tbuckley/cabot-search huggingface dataset:
Abstract 4449: Plinabulin, a microtubule destabilizing agent, improves tumor control by enhancing dendritic cell maturation and CD8 T cell infiltration in combination with immunoradiotherapy
Authors: Shinya Neri
Journal: Cancer Research (2020)

Abstract There are theoretical benefits of combining immune checkpoint blockade with radiotherapy, however, there are few indications that such combinations have translated to significant clinical benefit to patients. There is an unmet need to further enhance the effectiveness of these “immunoradiotherapy” combinations. We hypothesize that enhancing antigen presentation through augmenting dendritic cell (DC) activation could potentially improve the effectiveness of immunoradiotherapy. Towards this end, we have investigated the potential for combining the microtubule destabilizing first-in-class agent Plinabulin as the candidate DC activator, with radiotherapy and anti-PD1 immunotherapy (αPD1). First, we investigated how DCs could be affected by Plinabulin and irradiation in in vitro assays. We irradiated SP37A3 and XS106 DC lines with 10Gy and added Plinabulin to those cells. With the addition of Plinabulin, the phosphorylation of JNK and NFκB was upregulated and DC maturation was promoted with high MHC-II, CD86, CD80 and CD40 surface expressions (p&amp;lt;0.05, Dunnett's test). Combining Plinabulin and radiotherapy further augmented the response, particularly in sequence with plinabulin but not in combination. In in vivo models. TSA syngeneic breast cancer cells were implanted to the flank of BALB/c mice, irradiated with 24Gy/3fr, and treated with αPD1 and Plinabulin. There were no anti-tumoral effects with αPD1 alone, Plinabulin alone, and αPD1+Plinabulin groups. However, triple therapy showed much stronger tumor regression than the double therapy of irradiation and αPD1. Tumors were collected from the mice at 2.5-3 weeks after the irradiation and dissociated tumor cells were analyzed for DC activation and immune repertoire using flow cytometry. The percentage of CD8 T cells and CD86+ DCs in the tumor were significantly increased in the triple therapy group that were not seen for the monotherapy or bimodal therapy groups (p&amp;lt;0.05, Dunnett's test). Our findings may serve as a rationale for establishing clinical trial designs of synergistic combinational approaches to enhance immunoradiotherapy. Citation Format: Shinya Neri. Plinabulin, a microtubule destabilizing agent, improves tumor control by enhancing dendritic cell maturation and CD8 T cell infiltration in combination with immunoradiotherapy [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 4449.
Abstract 4443: Inhibition of PGE2/EP4 pathway by ONO-4578/BMS-986310, a novel EP4 antagonist, promotes T cell activation and myeloid cell differentiation to dendritic cells
Authors: Tohru Kotani, Hirotsugu Takano, Tomoko Yoshida, Ryota Hamasaki, Gary Kohanbash, Kazuhiko Takeda, Hideho Okada
Journal: Cancer Research (2020)

Abstract Prostaglandin E2 (PGE2) contributes to immunosuppression in the tumor microenvironment through one or more of its receptors (EP1-EP4), especially EP4 which is expressed at high levels on myeloid cells. ONO-4578/BMS-986310 is a novel EP4-selective antagonist that potently inhibits the PGE2-induced cAMP production in CHO cells expressing mouse and human EP4 receptors with single-digit nM IC50. Furthermore, ONO-4578/BMS-986310 shows excellent pharmacokinetic properties after oral dosing in mouse. ONO-4578/ BMS-986310 reverses PGE2-mediated suppression of T cell activation and promotes DC differentiation in vitro. Moreover, treatment with ONO-4578/BMS-986310 inhibits growth of CT26 and MC38 tumors in syngeneic mouse. The anti-tumor effect of ONO-4578/BMS-986310 is abrogated in immuno-deficient mice bearing CT26 tumors indicating that such effect is immune-mediated. ONO-4578/BMS-986310 treatment significantly prolongs survival of mice with highly aggressive SB28 gliomas in the brain. Flow cytometric analysis reveals that ONO-4578/BMS-986310 reduces infiltration of M2 macrophages in MC38 tumors compared with control mice. Microarray analysis of MC38 tumor tissues demonstrates up-regulation of cytotoxic T lymphocytes, natural killer cells and innate immunity-related genes after treatment with ONO-4578/BMS-986310. Finally, a combination of ONO-4578/BMS-986310 and anti-PD-1 antibody results in enhanced anti-tumor effects in GL261 and MC38 tumor-bearing mice compared with anti-PD-1 monotherapy.Our data demonstrate that ONO-4578/BMS-986310 promotes anti-tumor immunity and may be useful in the treatment of cancer patients. ONO-4578/BMS-986310 is being evaluated as monotherapy and in combination with nivolumab in an ongoing Ph1/1b clinical trials in patients with advanced solid tumors (NCT03155061, NCT03661632). Citation Format: Tohru Kotani, Hirotsugu Takano, Tomoko Yoshida, Ryota Hamasaki, Gary Kohanbash, Kazuhiko Takeda, Hideho Okada. Inhibition of PGE2/EP4 pathway by ONO-4578/BMS-986310, a novel EP4 antagonist, promotes T cell activation and myeloid cell differentiation to dendritic 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 4443.
Abstract 3650: A noncanonical histone target of NSD2 may contribute to oncogenesis
Authors: Nicole Weiss, Minkui Luo
Journal: Cancer Research (2020)

Abstract The NSD family of protein lysine methyltransferases (PKMTs), containing members NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1, cause epigenetic aberrations when dysregulated in cancer and are thus attractive therapeutic targets. These enzymes share a canonical activity catalyzing the dimethylation of histone 3 lysine 36 (H3K36me2), a mark associated with gene activation. In cancer, these enzymes are often overexpressed, amplified, or mutated, resulting in increased global H3K36me2 and transcriptional activation. In addition to transcriptional regulation, NSD2 has also been reported to be involved in pathways such as DNA replication and repair, which cannot be readily rationalized via its H3K36 methylation activity. This suggests that NSD2 has unidentified substrates that carry out its additional biological function(s), nonredundant with NSD1/3. Furthermore, NSD2 has a recurring glutamate to lysine mutation in the catalytic SET domain at 1099 (E1099K), which results in gain-of-function activity on H3K36. Our preliminary data has shown that NSD2 has noncanonical histone targets that are augmented by NSD2 E1099K to drive oncogenesis. We are using cell based approaches to dissect its downstream biology to reveal NSD2's oncogenic potential. Citation Format: Nicole Weiss, Minkui Luo. A noncanonical histone target of NSD2 may contribute to oncogenesis [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 3650.
Abstract 361: Pleckstrin-2 as a prognostic factor and mediator of gastric cancer progression
Authors: Bo Sun, Jian-Bin Xiang, Yi Xuan, Zong-You Chen, Xiao-Dong Gu, Da-Zhi Xu
Journal: Cancer Research (2020)

Abstract Background: Pleckstrin-2 (PLEK2) is a crucial mediator of cytoskeletal reorganization. However, the potential roles and clinical significance of PLEK2 in gastric cancer are still unknown. Methods: We aimed to illustrate the function of PLEK2 in gastric cancer. Pearson's correlation analysis was utilized to test the clinical impacts of the levels of PLEK2 in gastric cancer patients. Loss-of-function approaches were used to estimate the potential roles played by PLEK2 in modulating gastric cancer proliferation, self-renewal, and tumourigenicity. Immunoblotting and bioinformatics approaches were used to monitor the effect of PLEK2 on epithelial-mesenchymal transition (EMT) signalling pathways. Results: In gastric cancer tissue samples examined by western blot and real-time PCR, there was an increased level of PLEK2 compared with that in matched non-tumour samples. Kaplan-Meier plotter analysis revealed that gastric cancer patients with higher PLEK2 levels had substantially poorer overall survival (p=0.0028) compared with gastric cancer patients with lower PLEK2 levels. The upregulation or downregulation of PLEK2 in gastric cancer cell lines effectively enhanced or inhibited cell proliferation and pro-invasive behaviour, respectively. Additionally, we also found that PLEK2 enhanced EMT concomitantly with a reduction in E-cadherin and an elevation in Vimentin. Conclusions: Our findings demonstrated that PLEK2 plays a potential role in gastric cancer and may act as a prognostic factor for gastric cancer. Citation Format: Bo Sun, Jian-Bin Xiang, Yi Xuan, Zong-You Chen, Xiao-Dong Gu, Da-Zhi Xu. Pleckstrin-2 as a prognostic factor and mediator of gastric cancer progression [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 361.
Abstract 865: Using machine learning to detect heterogeneity in single cell multi-omics datasets
Authors: Saurabh Gulati, Shu Wang, Saurabh Parikh, Ben Liu, Kaustubh Gokhale, Manimozhi Manivannan, Sombeet Sahu, Dong Kim, Anup Parikh
Journal: Cancer Research (2020)

Abstract Background: While scRNA-seq helps in obtaining high-resolution views of single-cell heterogeneity through characterization of the functional state of cells, our understanding of the cellular properties and population architectures of heterogeneous tissues will be greatly advanced by the multi-omics investigation of single cells. Recently, several computational methods have been developed to integrate data from multiple different single cell experiments measuring individual analytes. But unambiguous inference that a cellular phenotype is caused by a genotype can only be achieved by their measurement from the same single cell. To address this gap, we have developed the Tapestri multi-omics workflow to analyze the RNA and DNA information from the same cell. Methods: After pre-processing of the reads, cell calling is done by identifying the good barcodes using both DNA and RNA reads. DNA reads are processed to identify genetic variants in each cell. The variant cell matrix is then filtered for data completeness to ensure only high-quality data is used in downstream processing. Ploidy is estimated using by normalizing DNA reads, genetic variants and ploidy information together is used to identify subclones. The RNA reads are log normalized and scaled within each cell. Next we set the mean expression of each transcript to 0 and scale the variance to 1. This avoids downstream analysis being skewed by high expressors. We then trained a random forest classifier to identify significantly differentially expressed transcripts across subclones which were identified using genetic variants and ploidy information. Results: Using the top differentially expressed transcripts we performed dimensionality reduction followed by clustering of cell types. The resulting visualization showed how well the genotypic and transcriptomic datasets integrated with one another. We tested this method on a model system with Raji and KG1 cell lines titrated at 50:50 ratio and were clearly able to associate the transcriptional variation with the genotypic variation of the 2 different cell lines. The method was also validated on a PBMC sample to ensure robustness of methods. We were able to identify the different cell types present the sample and were able to overlay that information with genetic variants to identify sub-clones in the identified cell types. Citation Format: Saurabh Gulati, Shu Wang, Saurabh Parikh, Ben Liu, Kaustubh Gokhale, Manimozhi Manivannan, Sombeet Sahu, Dong Kim, Anup Parikh. Using machine learning to detect heterogeneity in single cell multi-omics datasets [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 865.
Abstract 6133: Rats support cancer studies
Authors: Bisoye Towobola Adedeji, Noto K. Fallon, Sam Moody, Valeriya Steffey, Chris Brenzel, Jack Crawford, Tseten Yeshi Jamling, Goutham Narla
Journal: Cancer Research (2020)

Abstract The use of the most predictive model is essential in transferring scientific knowledge from bench to bedside. In In vivo cancer research, immunodeficient mice models are being used, but have been found with limitations. They fall short in tumor take rates, growth kinetics, and their ability to support the growth of some human Cancer cell lines. To address these limitations, we produced an immunodeficient rat, a Sprague-Dawley Rag2/Il2rg double knockout (SRG OncoRat) rat that lacks mature B cells, T cells, and circulating NK cells. Using a variety of human cell lines (VCaP, LNCaP, 22RV1) which have poor or highly variable growth kinetics in commercially available immunodeficient mouse models, we demonstrated that the SRG rat has superior tumor take rates and growth kinetics, providing a more efficient model for drug efficacy studies. Enhanced take rates enable the use of fewer animals for studies, allows for faster timelines to drug efficacy data, and overall, may provide a better platform for reproducible drug efficacy results. In addition, the SRG rat developed larger tumor volumes, allowing for serial fine needle aspirate biopsy for PK, PD and molecular analysis in the same animal throughout the course of the study without significantly affecting normal tumor growth. The SRG OncoRat is a valuable addition to current available rodent xenograft models for evaluating novel therapies. Citation Format: Bisoye Towobola Adedeji, Noto K. Fallon, Sam Moody, Valeriya Steffey, Chris Brenzel, Jack Crawford, Tseten Yeshi Jamling, Goutham Narla. Rats support cancer studies [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 6133.
Abstract 417: Developing mouse models to dissect the function of a driver gene epimutation in lung tumorigenesis
Authors: Li Yang, Anusha Mandala, Yi Chen, Lanlan Shen
Journal: Cancer Research (2020)

Abstract Background: Cancer is a complex disease caused by the accumulation of both genetic and epigenetic alterations in oncogenes and tumor suppressor genes. Although an extensive catalog of epigenetic changes has been generated in patients with lung cancer, we have only a fragmentary understanding of their functional roles, particularly for the initiation and maintenance of tumors. The use of genetically engineered mouse models definitively demonstrate that mutations at specific genes cause cancer. An analogous “epigenetically engineered mouse models” should not only lead to important insights about how cancer develop but could provide in vivo platforms in which to screen and validate novel epigenetic therapies. Methods and Results: We published the first epigenetically engineered mouse cancer model based on a driver gene epimutation of p16 (also known as cyclin-dependent kinase inhibitor 2A). In human lung cancers, p16 epimutation is common, occurring in ~50% of cases. Importantly, p16 epimutation is frequently detected in lung pre-neoplastic lesions and p16 is of the best documented gene that controls K-RAS oncogene-induced senescence. Therefore, to elucidate the functional role of p16 epimutation for lung cancer establishment and progression, we developed a mouse model that combines oncogenic K-ras with p16 epimutation. We found that mice with combined K-ras mutation and p16 epimutation (K-ras+/G12D; p16meth/meth) displayed substantially increased tumor numbers and sizes, with tumor progression to adenocarcinoma. In addition, to investigate the therapeutic effects of reversing p16 epimutation, we developed a mouse model that enables conditional and inducible CRISPR based epigenetic gene editing. Our system utilizes deactivated Cas9 (dCas9) fused to a repetitive protein scaffold known as SunTag, which recruits multiple copies of antibody-fused demethylase TET1. We showed that this system is robust and reproducible to achieve targeted DNA demethylation at CpGs within 100 bp from the sgRNA target site of p16 promoter and to reactivate p16. Conclusion: We have established clinically relevant and immunocompetent mouse models based on defined genetic and epigenetic alterations to drive benign lung tumor growths towards the ultimate malignant phenotype. Our model should prove useful as an in vivo preclinical platform for testing epigenetic therapeutic strategies. Citation Format: Li Yang, Anusha Mandala, Yi Chen, Lanlan Shen. Developing mouse models to dissect the function of a driver gene epimutation in lung tumorigenesis [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 417.
Factors associated with asymptomatic infection in health-care workers with severe acute respiratory syndrome coronavirus 2 infection in Wuhan, China: a multicentre retrospective cohort study
Authors: Shuai Zhang, Mengfei Guo, Feng Wu, Nian Xiong, Yanling Ma, Zhihui Wang, Limin Duan, Lan Chen, Haixia Ouyang, Yang Jin
Journal: Clinical Microbiology and Infection (2020)
Abstract 522: Optimization of novel anti-4-1BB antibodies on Biocytogen's <i>in vivo</i> drug screening platform
Authors: Chaoshe Guo, Yu Zhu, Yunyun Chen, Yi Yang, Zhihong Li
Journal: Cancer Research (2020)

Abstract 4-1BB (CD137, tumor necrosis factor receptor superfamily 9) is an inducible costimulatory receptor expressed on activated T and natural killer (NK) cells. 4-1BB ligation on T cells triggers a signaling cascade that results in upregulation of anti-apoptotic molecules, cytokine secretion, and enhanced effector function. In dysfunctional T cells that have a decreased cytotoxic capacity, 4-1BB ligation demonstrates a potent ability to restore effector functions. On NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity. Agonistic monoclonal antibodies targeting 4-1BB have been developed to harness 4-1BB signaling for cancer immunotherapy. We have interests in developing novel 4-1BB antibodies for boosting cancer patients' own immunity in light of other successful immune checkpoint modulators. We developed a cohort of 4-1BB specific antibodies using the classic hybridoma technology. Then, we took the advantages of Biocytogen's humanized mice and screened the purified antibodies in B-h4-1BB mice bearing MC-38 tumor cells. We found some antibodies that are as potent as Urelumab in vivo. We then humanized the antibody to obtain YH004. To determine the subtype of the antibody, we grafted the antigen-binding domain onto various human Fc backbones. Interestingly, we found that the human IgG1 isotype was more effective against tumors than the other isotypes in B-4-1BB mice with MC38 tumors and Treg depletion were noted in tumor-infiltrating lymphocyte analysis using the same murine model. In addition, we proved that the synergistic anti-tumor activity of YH004 in combination with pembrolizumab in B-hPD-1/h4-1BB mice. In brief, the 4-1BB antibody was validated in humanized mice to provide a favorable reference for future clinical evaluation. Citation Format: Chaoshe Guo, Yu Zhu, Yunyun Chen, Yi Yang, Zhihong Li. Optimization of novel anti-4-1BB antibodies on Biocytogen's in vivo drug screening platform [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 522.
Abstract 6114: Host and neoplastic cells utilize Axl for breast cancer bone metastasis
Authors: Mai Tanaka, Dietmar W. Siemann
Journal: Cancer Research (2020)

Abstract Breast cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related death for women in the United States. Approximately 90% of cancer-related death results from metastasis, and the bone is the most common site of metastasis for breast cancer. Upregulation of signaling pathways can promote the metastatic phenotypes of neoplastic cells, including cell migration, invasion, proliferation and angiogenesis. In addition, when breast cancer cells disseminate to the bone, neoplastic cells upregulate signaling pathways to activate osteoclast-induced bone resorption. A key pathway involved in metastatic spread of cancer cells is the receptor tyrosine kinase Axl. Genetic and pharmacologic Axl inhibition in both human and rodent breast cancer cell lines (MDA-MB-231 and 4T1) impaired tumor cell migration and invasion. Intracardiac inoculation of Axl knockdown (KD) MDA-MB-231 cells significantly decreased the number of bone metastases compared to the scrambled control MDA-MB-231 cells. Another mechanism by which Axl inhibition impaired bone metastasis is through the modulation of osteoclast maturation and activity. Co-culture of Axl KD breast cancer cells with murine osteoclast precursor cells (Raw264.7) significantly reduced the number of tumor cell-induced osteoclast resorption pits on bone slices. In addition, genetic and pharmacologic inhibition of Axl in Raw264.7 cells as well as bone marrow derived osteoclast precursor cells, significantly reduced osteoclast formation and activity. Scrambled control and Axl KD Raw264.7 cells were cultured in serum free medium for 24 hours, and their conditioned media were collected. The conditioned media of Axl KD Raw264.7 cells revealed significantly decreased levels of monocyte chemoattractant protein 1 (MCP-1), which known to promote osteoclastogenesis, compared to the scrambled control Raw264.7 cells. In summary, we have demonstrated that inhibition of Axl decreases breast cancer metastasis to the bone through modulation of the host and neoplastic cell functions. Collectively, these data indicate that Axl signaling may be a promising therapeutic target to impair tumor progression and metastasis. Citation Format: Mai Tanaka, Dietmar W. Siemann. Host and neoplastic cells utilize Axl for breast cancer bone metastasis [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 6114.
Response to: ‘Implications of SARS-CoV-2 infection for patients with rheumatic disease’ by Lin<i>et al</i>
Authors: Alexis Mathian, Zahir Amoura
Journal: Annals of the Rheumatic Diseases (2020)

We thank Lin et al for their interest in our study reporting on the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) in a case series of patients with systemic lupus erythematosus (SLE) under long-term treatment with hydroxychloroquine (HCQ).1 2 Our work intended to report the failure of HCQ to prevent COVID-19 in a series of patients with SLE. Since our publication, several other studies have also shown the lack of efficacy of HCQ in the treatment of SARS-Cov-2 infection. Lin et al discuss whether patients with SLE are more susceptible to infection with SARS-CoV-2, and, when they are infected, whether they progress to more severe disease and a poorer outcome. Our study however was not designed to address these questions. Hence, both studies cannot really be compared.

First, Lin et al observed that …