tbuckley/cabot-search huggingface dataset:
Abstract 5186: Human stem cell humanized mouse model for <i>in vivo</i> evaluation of bispecific antibody efficacy and drug-induced cytokine release
Authors: Li-Chin Yao, Danying Cai, Roberta Aliperta, Allison Colthart, Werner Meier, Mingshan Cheng, James G. Keck
Journal: Cancer Research (2020)

Abstract Bispecific antibodies have shown several promising advantages over monoclonal antibodies and are emerging as one of the growing cancer immunotherapies. Preclinical in vivo models to assess efficacy and cytokine release associated with immune cell engagement are needed. We have developed a human stem cell (HSC) humanized mouse model for testing efficacy and for quantifying cytokine release in response to bispecific antibody treatment. Here we evaluated an EGFR bispecific T cell engager (BiTE), using EGFR-positive MDA-MB-231 orthotopic breast cancer model in CD34+ HSC humanized NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG™) mice. BiTE treatment for 2 weeks resulted in complete tumor regression when dosing was initiated at an average tumor volume of around 100 mm3. In addition, BiTE treatment for 4 weeks effectively inhibited the tumor growth when dosing mice bearing larger tumors of around 400mm3 in volume. Sixteen hours after the first two doses as compared to PBS control, human cytokines IFN-γ, IL-6, and IL-10 were elevated. Cytokine levels then returned to the baselines following continuous dosing. We observed a similar time course and levels of cytokine release between these two BiTE-treated groups with different tumor sizes. T cell activation in the peripheral blood after the last dose was assessed by flow cytometry analysis. In the BiTE-treated group, T cell percentage decreased, as compared to the PBS control. Both CD4+ and CD8+ T cell subsets showed an increased frequency of CD69+ cells after BiTE treatment. Evaluation of drug efficacy and cytokine release in response to BiTE treatment using PBMC-humanized NSG™ mice with and without MDA-MB-231 tumors are underway and results will be discussed. Citation Format: Li-Chin Yao, Danying Cai, Roberta Aliperta, Allison Colthart, Werner Meier, Mingshan Cheng, James G. Keck. Human stem cell humanized mouse model for in vivo evaluation of bispecific antibody efficacy and drug-induced cytokine release [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 5186.
Abstract 5017: EphA2 is a clinically relevant target for breast cancer bone metastatic disease
Authors: Dana M. Brantley-Sieders
Journal: Cancer Research (2020)

Abstract While advances in molecular targeted therapies have increased survival for breast cancer patients, outcomes for patients with metastatic disease remain poor. EphA2 receptor tyrosine kinase (RTK) is highly expressed in breast tumor cells across multiple molecular subtypes and correlates with poor patient prognosis. As metastasis of breast cancer to bone is a major cause of morbidity and mortality in patients, we investigated the role of EphA2 in this clinically relevant phenomenon. Analysis of human patient gene expression datasets and human breast-to-bone metastasis samples revealed high level ephA2 expression in bone lesions relative to other sites of metastatic dissemination, and EphA2 positive staining on breast tumor cells in bone metastatic lesions, respectively. EphA2 loss of function in tumor cells reduced tumor-induced osteolysis in two independent intratibial tumor engraftment models (4T1 and MDA-MB-231) as well as in an intracardiac experimental metastasis model (MDA-MB-231) in vivo. We observed a significant reduction in osteoclasts in animals harboring EphA2 loss of function tumors relative to control tumors. Further in vitro analyses revealed that blocking EphA2 function resulted in defective precursor maturation into functional osteoclasts through an interleukin-6 (IL-6) dependent mechanism. Pharmacologic inhibition of EphA2 decreased breast tumor induced osteolytic disease severity in vivo. Together, these data provide pre-clinical validation of EphA2 as a clinically relevant molecular target for breast cancer bone metastatic, osteolytic disease, warranting further investigation of molecular mechanisms that link EphA2 to tumor-induced osteolysis and eventual clinical development. Citation Format: Dana M. Brantley-Sieders. EphA2 is a clinically relevant target for breast cancer bone metastatic 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 5017.
Abstract 1129: CADM1 is a novel serum marker for small cell lung cancer
Authors: Takeshi Ito, Toko Funaki, Goh Tanaka, Takahide Nagase, Yoshinori Murakami
Journal: Cancer Research (2020)

Abstract Small cell lung cancer (SCLC) accounts for about 15% of lung cancer. Although SCLC often responds favorably to combined-modality chemotherapy at the initial treatment, resistant tumors develop rapidly, which makes SCLC one of the representative cancers refractory to any therapeutic approaches. Moreover, molecular targeting therapy has not been developed for SCLC so far. Therefore, novel approaches to the diagnosis and treatment of SCLC on the basis of molecular understanding would be prerequisite to control this refractory cancer. One of the most critical issues of SCLC is its early detection in the initial screening and after chemotherapy. For this purpose, pro-gastrin releasing peptide (ProGRP) and neuron specific enolase (NSE) are widely used for serum markers for detection of SCLC, although combination of ProGRP and NSE can detect at most 60% of SCLC. We have previously demonstrated that CADM1, a member of the immunoglobulin superfamily cell adhesion molecules, is highly expressed in around 75% of SCLC. In addition, SCLC expresses a splicing variant, CADM1v8/9, which is observed specifically in normal testis. Here, we report that the extracellular fragment of CADM1v8/9 is digested by ADM17 and released into cell medium or human serum. So, we generated specific monoclonal antibody against CADM1v8/9 using Cadm1-deficient mice and developed a serum diagnostic marker system for SCLC. Preliminary study shows that CADM1v8/9 detects 47% of SCLC with specificity of 92%, which is independent of and partly overlapped with the cases detected by ProGRP or NSE. CADM1v8/9 can detect 25% of patients with limited disease and 77% of patients with extensive disease of SCLC. Furthermore, the amount of CADM1v8/9 fragments well correlates with the disease activity of SCLC before and after chemotherapy. These findings indicate that detection of CADM1v8/9 in serum from patients is a novel and promising approach to detect and follow up SCLC patients. Since CADM1 is highly expressed in cell membrane of SCLC, CADM1 would also provide a promising target for the treatment of SCLC. Citation Format: Takeshi Ito, Toko Funaki, Goh Tanaka, Takahide Nagase, Yoshinori Murakami. CADM1 is a novel serum marker for small cell lung cancer [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 1129.
Abstract LB-272: T-cell clonal dynamics determined by high resolution TCR-β sequencing in recipients of allogeneic hematopoietic cell transplantation
Authors: Rachel M. Gittelman, Mark Leick, Zachariah DeFilipp, Jerome Ritz, Erik Yusko, Catherine Sanders, Harlan Robins
Journal: Cancer Research (2020)

Abstract Delayed reconstitution of the immune system after allogeneic hematopoietic cell transplantation (HCT) is a long-recognized complication. Specifically, loss of T-cell diversity has been implicated in infectious complications, graft-versus-host disease (GVHD), and disease relapse. We performed serial high-resolution next generation sequencing using the immunoSEQ® Assay (Adaptive Biotechnologies, Seattle, WA) to characterize the TCRβ locus in 99 HCT recipients in the first 3 months after transplant. Transplant donor type included unrelated (n=57) and related (n=42) donors. Conditioning regimen intensity included reduced intensity (n=55) and myeloablative (n=44). We measured T-cell fraction, clonality, and richness in the donor and at days +15, +30, +50 and +100 post-transplant in the recipient, and correlated metrics to clinical variables. In agreement with prior studies, we found that although absolute T-cell numbers recover relatively quickly after transplant, repertoire diversity remains diminished. Restricted diversity was associated with conditioning intensity, use of ATG, and donor type. Increased T-cell clonal expansion at Day +30 compared to the donor sample was associated with the incidence of acute GVHD (HR=1.11, p=5x10-5). Even after exclusion of the twelve patients who had experienced acute GVHD by day +30, the association between acute GVHD and clonal expansion persisted (HR=1.098, p=0.041), indicating that clonal expansion preceded the development of acute GVHD. Our results indicate the importance of early post-transplant sampling and highlight T-cell clonal expansion as a potential novel biomarker for GVHD which warrants further study. Citation Format: Rachel M. Gittelman, Mark Leick, Zachariah DeFilipp, Jerome Ritz, Erik Yusko, Catherine Sanders, Harlan Robins. T-cell clonal dynamics determined by high resolution TCR-β sequencing in recipients of allogeneic hematopoietic cell transplantation [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-272.
Abstract 3681: Selective vulnerability of GBM PDX to a panel of EGFR tyrosine kinase inhibitors
Authors: Nanyun Tang, George Reid, C Ryan Miller, Michael E. Berens
Journal: Cancer Research (2020)

Abstract Glioblastoma (GBM), a particularly aggressive form of primary brain tumor, has poor survival due to a lack of effective treatments and high recurrence. Epidermal growth factor receptor (EGFR) (mapped to 7p 11.2), is frequently amplified and mutated (&amp;gt;50%) in GBM, and is suggested as a potential therapeutic target. To correlate chemo-vulnerability with genomic aberrations and further determine biomarkers for targeted therapies, a panel of seven EGFR tyrosine kinase inhibitors were tested in a selected nine human GBM patient-derived xenograft (PDX) panel; these preclinical models harbor different mutation combinations of CDKN2A deletion (C), PTEN deletion (P), wild-type EGFR (E) and/or EGFRvIII (Ev3) overexpression. A single agent drug dose response assay (DDR) was performed on GBM PDX neurospheres using drug concentrations ranging from 100uM to 0.5nM with a 12-point serial 3-fold dilution scheme. The cytotoxic efficacy of EGFR inhibition was dependent on both the PDX line and the EFGR inhibitor applied. GBM59 and GBM76 – both triple CEv3P mutants – were the most responsive to EGFR inhibition relative to the other GBM models tested. For GBM59, the IC50 values of afatinib, canertinib and neratinib, were sub-micromolar, and low micromolar (&amp;lt;3uM) for erlotinib, gefitinib and lapatinib. GBM76 had IC50 values of 1-8uM with all seven EGFR inhibitors including AZD3759. However, GBM155 and GBM126 with CEv3 but wildtype PTEN only responded to afatinib, canertinib and neratinib at low micromolar IC50 values (&amp;lt;3uM) but not to erlotinib, gefitinib and lapatinib. A deletion in PTEN may sensitize GBM cells with CEv3 mutations to erlotinib, gefitinib and lapatinib in vitro. The other group of GBM PDX lines (C only) represented by GBM122, GBM150 and GBM182 responded well to afatinib, canertinib and neratinib with IC50 values of 2- 9uM. GBM156 with CE had a similar profile to the group of C only or CEv3. GBM56 with CP showed the most resistance with mild responses to afatinib, canertinib and neratinib, as observed in its high micromolar IC50 values (6-9uM). Overall, neratinib is the most effective compound among the tested EGFR inhibitors based on IC50 values. Canertinib, the triple tyrosine kinase inhibitor against EGFR/HER2/ErbB-4, is the second most effective agent. Afatinib has similar drug efficacy to canertinib. All three compounds moderately inhibit all GBM PDX lines. The drug response mechanism and its correlation with the mutation status of CDKN2A, EGFR, and PTEN will be further investigated cross a broad array of GBM PDX models. Supported by NIH NCI R01 CA204136 Citation Format: Nanyun Tang, George Reid, C Ryan Miller, Michael E. Berens. Selective vulnerability of GBM PDX to a panel of EGFR tyrosine kinase inhibitors [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 3681.
Bistratal Au@Bi2S3 nanobones for excellent NIR-triggered/multimodal imaging-guided synergistic therapy for liver cancer
Authors: Ruizhuo Ouyang, Penghui Cao, Pengpeng Jia, Hui Wang, Tianyu Zong, Chenyu Dai, Jie Yuan, Yuhao Li, Dong Sun, Ning Guo, Yuqing Miao, Shuang Zhou
Journal: Bioactive Materials (2020)

To fabricate a highly biocompatible nanoplatform enabling synergistic therapy and real-time imaging, novel Au@Bi
Abstract 4818: miR-34-AGO-TNRC6A complex transcriptionally up-regulates <i>BLU</i> tumor suppressor via binding of a novel promoter-associated lncRNA in lung cancer
Authors: Shinichiro Ohno, Keiki Oikawa, Yuichirou Harada, Masahiko Kuroda
Journal: Cancer Research (2020)

Abstract We focused on genes whose expression is induced by miR-34a, a potent tumor suppressor microRNA (miRNA) in lung cancer and many other types of cancer, and sought to elucidate the mechanisms underlying the tumor suppressor function of miR-34a. We found that the miR-34a inhibited the proliferation of lung cancer cells by inducing expression of the BLU(also known as ZMYND10) tumor suppressor. The next-generation sequencing analysis of RNA extracted from lung cancer tissues identified a novel divergent lncRNA expressed from promoter of BLUthat include two predicted miR-34 binding sites. Interestingly, miR-34a failed to induce the BLUtranscription in the mutants lacking these miR-34 binding sites in the lncRNA. In addition, the miR-34-AGO-TNRC6A complex induced transcription of BLUby binding to the lncRNA. This non-canonical miRNA pathway, which induces gene expression via cooperation between an miRNA and promoter-associated lncRNA, is a previously unknown tumor suppression mechanism of miR-34a. Citation Format: Shinichiro Ohno, Keiki Oikawa, Yuichirou Harada, Masahiko Kuroda. miR-34-AGO-TNRC6A complex transcriptionally up-regulates BLU tumor suppressor via binding of a novel promoter-associated lncRNA in lung cancer [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 4818.
Abstract 1587: Stress keratin 17 overexpression downregulates CD8+ T cell infiltration in papillomavirus-associated disease
Authors: Wei Wang, Ellery Gronski, Paul Lambert
Journal: Cancer Research (2020)

Abstract High-risk human papillomaviruses (HPVs) cause 5% of human cancers. Despite the availability of HPV vaccines, there remains a strong urgency to find ways to treat persistent HPV infections, as current HPV vaccines are not therapeutic for individuals already infected. It has not well understood how papillomaviruses evade host immune surveillance to establish long-term infections, which can lead to neoplastic disease including cancer. Using a mouse papillomavirus (MmuPV1) infection model in immunocompetent FVB/N mice, we found that stress keratins are upregulated in mouse papillomavirus-induced papillomas. In mice deficient for stress keratin K17 (K17KO), we observed early regression of papillomas dependent on T-cells. Expression of cellular genes involved in immune response were significantly upregulated in the papillomas arising on the K17KO mice correlating with increased numbers of infiltrating CD8+T cells and upregulation of IFNγ-related genes, including CXCL9 and CXCL10, prior to complete regression. This T cell-dependent regression also required ligand accessibility to CXCR3, a receptor for CXCL9 and CXCL10. By analyzing public available TCGA data, we found an inverse correlation between K17 mRNA expression and CD8A, GZMB and CXCL9 mRNA expression in a cohort of head and neck cancer patients. We validated these observations by antibody immunofluorescence staining of a tissue microarray (TMA) composed of 380 tumor tissues from head and neck cancer patients (HPV+ n=265, HPV- n=49, HPV unknown n=66). We stained TMA with CD8 and K17. Out of 380 cancer specimens, there are n=46 that had either high percentage of CD8+ cells in tumor (Z score&amp;gt;=1.64, n=14) or a high mean fluorescence intensity of K17 (Z score&amp;gt;=1.64, n=33). The heatmap of these 46 samples showed that the high K17 stained tissue and high CD8+ T cell infiltrated tissues are mutually exclusive, consistent with our prior analysis from TCGA mRNA data from head and neck cancer patients. In the process of exploring the mechanism of K17-mediated immunosuppression, we found that mouse papillomas arising from K17 knockout mice lacked nuclear staining for YAP1 whereas a significant amount of nuclear staining for YAP1 was observed in WT FVB papillomas, suggesting K17 may regulate Yap1 activation to mediate downstream immunosuppressive effect. Citation Format: Wei Wang, Ellery Gronski, Paul Lambert. Stress keratin 17 overexpression downregulates CD8+ T cell infiltration in papillomavirus-associated 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 1587.
Abstract 2934: The role of Globo H in cancer cell survival
Authors: Tzer-Min Kuo, Yi-Chien Tsai, Chin-Chan Lee, Jiann-Shiun Lai
Journal: Cancer Research (2020)

Abstract BACKGROUND: Globo H (GH), a glycosphingolipid (GSL) carbohydrate antigen, is found on a variety of epithelial tumors and is a promising target for cancer immunotherapy given the marked difference in expression of GH between cancer cells and normal tissues. Globo series antigens (Globo H, SSEA-4) have been implicated in playing important roles in protecting tumor cells from apoptosis, suppression of immune cell activity in the tumor microenvironment, and promoting endothelial cell angiogenesis through shedding the glycosphingolipids to immune cells and endothelial cells, respectively. Recently, apoptosis regulation by protein interaction with Globo-series GSLs in breast cancer cells was reported. This study aims to investigate the GH and anti-GH antibody effects on cancer cell survival. METHODS: In vivo: After allografting murine B16F10 melanoma subcutaneously, C57BL/6 mice, n=5, were treated with Globo-H ceramide (GHCer) by peritumoral injection and monitored for 26 days. In vitro: GH expression on the surface of tumor cells and colony formative activity in GHCer-treated human cells were measured. Cytokine antibody array and Microwestern protein array analyses were performed in the GHCer-treated A549 cells. Cell viability in high GH–expressing lung cancer cells treated with erlotinib was assessed. Erlotinib resistance and cytokine levels in high GH–expressing tumor cells treated with anti-GH antibody were measured. RESULTS: In vivo: GHCer-treated mice showed accelerated B16F10-tumor growth rates (3.36-fold; P&amp;lt;0.01, n=5) with less tumor necrosis and higher proliferating cell nuclear antigen expression in the internal tumor tissues. In vitro: In GHCer-treated human lung cancer A549 and breast cancer MDA-MB-231 cells, higher colony formative activity and increased exogenous GH expression on the surface of tumor cells compared to the control group were observed, while cell proliferation was not enhanced. Up-regulated erlotinib-resistant cytokine IL-8 and FGF2 and K-RAS-related signaling were observed in A549 cells with exogenous high GH expression. Exogenously GHCer-added lung cancer cells displayed higher cell viability (37.8% increase) during erlotinib challenge, and an anti-GH antibody treatment decreased the GH effects of erlotinib resistance. CONCLUSION: GH promotes cancer cell viability in vitro and in vivo, indicating an important role in cancer cell survival during tumor progression. Anti-GH antibody treatment was shown to be able to abolish the GH effects on erlotinib resistance of lung cancer cells in vitro. Citation Format: Tzer-Min Kuo, Yi-Chien Tsai, Chin-Chan Lee, Jiann-Shiun Lai. The role of Globo H in cancer cell survival [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 2934.
Abstract 6310: <i>Ex vivo</i> phosphoflow cytometry to capture fast changes of phospho-proteins at single cell level
Authors: Qiyao Zhang, Jingjing Wang, Yun Ge, Yajie Xiong, Beibei Qin, Qingyang Gu, Qunsheng Ji
Journal: Cancer Research (2020)

Abstract BACKGROUND: Protein phosphorylation is an important cellular regulatory process and a key indicator of signaling activation or deactivation. However, the fast switch-on/off of the process makes difficult the timely and accurate detection of the phosphorylation status. It is even more challenging to monitor the protein phosphorylation during cancer immune response in vivo, whereas immune responses vary among different cell types and can sometimes only be detected in certain rare populations like Treg (T regulatory) and TCM (T central memory) cells. The ability of Phosphoflow cytometry to accurately and rapidly detect many phospho-protein targets simultaneously at single cell level provides significant advantages over conventional methods. Ex vivo phosphoflow cytometry is increasingly being used as a tool for the discovery of biomarkers used in monitoring of disease and therapy progress. RESULTS: We established an ex vivo phosphoflow system to evaluate fast changes of pStat5 at single cell level in mouse models. Method validation was carried out step by step to ensure the reproducibility of this assay. The method development included optimizing gating strategy for non-phosphorylated proteins, selecting the reagents and optimizing the procedures of Lyse/Fix, perm, setting up positive controls under in vitro and ex vivo conditions, and optimizing phosphorylated protein staining and detection. Our data showed that the test articles induced differential pStat5 expression in different cell types, and in a dose-dependent manner. SUMMARY: We have established reliable ex vivo phosphoflow method to detect the fast changes of phospho-proteins at single cell level in animal models. This powerful method will enable us to examine protein post-translational modification in complicated host systems. Citation Format: Qiyao Zhang, Jingjing Wang, Yun Ge, Yajie Xiong, Beibei Qin, Qingyang Gu, Qunsheng Ji. Ex vivo phosphoflow cytometry to capture fast changes of phospho-proteins at single cell level [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 6310.