tbuckley/cabot-search huggingface dataset:
Abstract 274: Multifaceted function of microRNA-299-3p fosters an antitumor environment through modulation of androgen receptor and VEGFA signaling pathways in prostate cancer cells
Authors: Kavya Ganapathy, Stephen Staklinski, Md Faqrul Hasan, Richard Ottman, Thomas Andl, Anders Berglund, Jong Park, Ratna Chakrabarti
Journal: Cancer Research (2020)

Abstract MicroRNAs (miRNAs) play crucial roles in the regulation of prostate cancer (PCa) through modulation of signaling pathways. Androgen receptor (AR) signaling is central to PCa and PCa therapy. The therapeutic suitability of miRNAs that target AR has not been investigated thoroughly. Here, we illustrate the clinical relevance, functional significance and therapeutic benefit of miR-299-3p, an AR targeting microRNA, in PCa progression. We noted a loss of expression of miR-299-3p in prostate tumors compared to noncancerous prostate tissue in clinical specimens. Studies on the impact of miR-299-3p restoration on AR function, phenotypic changes associated with cancer progression and involvement of the downstream components of the AR signaling pathway were conducted using in vitro and in vivo model systems. Replenishment of miR-299-3p in C4-2B, 22Rv-1, and PC-3 cells contributed to cell cycle arrest, reduced cell proliferation, migration and increased expression of apoptotic markers. Additionally, expression of miR-299-3p reduced AR, PSA and VEGFA expression. AGO-RNA pulldown experiment showed enrichment of AR, VEGFA and miR-299-3p in the RISC in the extracts of C4-2B cells overexpressing miR-299-3p. Overexpression of miR-299-3p inhibited epithelial-mesenchymal transition signaling, through inhibition of expression of Slug, TGF-Β3, phospho-AKT, and phospho-PRAS40 and up-regulation of E-cadherin. Replenishment of miR-299-3p showed reduced tumor growth in xenograft mice models. Furthermore, we also tested the benefit of miR-299-3p restoration in combination treatment with enzalutamide and docetaxel which showed a synergistic effect on drug sensitivity. In conclusion, this study has identified novel mechanisms of antitumor and antimigration functions of miR-299-3p through modulation of AR and VEGFA signaling pathways which leads to improved drug sensitivity of PCa. Citation Format: Kavya Ganapathy, Stephen Staklinski, Md Faqrul Hasan, Richard Ottman, Thomas Andl, Anders Berglund, Jong Park, Ratna Chakrabarti. Multifaceted function of microRNA-299-3p fosters an antitumor environment through modulation of androgen receptor and VEGFA signaling pathways in prostate cancer 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 274.
Abstract 6129: A scalable, non-biased screen for isolating functionally metastatic cell populations
Authors: Jerry Xiao, Alex Lekan, Kelly Stanton, Eric Glasgow, Seema Agarwal
Journal: Cancer Research (2020)

Abstract Up to 90% of cancer-associated deaths are due to metastasis. Nonetheless, the mechanisms of metastasis are poorly understood, largely because of a lack of technologies to routinely and robustly isolate, propagate, and culture metastatic cells. Current cellular models for metastasis are hindered by a lack of scalability, a high cost per experiment, and the length of experiments. In this proof-of-principle study, we injected an invasive triple-negative breast cancer cell line, MDA-MB-231, into zebrafish embryos. Cells were monitored for invasion from the yolk sac into the zebrafish circulatory system, representing a cell population analogous to metastatic, circulating tumor cells. Within 5 days, cells had migrated from the primary injection site to the tail. Tails showing migration of cells were excised, digested, and the labeled human-cancer cells were propagated. Re-injection of propagated cells resulted in serial generations (F1 and F2). The time required for migration decreased with each succeeding generation; with the latest (F2) generation migrating to the tail within 24 hours. In addition to being more invasive, cells that migrated to the tail displayed a more mesenchymal phenotype compared to parental cells. Consistent with this finding, RNA-seq analysis showed an upregulation of genes involved in an epithelial to mesenchymal transition. Moreover, the highest differentially expressed genes have been independently associated with metastasis. Finally, in silico analyses demonstrated that the upregulated genes were clinically significant. Together these data provide proof-of-principle that we have established a scalable, rapid, and robust method that can provide routine access to invasive metastatic cells. The platform combines in vivo and in vitro components that can be used to isolate, enrich, and propagate metastatic cells from individual patients, and has the potential to advance basic and translational research in tumor metastasis. This cellular model relies solely on cell behavior and is a non-biased method that can be widely applied to all tumor types as it does not require specific biomarkers. In addition to providing a tool for advancing our understanding of metastases, the technology has the potential to be used in screening for drugs that specifically target metastatic cells; a critical unmet need in the treatment of human cancers. Citation Format: Jerry Xiao, Alex Lekan, Kelly Stanton, Eric Glasgow, Seema Agarwal. A scalable, non-biased screen for isolating functionally metastatic cell populations [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 6129.
Efficacy of an internal anchoring plastic stent to prevent migration of a fully covered metal stent in malignant distal biliary strictures: a randomized controlled study
Authors: Woo Hyun Paik, Sang Myung Woo, Jung Won Chun, Byeong Jun Song, Woo Jin Lee, Dong-Won Ahn, Yoon Suk Lee, Young Hoon Choi, Ji Kon Ryu, Yong-Tae Kim, Sang Hyub Lee
Journal: Endoscopy (2020)

Background Two types of self-expandable metal stents (SEMS) are available for malignant distal biliary obstruction: fully covered SEMS (FCSEMS) and uncovered SEMS. FCSEMS can prevent stent ingrowth, but a major concern is spontaneous migration. This study aimed to determine whether the additional insertion of a double-pigtail plastic stent to anchor the FCSEMS can prevent migration. Methods 68 patients with unresectable, malignant, distal, biliary obstruction were included in this multicenter, randomized, superiority trial. The patients were randomly assigned to receive either the FCSEMS plus an anchoring plastic stent (n = 33) or an FCSEMS alone (n = 35). After placement of the FCSEMS, the anchoring stent was inserted inside the FCSEMS. The primary outcome was the rate of stent migration during the 6-month follow-up. The secondary outcomes were stent-related adverse events, stent patency, and survival rates. Results The baseline characteristics were similar between the two groups. The rate of stent migration at 6 months was significantly lower in patients with the FCSEMS plus anchoring stent (15 % vs. 40 %; P = 0.02). The mean stent patency was significantly longer in the FCSEMS plus anchoring group (237 days [95 % confidence interval [CI] 199 to 275] vs. 173 days [95 %CI 130 to 217]; P = 0.048). There were no significant differences in stent-related adverse events and overall survival rates at 6 months between the two groups. Conclusions Our data suggest that the additional double-pigtail plastic stent anchored the FCSEMS to prevent migration and prolonged patency without any serious adverse events.
60才以上の患者における年齢,性,血圧,及び心血管疾患既往症に関する抗高血圧剤治療の効果
Authors: Amery A, Birkenhaeger W, Brixko R, Bulpitt C, Clement D, Deruyttere M, De Schaepdryver A, Dollery C, Fagard R
Journal: The Lancet (1986)
Abstract 3167: Immune checkpoint inhibition re-challenge after a planned treatment interruption in patients with pancreatic adenocarcinoma with mismatch repair deficient tumors
Authors: Vaia Florou, Chris Nevala-Plagemann, Kristin Barber, Jenna Mastroianni, Courtney Christine Cavaliery, Ignacio Garrido-Laguna
Journal: Cancer Research (2020)

Abstract Background: Immune checkpoint inhibitors (CPI) are used in numerous solid cancers as well as hematologic malignancies. The optimal duration of immunotherapy to maintain durable responses has not been defined, neither is the efficacy of CPI when the disease progresses during a planned treatment interruption. Pembrolizumab has been approved for all mismatch repair deficient tumors regardless of histology, based on cumulative data of five clinical trials including multiple solid tumors. Only eight patients with pancreatic cancer were included in those trials used for CPI approval in this setting. Outside of this, there is currently no role for standard of care CPI in pancreatic cancer. Methods: We screened all patients with pancreatic adenocarcinoma treated at our institution and identified two patients who had mismatch repair deficient tumors and received immune checkpoint inhibitors. Results: Two patients with metastatic pancreatic cancer were retreated with an anti- PD-1 antibody after a planned treatment interruption which, did not occur in the context of disease progression or development of immune-related adverse events. Both patients were initially treated for more than one year (17 and 22 months each) with partial response of their disease, before therapy was discontinued after at least six months of stable radiographic findings were achieved. One patient had disease progression after ten months off therapy and the other 16 months after treatment discontinuation. Both were treated with the same checkpoint inhibitor upon progression and had radiographic regression of their disease within two months after treatment initiation. Both remain on CPI with continuing radiographic and clinical response. Conclusions: CPI re-challenge may be an efficient therapy when discontinued after maximal response has been achieved. Only twelve cases have been described in the literature where patients were retreated with CPI upon progression of disease while off therapy. Our case series contributes to that body of literature and is the first to describe patients with pancreatic cancer re-challenged with CPI. Mismatch repair deficient pancreatic cancers are rare, but CPI have similar efficacy compared to other tumors with similar molecular features. Citation Format: Vaia Florou, Chris Nevala-Plagemann, Kristin Barber, Jenna Mastroianni, Courtney Christine Cavaliery, Ignacio Garrido-Laguna. Immune checkpoint inhibition re-challenge after a planned treatment interruption in patients with pancreatic adenocarcinoma with mismatch repair deficient tumors [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 3167.
Abstract 5637: Investigating tumor intrinsic PD-1/PD-L1 signaling in canine osteosarcoma cell lines as a spontaneous model for human disease
Authors: Dziubek Katarzyna, Mikolaj Kocikowski, Borek Vojtesek, David Argyle, Malgorzata Lisowska, Ted Hupp, Maciej Parys
Journal: Cancer Research (2020)

Abstract There is limited advancement in osteosarcoma therapy in humans. Interestingly, dogs spontaneously develop very similar disease at higher frequency, making canines a perfect model to study OS. Recent introduction of immune checkpoint blockade has revolutionized cancer therapy. Despite huge success, immunotherapy is still not effective in some group of patients or cancer types, and largely ineffective in sarcomas. Until recently, immune-checkpoint therapy was considered to block the interaction between PD-L1 expressed by cancer cells and PD-1 receptor localized on T-cells. Surprisingly, latest studies showed that cancer cells not only express PD-L1 but also PD-1 what is associated with increased growth, proliferation and survival via mTOR pathway signalling. Our group use canine osteosarcoma cell lines to investigate the role of PD-1/PD-L1 intrinsic signalling in disease pathogenesis. Flow cytometry confirmed PD-1 spontaneous expression on many OS cell lines, which ranged between 0.26% and 33.3%. Phenotypic changes were observed in PD-1/PD-L1 transfected over-expressing cells (OE). Strikingly, when grown in 3D culture, over-expressing cells shown accelerated growth and formation of spheres. Upregulation of pS6RP in PD-1 and PD-L1 OE cell lines indicated increased mTOR pathway signaling as demonstrated by Western Blot analysis. To confirm the impact of PD-1 antibody on canine cells, cell viability assay was performed after PD-1 blocking antibody treatment. Interestingly although in many of the cell lines, the addition of the antibody did not alter the growth, in one cell line the growth accelerated, while in another the proliferation decreased. Our data implies that the PD-1/PD-L1 intrinsic signalling may be important in canine osteosarcoma and targeting it could help enhance the therapeutic effect in both dogs and humans. Citation Format: Dziubek Katarzyna, Mikolaj Kocikowski, Borek Vojtesek, David Argyle, Malgorzata Lisowska, Ted Hupp, Maciej Parys. Investigating tumor intrinsic PD-1/PD-L1 signaling in canine osteosarcoma cell lines as a spontaneous model for human disease [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 5637.
Abstract 2219: OnxoVEXmGM-CSF promotes systemic response to PD-L1 /PD-1 blockade in multiple mouse syngeneic tumor models
Authors: Keegan Cooke, Juan Estrada, Petia Mitchell, Jinghiu Zhan, Pedro J. Beltran, Jing Qing, Jude Canon
Journal: Cancer Research (2020)

Abstract Inhibition of the immune-checkpoint axis that involves PD-L1/PD-1 has improved responses and outcomes for certain cancer patients, but there remains unmet need as only a fraction of patients respond to these therapies. Talimogene laherparepvec (T-VEC) is an FDA-approved, first-in-class oncolytic immunotherapy based on a modified herpes simplex virus type 1 (HSV-1) designed to selectively replicate in tumors and produce granulocyte-macrophage stimulating factor (GM-CSF) to enhance a tumor-antigen specific adaptive immune response. Intratumoral treatment with T-VEC has been shown to promote an inflammatory tumor microenvironment both preclinically and clinically. Combining T-VEC with immune checkpoint inhibitors is of high interest to potentially broaden and deepen the clinical responses in checkpoint-resistant tumors. In the current study, we evaluated the efficacy of OncoVEXmGM-CSF (an HSV modified like T-VEC, except that it produces murine GM-CSF) in combination with anti-PD-1/PD-L1 treatment in multiple syngeneic mouse tumor models. Bilateral tumor models were used, where only one tumor was treated with OncoVEXmGM-CSF (representing the local oncolytic effect), allowing the evaluation of systemic abscopal effect in the uninjected contralateral tumors. OncoVEXmGM-CSF in combination with anti-PD-L1/PD-1 enhanced tumor growth inhibition in both treated and contralateral tumors in the A20 and MC38 syngeneic models and overcame anti-PD-L1 resistance in the CT26 model. The combination treatment also led to a significant increase in median overall survival compared to either agent as a monotherapy. In addition, tumor antigen epitopes were identified by combining exome sequencing and MHC/HLA-binding prediction algorithms. Antigen-specific T cell response was measured in an IFN-γ ELISPOT assay using splenocytes from treated mice. OncoVEXmGM-CSF induced and /or enhanced systemic T cell responses directed against both tumor neoantigens and tumor-associated antigens. Together, these data reveal that OncoVEXmGM-CSF treatment can cause direct tumor lysis along with the potentiation of an adaptive, systemic T cell-mediated anti-tumor immune response that can be enhanced by the addition of PD-L1/PD-1. Our study provides a strong rationale for the ongoing clinical evaluation of the combination of T-VEC and PD1-/PD-L1-targeted therapy in cancer patients. Citation Format: Keegan Cooke, Juan Estrada, Petia Mitchell, Jinghiu Zhan, Pedro J. Beltran, Jing Qing, Jude Canon. OnxoVEXmGM-CSF promotes systemic response to PD-L1 /PD-1 blockade in multiple mouse syngeneic tumor models [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 2219.
Proteomics identifies EGF‐like domain multiple 7 as a potential therapeutic target for epidermal growth factor receptor‐positive glioma
Authors: Fei‐yi‐fan Wang, Si‐yi Wang‐gou, Hang Cao, Nian Jiang, Qi Yang, Qi Huang, Chun‐hai Huang, Xue‐jun Li
Journal: Cancer Communications (2020)

Abstract Background Glioma, the most frequent primary tumor of the central nervous system, has poor prognosis. The epidermal growth factor receptor (EGFR) pathway and angiogenesis play important roles in glioma growth, invasion, and recurrence. The present study aimed to use proteomic methods to probe into the role of the EGF‐EGFR‐angiogenesis axis in the tumorigenesis of glioma and access the therapeutic efficacy of selumetinib on glioma. Methods Proteomic profiling was used to characterize 200 paired EGFR‐positive and EGFR‐negative glioma tissues of all pathological types. The quantitative mass spectrometry data were used for systematic analysis of the proteomic profiles of 10 EGFR‐positive and 10 EGFR‐negative glioma cases. Consensus‐clustering analysis was used to screen target proteins. Immunofluorescence analysis, cell growth assay, and intracranial xenograft experiments were used to verify and test the therapeutic effect of selumetinib on glioma. Results Advanced proteomic screening demonstrated that the expression of EGF‐like domain multiple 7 (EGFL7) was higher in EGFR‐positive tumor tissues than in EGFR‐negative tumor tissues. In addition, EGFL7 could act as an activator in vitro and in vivo to promote glioma cell proliferation. EGFL7 was associated strongly with EGFR and prognosis. EGFL7 knockdown effectively suppressed glioma cell proliferation. Selumetinib treatment showed tumor reduction effect in EGFR‐positive glioblastoma xenograft mouse model. Conclusions EGFL7 is a potential diagnostic biomarker and therapeutic target of glioma. Selumetinib could target the EGFR pathway and possibly improve the prognosis of EGFR‐positive glioma.
Abstract 5408: Chloroquine inhibits PARP expression in hepatoblastoma
Authors: Marjut Pihlajoki, Katja Eloranta, Antti Kyrönlahti, Markku Heikinheimo
Journal: Cancer Research (2020)

Abstract Hepatoblastoma is the most common pediatric liver malignancy accounting 1 % of all pediatric malignancies. Despite advances in medical treatment and surgical techniques, the prognosis for advanced metastatic hepatoblastoma remains poor, underscoring the need for new therapeutic modalities. Chloroquine (CQ), a drug used to treat malaria and rheumatologic diseases, has been shown to inhibit the growth and survival of various cancer types. In this study we examined the antineoplastic activity of CQ on HB cells. Established human HB cell line (HUH6) cells were cultured in presence of clinically acceptable concentrations of CQ. Morphology, viability, and apoptosis were assessed after 48 h and 96 h of CQ treatment showing decreased cell survival and increased caspase 3/7 activity representing induction of apoptosis. Metabolomic profiling of CQ treated HUH6 cells demonstrated significant decrease in NAD+ and aspartate concentration. Furthermore, RT-qPCR based Death Pathway Finder array was conducted to elucidate the molecular mechanisms underlying the CQ effect showing downregulated expression of PARP1 and PARP2. Quantitative western blotting was performed to validate differentially expressed genes at the protein level. Taken together, CQ treatment inhibits cell survival in HB cells in vitro, presumably by disturbing NAD+/NADH balance, impairing aspartate biosynthesis, and reducing PARP expression. CQ thus holds potential as a new treatment modality in HB management. Citation Format: Marjut Pihlajoki, Katja Eloranta, Antti Kyrönlahti, Markku Heikinheimo. Chloroquine inhibits PARP expression in hepatoblastoma [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 5408.
Abstract 4560: Conditionally active biologics (CAB): A novel class of molecules targeting solid tumors
Authors: Jing Wang, Charles Xing, Haizhen Liu, Ana Paula G. Cugnetti, Christina Wheeler, Matthew Lucas, Gerhard Frey, Cathy Chang, William J. Boyle, Jay M. Short
Journal: Cancer Research (2020)

Abstract Conditionally Active Biologics (CAB) technology is a proprietary platform that selects antibodies binding to target antigens in the context of diseased tissues, but not normal tissues, taking advantage of the unique conditions in the tumor microenvironment. Using our CAB technology, we have developed CAB ADCs to various well-established tumor associated antigens (TAA), including Nectin-4, Her2 and CD46. Each of these molecules play an important role in cancer biology and are attractive targets for the development of therapeutic antibodies. These targets, however, are expressed on many normal tissues and have been implicated in a wide range of biological processes; therefore, limiting the use of traditional ADCs as cancer therapy. Using CAB technology, we have developed conditionally active ADCs that have no or very little binding to the target antigen in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (including Warburg effect). In vitro and in vivo efficacy data demonstrating the abilities of CAB ADCs to induce cytotoxicity of human target-expressing tumor cell lines, and to inhibit tumor growth in human tumor xenograft models will be presented. In conclusion, our data is consistent with our previous work on EpCAM, our clinical stage AXL and ROR2 CAB ADCs, and suggests that conditionally active ADCs generated using the CAB technology will provide a new generation of biologics with increased safety margin and therapeutic index in the clinic. Citation Format: Jing Wang, Charles Xing, Haizhen Liu, Ana Paula G. Cugnetti, Christina Wheeler, Matthew Lucas, Gerhard Frey, Cathy Chang, William J. Boyle, Jay M. Short. Conditionally active biologics (CAB): A novel class of molecules targeting solid tumors [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 4560.