under control of super-enhancers. This can occur through translocations, amplifications, or creation of de novo transcription factor binding sites. We hypothesize that mapping tumor-specific super-enhancer patterns in TNBC will identify novel tumor-specific gene-regulatory networks, and dysregulated genes that contribute uniquely to the development of tumors. We have conducted a CRISPR-mediated drop-out screen on a number of TNBC cell lines for genes that are controlled by cancer-specific super-enhancers with the hope of identifying novel oncogenic drivers. Citation Format: Ryan Raisner, Russ Bainer, Karen Gascoigne. Enhancer mapping in triple-negative breast cancer as a tool for novel biomarker and oncogene discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4329.
Abstract 2833: Single-cell imaging reveals MAPK pathway reactivation in drug-tolerant melanoma cells
Authors: Chen Yang, Chengzhe Tian, Sabrina L. Spencer
Journal: Cancer Research (2018)

Abstract Spontaneous genetic mutations allow an initially drug-sensitive population of cancer cells to acquire a drug-resistant phenotype. However, little is known about how drug-sensitive cells first evade drug action and survive in the presence of drug, referred to as "drug tolerance," a crucial step on the road to resistance. In this study, we combined single-cell time-lapse microscopy and MATLAB-based automated cell tracking to identify the molecular basis of drug tolerance. By simultaneously monitoring CDK2 and ERK activity in single cells, we found that melanoma cells harboring a BRAF-V600E mutation have high ERK activity and consecutively cycled with an inter-mitotic time of around 14 hr in full growth media. Upon treatment with dabrafenib, an ATP competitive B-Raf inhibitor, all cells entered a CDK2-low quiescence with reduced ERK activity. Strikingly, after 72 hr of dabrafenib treatment, a fraction of cells escaped drug action, re-entered the cell cycle, and divided once in presence of drug before re-entering a transient quiescence. Additional cells continued to escape and divide in the presence of drug, with a steady-state level of about 10% of the population engaged in the cell cycle at any point during the week-long observation period. We refer to cells that re-entered the cell cycle as "escapees" and cells that stayed in quiescence during the observation period as "non-escapees." Remarkably, we found that escapees showed significantly higher ERK activity than non-escapees after a few days of treatment, even though their initial ERK activities were indistinguishable. To test whether reactivation of the MAPK pathway is the cause of cell cycle re-entry, we co-treated cells with dabrafenib and the MEK inhibitor trametinib. This co-treatment resulted in even lower ERK activity and elimination of the escapee population. This result implies that dabrafenib, even at high doses, does not fully turn off the MAPK pathway, thereby enabling eventual escape from drug. By monitoring escaping cells at the molecular level in real time, our work thus suggests a possible mechanism for cells to develop drug tolerance in less than three days, long before acquiring genetic mutations. Citation Format: Chen Yang, Chengzhe Tian, Sabrina L. Spencer. Single-cell imaging reveals MAPK pathway reactivation in drug-tolerant melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2833.
Abstract 5125: The relationship between microbiomeFusobacterium nucleatumand autophagy in esophageal cancer
Authors: Yang Liu, Yoshifumi Baba, Shigeki Nakagawa, Hiroshi Sawayama, Takatsugu Ishimoto, Masaaki Iwatsuki, Yoichi Yamashita, Yuji Miyamoto, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2018)

Abstract Background: Research into the microbiome is a rapidly advancing field in human cancers. The gut microbiome has recently been shown to play an important role in health, as well as in diseases such as obesity, inflammatory bowel disease, diabetes, non-alcoholic fatty liver disease, and several types of cancers. Fusobacterium nucleatum is a component of the human microbiome that primarily inhabits the oral cavity. It causes periodontal disease and has also been implicated in the development of human cancers. We have recently reported that Fusobacterium nucleatum in esophageal cancer tissues was associated with shorter survival, suggesting a potential role as a prognostic biomarker. In addition, It has been revealed that Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Nonetheless, the relationship between Fusobacterium nucleatum and autophagy in esophageal cancers have been still unknown. We constructed this study to examine the relationship between Fusobacterium nucleatum and autophagy. Methods: Using 284 esophageal cancers, we detected ATG-7 and ULK -1 expression by IHC staining in tumors. Results: 21% cases showed ATG-7 positive and 25% cases showed ULK-1 positive. ATG-7 and ULK-1 expression in Fusobacterium nucleatum-positive tumors were significantly higher compared with that of Fusobacterium nucleatum-negative tumors (P=0.026 and P=0.0077). In addition, ATG-7 expression was associated with cancer-specific survival rate in esophageal cancer patients (P=0.0496). There was no relationship of ULK-1 expression and prognosis. Conclusion: Fusobacterium nucleatum was related with ATG-7 and ULK-1. Our findings may shed lights on understanding the mechanism by which Fusobacterium nucleatum affects chemoresistance in esophageal cancer. Citation Format: Yang Liu, Yoshifumi Baba, Shigeki Nakagawa, Hiroshi Sawayama, Takatsugu Ishimoto, Masaaki Iwatsuki, Yoichi Yamashita, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. The relationship between microbiome Fusobacterium nucleatum and autophagy in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5125.
Abstract 2925: Tandem targeting of poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) as a novel strategy for enhancing radio- and chemosensitivity of refractory tumors
Authors: Martin Rupp, Zhor Senhaji Mouhri, Ursula Stochaj, Bertrand Jean-Claude
Journal: Cancer Research (2018)

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel therapeutic approach for the selective targeting of tumours with BRCA1/2 hereditary deficiencies. BRCA1/2 are two key proteins involved in homologous recombination (HR) repair. Although the therapeutic benefit of PARP inhibitors has now been proven in the clinic in patients with BRCA1/2 mutations, much effort has been deployed to expand the use of PARP inhibitors beyond tumours harbouring inherited deficiencies in HR- mediated DNA repair. Several combination modalities with agents that can induce HR deficiency and exploit the concept of “contextual synthetic lethality” have been reported for PARP inhibitors. Here we exploited the contextual synthetic lethality between PARP and the epidermal growth factor receptor (EGFR) to design and synthesize a novel dual EGFR targeted PARP inhibitor, termed ZSMR06. The results showed that: a) ZSMR06 is capable of inhibiting EGFR and PARP in whole cells in the nanomolar range (36-63 nM); b) it was selectively potent against BRCA2 mutant and EGFR expressing isogenic cells; c) as monotherapy, ZSMR06 was extremely potent with growth inhibitory activities superior to that of an equimolar combination of olaparib (a clinical PARP inhibitor) and gefitinib (a clinical EGFR inhibitor) in a large panel of tumour cell lines; d) ZSMR06 strongly potentiated the effect of temozolomide (TMZ) and induced significantly stronger (p&amp;lt;0.05-0.001) growth inhibition than olaparib + TMZ combination in cells expressing O6-methylguanine-DNA methyltransferase (MGMT), an enzyme that confers a robust resistance to TMZ; e) ZSMR06 selectively potentiated TMZ on EGFR expressing cells; f) it was able to strongly sensitize bladder cancer cells to radiation (DMF50= 2.96-9.5). These results in toto showed that ZSMR06 due to its dual mechanism of action is capable of behaving as a strong potentiator of TMZ and radiation in resistant cells. Its potency in non-BRCA1/2 mutant tumour cells indicates that it may be the first prototype of hybrid molecules capable of expanding the use of PARP inhibition beyond BRCA1/2 mutations. Citation Format: Martin Rupp, Zhor Senhaji Mouhri, Ursula Stochaj, Bertrand Jean-Claude. Tandem targeting of poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) as a novel strategy for enhancing radio- and chemosensitivity of refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2925.
Endoscopic management of stent displacement after pancreatic pseudocyst drainage
Authors: Juliana Costa, Bruno Gonçalves, Rita Costa, Filipa Costeira, Nuno Dias, Raquel Gonçalves, João Soares
Journal: Endoscopy (2018)

A 50-year-old man who had experienced acute alcoholic pancreatitis 2 years earlier presented with abdominal pain. An abdominal computed tomography (CT) scan revealed a pseudocyst, 16 × 8 cm in size, in the pancreatic tail ([Fig. 1]). After multidisciplinary discussion, the patient was referred for endoscopic pseudocyst drainage.
Abstract 3949: p53-restoring small molecule CB001 suppresses tumor growth and metastasis
Authors: Shengliang Zhang, Lanlan Zhou, Jessica Wagner, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2018)

Abstract The uncontrolled growth and metastasis of tumor cells leads to morbidity and mortality in patients with cancer. The tumor suppressor p53, as a guardian of genome integrity, plays an important role in suppressing tumor growth and metastasis. However, loss of p53 pathway signaling frequently occurs in advanced tumors. Dysfunction of the p53 pathway is due to either p53 gene mutation or inactivation of p53. Mutations not only result in loss of wild-type p53 function, but also endow mutant p53 with a gain-of function, which further confers tumor aggressiveness and metastasis. Restoring p53 pathway signaling is an attractive strategy for suppressing tumor growth and metastasis in cancer therapy. Small-molecule CB001 restores p53 pathway signaling in p53-deficient colorectal cancer cells. We examined p53 pathway signaling based on the p53-responsive bioluminescence and the protein level of p53 targets. CB001 restores p53 pathway signaling in a p53-dependent and -independent manner in cancer cells. CB001 restores p53 pathway signaling via p73 in mutant p53-expressing cancer cells, and activates the p53 pathway in wild-type p53-expressing cancer cells. Correlated with restoration of p53 pathway signaling, CB001 induces cell death in cancer cells, but not in normal cells. Neither phosphorylation of H2AX in cancer cells nor DNA intercalation was observed upon CB001 treatment at the tested doses, suggesting little or no genotoxicity of CB001 in human colorectal cancer cells. Furthermore, both cell scratch assay and Boyden chamber assay reveal that CB-001 inhibits cancer cell migration. We further demonstrate that CB001 induces cell death and inhibits cell migration via p73 in p53-mutant colorectal cancer cells. These results taken together suggest that CB001 is a promising lead for drug development with a strong capability to suppress tumor growth and metastasis through restoring p53 pathway in cancer cells. Citation Format: Shengliang Zhang, Lanlan Zhou, Jessica Wagner, David T. Dicker, Wafik S. El-Deiry. p53-restoring small molecule CB001 suppresses tumor growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3949.