tbuckley/cabot-search huggingface dataset:
Abstract 3368: A novel anti-CTLA-4 antibody with potent anti-tumor activity emerged using humanized CTLA-4 mouse model
Authors: Chaoshe Guo, Yi Yang, Zhihong Li, Yanan Li, Yunyun Chen
Journal: Cancer Research (2020)

Abstract CTLA-4 (Cytotoxic T-lymphocyte antigen 4), also known as CD152, belongs to immunoglobulin superfamily. It is an intracellular protein expressed in resting T cells; CTLA-4 translocates to the cell surface and transmits an inhibitory signal to T cells. In addition, CTLA-4 competes with its homologous T-cell co-stimulatory protein CD28 for ligands expressed on APC, namely CD80 (B7-1) and CD86 (B7-2), thereby antagonizing CD28 and inhibiting CD28 signaling, resulting in inhibition of IL-2, IFN-γ, IL-4 cytokines production, IL-2 receptor expression and cell cycle progression. Because Tregs constitutively express CTLA-4 at high levels, anti-CTLA-4 therapy would be expected to have the greatest effect on these cells. Ipilimumab, a fully human IgG1 monoclonal antibody, is the only commercially available CTLA-4 antagonist. It has been approved by FDA for treatment of metastatic melanoma, adjuvant melanoma and advanced renal cell carcinoma, based on its significant effect of tumor suppression demonstrated in clinical trials. We have interests in searching for potent CTLA-4 antagonists. We selected an antibody with the best efficacy, namely YH001, from the candidate molecules through Biocytoge's in vivo drug screening platform. YH001 is a recombinant humanized anti-CTLA-4 IgG1 monoclonal antibody and it can bind with human CTLA-4 potently and specifically, without reactivity with other CD28 family receptors. YH001 was able to block the CTLA-4/CD80 and CTLA-4/CD86 interactions and potentiate CD28 signaling in the presence of cognate TCR stimulation. Moreover, YH001 also induced stronger bioluminescence than ipilimumab in the reporter assay. YH001 showed more potent ADCC activities than ipilimumab. YH001 showed dose-dependent in vivo anti-cancer efficacy, as well as Treg depletion and increased CD8+/Treg ratio in human CTLA-4 knock-in mice bearing MC38 tumors. Exposure to YH001 was dose proportional with a half-life of approximately 5 days in cynomolgus monkey. Our preclinical investigation of YH001 demonstrates Biocytogen's capability in discovering clinical candidates using its robust antibody discovery platform. Citation Format: Chaoshe Guo, Yi Yang, Zhihong Li, Yanan Li, Yunyun Chen. A novel anti-CTLA-4 antibody with potent anti-tumor activity emerged using humanized CTLA-4 mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3368.
In situ pocket-type microcarrier (PMc) as a therapeutic composite: Regeneration of cartilage with stem cells, genes, and drugs
Authors: Hye Jin Kim, Jong Min Park, Sujin Lee, Suk Jun Hong, Ji-In Park, Min Suk Lee, Hee Seok Yang, Ji Sun Park, Keun-Hong Park
Journal: Journal of Controlled Release (2020)

We prepared pocket-type micro-carriers (PMc) with pores larger than 30 μm for use in cell delivery by adding 40 mg pluronic F-127 copolymers (F-127) to biodegradable PLGA dissolved in dichloromethane solution. The controlling the size of the pockets in this way facilitates the adhesion of cells by regulating the size of the pockets according to the cells having various sizes. The size of PMc pores could be controlled within a range of 2 to 30 μm by varying the F-127 content. The ratio of F-127 to DOPA-bPEI was most appropriate at 1: 1, and the pocket size at 10 mg/ml of F-127 was appropriate for adhering 20–30 μm stem cells. F-127 containing SOX9 pDNA, in combination with DOPA-polyethylene–coated gold nanoparticles and dexamethasone loaded in PMcs, promoted cartilage differentiation. Gold nanoparticles complex and dexamethasone (DEX) loaded in PMcs were identified by micro-CT imaging and fluorescence imaging, respectively. By captured in pore generated on/in microspheres, the stem cells were safe and stable for use in delivery, both in vitro and in an animal model. Thus, microsphere pores can safely capture stem cells, and at the same time provide a microenvironment in which the captured stem cells can differentiate into chondrocytes.
Abstract 5607: Broad acting glutamine antagonism remodels the tumor microenvironment, induces distinctive immune modulation, and synergizes with immune checkpoint blockade
Authors: Yumi Yokoyama, Robert Wild
Journal: Cancer Research (2020)

Abstract We previously reported that DRP-104, a novel broad acting glutamine antagonist, has significant therapeutic potential in cancer via directly targeting tumor metabolism and inducing a potent antitumor immune response. Here we sought to further elucidate the immunomodulatory effect of DRP-104 on tumor growth inhibition as a single agent and in combination with PD-1/PD-L1 checkpoint inhibitors in the MC38 and CT26 colon cancer syngeneic models. We utilized multiple technologies to assess mechanistic effects on immune cells in vivoincluding flowcytometry, multiplex immunoassay, gene expression profiling and GeoMx™ digital spatial profiling. DRP-104 mediated tumor growth inhibition was associated with increased tumor-infiltrating leukocytes (TIL) including T, NKT, and NK cells, M1-polarized tumor associated macrophages, and decreased immune-suppressive cells such as MDSCs. Nanostring® IO360 analysis revealed broad immunological modulation such as increase in cytotoxicity/antigen presentation score, increase in tumor metabolic stress/apoptotic score and decrease in cell proliferation score. GeoMx™ profiling also showed increased tumoral T cells and granzyme B expression. Luminex analysis of tumor lysates revealed DRP-104 treatment decreased pro-tumorigenic proteins, such as VEGF and IL-8. DRP-104 showed significant dose dependent tumor growth inhibition and regressions as a single agent in mouse syngeneic tumor models, including those resistant to immune checkpoint inhibitors. Lastly, combination of DRP-104 with anti-PD-1 Ab or anti-PD-L1 Ab further reduced tumor growth resulting in significant improvement in survival with long-term durable cures. In summary, DRP-104 treatment resulted in broad remodeling of the tumor microenvironment including enhanced infiltration and function of multiple immune cells distinct from activities obtained by a checkpoint inhibitor treatment. Combination therapy of DRP-104 with anti-PD-1/PD-L1 achieved significantly enhanced anti-tumor efficacy including long-term durable cures even in checkpoint inhibitor resistant models. This unique and non-overlapping mechanism of action supports clinical development of DRP-104 alone and in combination with PD-1/PD-L-1 checkpoint inhibitors. Citation Format: Yumi Yokoyama, Robert Wild. Broad acting glutamine antagonism remodels the tumor microenvironment, induces distinctive immune modulation, and synergizes with immune checkpoint blockade [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5607.
Abstract 683: Identification of a macrocyclic peptide that blocks the CD47-SIRPα interaction and its antitumor effect
Authors: Daisuke Hazama, Yoji Murata, Takeshi Okamoto, Daisuke Tanaka, Mariko Sakamoto, Yuka Kakuchi, Yasuyuki Saito, Takenori Kotani, Yoshihiro Nishimura, Takashi Matozaki
Journal: Cancer Research (2020)

Abstract Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. Immune checkpoint inhibitors, such as monoclonal antibodies (mAbs) to CTLA-4, PD-1, and PD-L1, have provided clinical benefit in patients with a variety of types of cancer, and a growing number of agents targeting immune checkpoints are in preclinical and clinical development. SIRPα is a transmembrane protein that is abundant in myeloid cells, such as macrophages and dendritic cells. SIRPα interacts with another transmembrane protein CD47 through their ectodomains, and they constitute the cell-cell communication system (the CD47-SIRPα system). We previously demonstrated that the interaction of SIRPα on macrophages with CD47 on tumor cells prevented the phagocytosis of tumor cells by macrophages. In contrast, blockage by anti-SIRPα antibodies of the CD47-SIRPα interaction enhanced the phagocytic activity of macrophages against antibody-opsonized tumor cells, suggesting that the CD47-SIRPα axis acts as an immune checkpoint pathway involved in tumor escape from immunosurveillance. Here, by the use of random nonstandard peptide integrated discovery (RaPID) system, we have identified novel macrocyclic peptides that bind to the extracellular domain of SIRPα with high affinity. These SIRPα-binding macrocyclic peptides inhibited the CD47-SIRPα interaction. Moreover, one of the SIRPα-binding macrocycles promoted the phagocytosis of antibody-opsonized tumor cells by macrophages in vitro and enhanced the antitumor effect of mAbs against tumor antigens in xenograft or syngeneic mouse models of cancer. Our results thus suggest that macrocyclic peptides against SIRPα hold promise as a novel tool for cancer immunotherapy. Citation Format: Daisuke Hazama, Yoji Murata, Takeshi Okamoto, Daisuke Tanaka, Mariko Sakamoto, Yuka Kakuchi, Yasuyuki Saito, Takenori Kotani, Yoshihiro Nishimura, Takashi Matozaki. Identification of a macrocyclic peptide that blocks the CD47-SIRPα interaction and its antitumor effect [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 683.
Value of 10-2 Visual Field Testing in Glaucoma Patients with Early 24-2 Visual Field Loss
Authors: Michael E. West, Glen P. Sharpe, Donna M. Hutchison, Paul E. Rafuse, Lesya M. Shuba, Marcelo T. Nicolela, Jayme R. Vianna, Balwantray C. Chauhan
Journal: Ophthalmology (2020)
Abstract 809: nCounter for detection of clinically relevant alterations in exosomes of non-small cell lung cancer cells and patients
Authors: Ana Giménez Capitán, Jill Bracht, Chung-Ying Huang, Cristina Teixidó, Noemí Reguart, Rich Boykin, Sarah Warren, Joseph M Beechem, Santiago Viteri Ramirez, Juan José García, Andrés Aguilar, Rafael Rosell Costa, Jay Gerlach, Miguel Angel Molina-Vila
Journal: Cancer Research (2020)

Abstract Background: ALK, ROS1 and RET fusions and MET exon 14 skipping variant (METex14) are present in 10-15% of advanced non-small-cell lung cancer (NSCLC) patients and their accurate identification is critical to guide targeted therapies. In a significant number of cancer patients, the tumor tissue available is insufficient for genetic analysis and repeated tissue biopsies for monitoring the course of the disease and the emergence of resistance are not feasible. Liquid biopsies constitute the only alternative available in these cases, but NGS techniques have shown insufficient sensitivity for fusion detection in blood samples. The nCounter technology has been adapted to detect fusions and skipping variants in FFPE tumor biopsies and we aimed to validate it for exosomes. Methods: Exosomes were purified using a miRCURY kit (Qiagen) and RNA was extracted using the TRI reagent (MRC Inc). A customized nCounter panel (Nanostring) for detection ALK, ROS1 and RET fusion transcripts and MET ex14 mRNA was used with a 10-cycles preamp step. First, proof-of-concept experiments were run by testing exosomes isolated from the culture medium of cell lines. Next, we tested exosomes isolated from the blood of NSCLC patients with know genotypes. Results: nCounter fusion probes successfully detected ALK, RET and ROS1 fusion transcripts in exosomes isolated from the culture medium of the cell lines H3122 (EML4-ALKv1), H2228 (EML4-ALKv3), HCC78 (SLC34A2-ROS1) and LC/2-Ad (CCDC6-RET). Exosomes from a cell line established from a patient progressing to alectinib were also positive for EML4-ALKv1and showed high MET expression levels, while exosomes from the fusion-negative cell lines A549 and H23 tested negative. Finally, fusion transcripts were detected in exosomes purified from the blood of fusion positive NSCLC patients but not in fusion negative cases. Conclusions: nCounter can detect ALK, RET and ROS1 fusion transcripts in exosomes purified from the blood of advanced NSCLC patients Citation Format: Ana Giménez Capitán, Jill Bracht, Chung-Ying Huang, Cristina Teixidó, Noemí Reguart, Rich Boykin, Sarah Warren, Joseph M Beechem, Santiago Viteri Ramirez, Juan José García, Andrés Aguilar, Rafael Rosell Costa, Jay Gerlach, Miguel Angel Molina-Vila. nCounter for detection of clinically relevant alterations in exosomes of non-small cell lung cancer cells and patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 809.
Abstract 2565: NANOG sustains ovarian cancer cell survival and disrupts ER stress signaling through BiP/PERK under glutamine depletion
Authors: Astrid Man-Yee Suen, Ivy Tsz-Lo Wong, Cindy Yin-Si Tse, Ka-Kui Chan, Oscar Gee-Wan Wong, Annie Nga-Yin Cheung
Journal: Cancer Research (2020)

Abstract Metabolic reprogramming is a common hallmark of multiple cancers which functions to meet their high proliferation needs. High demand for the amino acid glutamine is frequently observed in many cancers. Catalyzed by glutaminase, glutamine is readily converted to glutamate which then further fuels the tricarboxylic acid cycle. In ovarian cancer, depletion of glutamine significantly inhibited cell growth suggesting that targeting glutamine metabolism might be an effective therapeutic strategy for ovarian cancer. However, the molecular mechanisms involved were not completely understood. In this study, we aim to identify molecular targets and the signaling involved in ovarian cancer cells under glutamine depletion. We observed that glutamine depletion stimulated the expression of the stem cell transcriptional factor NANOG in the serous ovarian cancer cell line OVCAR3. Stable knockdown of NANOG in OVCAR3 (shNANOG-OVCAR3) enhanced the level of reactive oxygen species under glutamine depletion. It was also found that under glutamine depletion, growth rate was not altered in shNANOG-OVCAR3 when compared to control shCtrl-OVCAR3 cells. However, shNANOG-OVCAR3 were more sensitive to glutamine depletion compared to shCtrl-OVCAR3 suggesting that NANOG is in part required to sustain growth of ovarian cancer cells under glutamine depletion. To further decipher the signaling involved in NANOG under glutamine depletion, expressions of markers of ER stress were detected by western blot. We found that shNANOG-OVCAR3 cells expressed lower levels of BiP, a master regulator of ER stress. Under glutamine depletion, knockdown of NANOG further enhanced the expression of phosphorylated PERK but did not alter the levels of cleaved ATF6 or phosphorylated IRE-1a, suggesting NANOG regulates ER stress pathway through BiP/PERK signaling in glutamine-depleted environment. Immunohistochemical studies were performed to determine the expressions of NANOG and BiP in our ovarian cancer patient cohort. NANOG expression was positively correlated with the expression of nuclear BiP. Total BiP expression was significantly higher in cancerous tissue than in benign and borderline ovarian tumor tissue. Altogether, these findings suggested a hitherto unreported role of the stem cell transcription factor NANOG in regulating ER stress through BiP/PERK signaling under glutamine depleted environment. Citation Format: Astrid Man-Yee Suen, Ivy Tsz-Lo Wong, Cindy Yin-Si Tse, Ka-Kui Chan, Oscar Gee-Wan Wong, Annie Nga-Yin Cheung. NANOG sustains ovarian cancer cell survival and disrupts ER stress signaling through BiP/PERK under glutamine depletion [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2565.
TCT-742 Percutaneous left atrial appendage closure following transcatheter aortic valve replacement: results from the ATTRACTIVE study
Authors: Yam Hong Wong, Liesbeth Rosseel, Sigitas Cesna, Fadi Sawaya, Gintautas Bieliauskas, Olaf Franzen, Lars Sondergaard, Ole De Backer
Journal: Journal of the American College of Cardiology (2018)
Abstract 3704: MicroRNA-3977 acts as a tumor suppressor and inhibits triple-negative breast cancer tumorigenesis by targeting FoxM1
Authors: Selda Karamil, Nuray Altintas, Bulent Ozpolat
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) is an aggressive type of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). TNBC is associated with poor prognosis, high rates of relapse and distant metastasis despite surgery and adjuvant chemotherapy. The lack of effective targeted therapies for TNBC requires new therapeutic approaches. The Forkhead box protein M1 (FoxM1) is a member of forkhead superfamily transcription factors that has been associated with normal cell growth and proliferation through cell cycle transition and mitotic spindle control. FoxM1 is also identified as a master regulator of tumor metastasis. Based on analysis of pooled clinical datasets derived from online accessible databases as Breast Cancer Gene-Expression Miner v4.3 and Kaplan-Meier plotter, the expression and prognostic values of FoxM1 increase in TNBC compare with other breast cancer subtypes. Directly binding to the 3'-untranslated region (3' UTR) of FoxM1 mRNAs suppress its high expression in TNBC that leads to inhibition of cell proliferation, motility, and invasion. These results implied that FoxM1 is an essential poor prognostic factor and promising candidate target in the treatment of TNBC. We identified miR-3977 as a potential regulator of FoxM1 by using in silico prediction algorithms, and we investigated its role in TNBC. In this study, we found miR-3977 expression is significantly suppressed in TNBC cell lines and inversely correlated with FoxM1 levels. We demonstrate that miR-3977 directly bound to the 3′ UTR of FoxM1 mRNA and repressed its expression. We also find reduced miR-3977 expression is associated with shorter patient survival in TNBC based on Kaplan-Meier plotter database. Moreover, in vivo delivery of miR-3977 nanoparticles inhibited FoxM1 expression and tumor growth in TNBC xenograft mouse models. In conclusion, we provide the first evidence that miR-3977 functions as a tumor suppressor and gain of miR-3977 expression leads to decrease in FoxM1 expression and inhibits to cell growth, colony formation, invasion, and progression of TNBC. Taken together, our data suggest that miR-3977-based gene therapy is a potential therapeutic strategy in TNBC. Citation Format: Selda Karamil, Nuray Altintas, Bulent Ozpolat. MicroRNA-3977 acts as a tumor suppressor and inhibits triple-negative breast cancer tumorigenesis by targeting FoxM1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3704.
Abstract LB-177: BET and CDK9 protein inhibitors: Novel epigenetic therapy to synergistically kill human melanoma cells
Authors: Abdullah Al Emran, Hsin-Yi Tseng, Dilini Gunatilake, Stuart Cook, Jessamy Tiffen, Stuart Gallagher, Peter Hersey
Journal: Cancer Research (2020)

Abstract Background: Dysregulation of epigenetic modifiers is a frequent event in melanoma and underlies many aspects of melanoma biology including resistance to targeted and immunotherapies. Here we report that dual targeting of BET and CDK9 proteins have synergistic effect in melanoma cells in vitro and in vivo. Methods: Cell viability was measured by Cell titre glow and colony forming assays. Annexin V/PI staining was performed to assess apoptosis. Apoptotic, anti-apoptotic, pro-survival signalling proteins were probed by immunoblotting. Genome wide expression analysis were performed by RNA-seq analysis of sensitive cell lines. Live-dead staining and apoptosis were performed in 3D spheroid models. In vivo studies were carried out on the YUMM1.1 mouse model in C57BL/6 syngeneic mice. Results: We report that BET and CDK9 inhibitor iBET151 and CDKI73 synergistically killed melanoma cells independent of their genetic background compared to single inhibitors. Combination index (CI) was calculated by calcusyn software also showed strong synergism (&amp;lt;0.3). However, these drugs did not kill human dermal fibroblast suggestive of a cancer cell specific effect. There was a time dependent increase in cell death that was associated with downregulation of anti-apoptotic proteins BCL2 and MCL1 and the oncogene c-MYC. These findings in 2D models were corroborated in 3D spheroid models. Gene Set Enrichment Analysis (GSEA) revealed that HALLMARK G2M CHECKPOINT, HALLMARK E2F TARGETS, HALLMARK MYC TARGETS were negatively enriched in the combination treatment (Normalized enrichment score =&amp;lt;-2.5). The in-vivo studies on the anti-PD1 resistant mouse melanoma cell line YUMM 1.1. showed that iBET151 and CDKI73 combination had marked effects on tumour growth compared to vehicle control and the individual drugs (p&amp;lt;0.05). Conclusion: Our findings have revealed that this novel combination of two epigenetic inhibitors targets multiple downstream genes associated with cell cycle, oncogenesis and, apoptotic pathways which augments cell death compared to effects of the single drugs. Overall, the findings warrant further investigation of key targets involved in the responses and the extent to which effects of CDK9 inhibition is due to effects on chromatin modelling. The combination would appear promising to consider for future clinical trial in melanoma patients not responding to current therapies. Citation Format: Abdullah Al Emran, Hsin-Yi Tseng, Dilini Gunatilake, Stuart Cook, Jessamy Tiffen, Stuart Gallagher, Peter Hersey. BET and CDK9 protein inhibitors: Novel epigenetic therapy to synergistically kill human melanoma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-177.