tbuckley/cabot-search huggingface dataset:
Abstract PR17: Immunogenomic landscape of pediatric solid malignancies
Authors: Jun S. Wei, Andrew S. Brohl, Sivasish Sindiri, Young K. Song, Sushma Najaraj, Vineela Gangalapudi, Xinyu Wen, Marc Ladanyi, Javed Khan
Journal: Cancer Research (2020)

Abstract Malignancy remains the leading cause of disease-related death in children. To identify potential tumor-driving molecular targets and immunogenomic profiles in pediatric cancers, we performed RNA-seq analysis on a cohort of 788 pediatric solid malignant tumors across 14 different diagnoses in conjunction with additional 147 normal tissues for comparison. Sequencing data were analyzed for expressed mutations, fusion events, and expressional patterns, providing therapeutic targets and rich cancer biology for these childhood cancers. Furthermore, we describe immunogenomic features of these solid tumors including immune cell infiltrate, neoantigen expression, expression of immunomodulatory molecules, and T-cell receptor repertoire. Across the cohort, we observed a striking correlation between the expressed neoantigen burden in tumors and enrichment of the effector immune signatures. Histology-specific immunogenomic patterns were also apparent. Several of the pediatric cancers such as alveolar soft part sarcoma and osteosarcoma exhibit rich immune cell infiltration and evidence for activated T-cell activities, whereas others such as Wilms’ tumors and synovial sarcoma generally have a very low T-cell infiltration. We demonstrate that RNA-seq is a powerful tool to identify clinically relevant and histology-specific recurrent mutations, novel oncogenic fusions, and translationally relevant immunogenomic patterns for pediatric cancers. This study also represents one of the largest of its type to date and provides a framework for future translational efforts in pediatric cancer. This abstract is also being presented as Poster A69. Citation Format: Jun S. Wei, Andrew S. Brohl, Sivasish Sindiri, Young K. Song, Sushma Najaraj, Vineela Gangalapudi, Xinyu Wen, Marc Ladanyi, Javed Khan. Immunogenomic landscape of pediatric solid malignancies [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR17.
Abstract 3499: Dianhydrogalactitol (VAL-083) in combination with AZD1775 increases survival in diffuse intrinsic pontine glioma (DIPG), in vivo
Authors: Anne Steino, Xiaodong Yang, Cassie Kline, Jeffrey Bacha, Dennis M. Brown, Sabine Mueller
Journal: Cancer Research (2019)

Abstract OBJECTION: VAL-083 is a structurally unique bi-functional DNA targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. VAL-083 induces interstrand crosslinks leading to DNA double-strand breaks and S/G2 cell cycle arrest. By inhibiting the G2 checkpoint regulator kinase Wee1, AZD1775 allows a cancer cell with DNA damage to progress past the G2 checkpoint and into premature mitosis leading to cancer cell death. Herein we assess the activity of VAL-083 as single agent as well as in combination with Wee1 Kinase inhibitor AZD1775 in patient derived model systems of DIPG. METHODS: DIPG derived cell lines SF8628 and NEM157 (H3.3K27) as well as SF10693 (H3.1K27M) and pediatric glioblastoma cell lines SF188 (H3.3K27 wildtype) were treated with increasing concentrations of single agent VAL-083 as well as in combination with AZD1775. To determine potential synergistic activity, we applied the Chou-Talalay method, which allows the quantitative determination of drug interactions by calculating a combination index (CI). In vivo activity of VAL-083 (3 mg/kg) as single agent as well as in combination with AZD1775 (60 mg/kg) was assessed in an orthotopic engraftment model of pediatric DIPG (SF8628). RESULTS: The IC50 of VAL-083 as single agent ranged from 1µM to 10µM. VAL-083 exhibited synergistic activity in combination with AZD1775 in cell lines SF8628 and SF188 and additive effect in NEM157 with CI values ranging from 0.04 to 0.95, with CI &amp;lt; 1 indicating synergy. In vivo, treatment with VAL-083 as single agent and in combination with AZD1775 conferred significant survival benefit to mice with engrafted DIPG tumors compared to control as well as single agent treatment with AZD1775. The median survival for mice treated with VAL-083 alone was 54.5 days (p=0.0004, VAL-083 vs. control) and for the VAL-083/AZD1775 combination it was 62 days (p&amp;lt;0.0001, VAL-083/AZD1775 vs. control), compared to 44 days for control and 47 days for mice treated with AZD1775 alone (p=0.0839, AZD1775 vs. control). CONCLUSION: Our present study highlights that the combination of VAL-083 and AZD1775 might be a promising new therapeutic strategy for children with DIPG. Ongoing studies continue to assess the in vivo activity in other DIPG models as well explore the underlying mechanism of action of the combination strategy. Citation Format: Anne Steino, Xiaodong Yang, Cassie Kline, Jeffrey Bacha, Dennis M. Brown, Sabine Mueller. Dianhydrogalactitol (VAL-083) in combination with AZD1775 increases survival in diffuse intrinsic pontine glioma (DIPG), in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3499.
Abstract 2330: Preclinical evaluation of TC-110: CD19-specific T cell receptor (TCR) fusion construct (TRuC™) T cell for the treatment of hematologic malignancies
Authors: Holly Horton, Jian Ding, Seema Shah, Jessica Gierut, Niko Thorausch, Anna Morath, Wolfgang Shamel, Marcela Maus, Patrick Baeuerle, Robert Hofmeister, Daniel R. Getts
Journal: Cancer Research (2019)

Abstract T cells expressing chimeric antigen receptors (CARs) have demonstrated clinical benefit in certain hematological malignancies albeit with disease relapse as well as side effect such as cytokine release syndrome. To overcome potential hurdles of CAR-T cells and other T cell receptor modalities, we have designed a novel T cell engineering platform. Specifically, we have generated T Cell Receptor Fusion Constructs (TRuC™) that fuse a binder domain to subunits of the T cell receptor. These constructs when introduced using lentiviral technology, integrate into endogenous TCR, reprograming T cells to target tumor antigen in a non-major histocompatibility complex (MHC) restricted fashion and harnessing the full spectrum of TCR signaling. Here, we present the results of the preclinical evaluation of TC-110, a CD19-specific ϵ-TRuC™ variant. In vitro, TC-110 T cells are equally potent as CAR T cells in eliminating tumor cells, while producing less inflammatory cytokines. In preclinical mouse models of ALL and Burkitt’s lymphoma, TC-110 T cells demonstrate better efficacy than 2nd generation CAR-T cells bearing CD28 or 41BB co-stimulatory domains. Of note, the efficacy of TC-110 T cells, both in vitro and in vivo, is not dependent on co-stimulatory signal. Overall, we demonstrate the efficacy of TC-110 T cells both in vitro and in preclinical mouse models, indicating the clinical potential of TRuC™ platform for treating hematologic malignancy. Citation Format: Holly Horton, Jian Ding, Seema Shah, Jessica Gierut, Niko Thorausch, Anna Morath, Wolfgang Shamel, Marcela Maus, Patrick Baeuerle, Robert Hofmeister, Daniel R. Getts. Preclinical evaluation of TC-110: CD19-specific T cell receptor (TCR) fusion construct (TRuC™) T cell for the treatment of hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2330.
Abstract 1570: Genome-wide association study identifies variants at 3p26.1 linked to survival in ovarian cancer patients among Chinese women
Authors: Hongji Dai, Xinlei Chu, Wei Wang, Huijun Yang, Qiong Wang, Mulin Jun Li, Qingyi Wei, Kexin Chen
Journal: Cancer Research (2019)

Abstract Survival rates for ovarian cancer varies considerably among patients, and some of this variation could be explained by germline genetic variation. In order to identify genetic markers associated with ovarian cancer-specific survival, we performed a genome-wide association study (GWAS) of ovarian cancer survival among Chinese women. In a meta-analysis of 2,130 ovarian cancer patients from the southeast and north part of China, we found a significant association between SNPs at the 3p26.1 and overall survival (lead SNP rs3804994; combined P=9.8×10-9). Patients with the minor allele are at increased risk for mortality (HR: 1.55; 95% CI: 1.33-1.80) relative to patients with the major allele. Statistical fine-mapping and functional prioritization recommend a potential casual SNP rs9311399 that locates in the active chromatin region of ovarian tissue. Using EMSA, luciferase assay and ATAC-seq, we demonstrated that risk allele of rs9311399 could alter the regulatory activity of DNA sequence. Our findings suggest that genetic variants at the 3p26.1 may be promising prognostic biomarkers for ovarian cancer patients. Citation Format: Hongji Dai, Xinlei Chu, Wei Wang, Huijun Yang, Qiong Wang, Mulin Jun Li, Qingyi Wei, Kexin Chen. Genome-wide association study identifies variants at 3p26.1 linked to survival in ovarian cancer patients among Chinese women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1570.
Abstract 2001: Inhibiting voltage-gated sodium channel activity in medullary thyroid cancer using small molecule compounds
Authors: Paras Ahuja, Rachael Guenter, Jaden Cowan, Yazen Shihab, Jason Whitt, Herbert Chen, Sadanandan Velu, Renata Jaskula-Sztul
Journal: Cancer Research (2019)

Abstract Medullary thyroid cancer (MTC) is a type of neuroendocrine cancer (NE) with increasing incidence worldwide. Compared with well-differentiated thyroid cancers, distant metastases are more commonly observed in MTC patients, ranging from 7-23%. The inability to treat metastatic MTC contributes to a decreased patient survival rate. Currently, at least nine mammalian voltage-gated sodium channels (VGSCs) named Nav1.1-Nav1.9 have been identified as potential safe drug targets for treating metastasis in various cancers. Herein, we investigate the effects of targeting VGSCs in MTC using small molecule inhibitors. Two MTC cell lines, TT and MZ, were treated with four compounds and the changes in mRNA and protein expression of VGSC isoform Nav1.7 were assessed through RT-PCR and western blotting. Treatment by one of the compounds exhibited a 28-fold decrease in mRNA expression of VGSC isoform 1.7. Furthermore, a cell proliferation assay, proliferation assay (MTT) a MTT, assay to study cell proliferation after treatment showed decreasing cell viability resulted from the treatment. and Additionally, morphological changes characteristic of apoptosis in fluorescently labeled MTC cell lines after 48 hours of treatment with VGSC inhibitory compounds were observed. A Boyden chamber assay was also performed on MTC cell lines to examine changes in migration and invasion after administering the potential inhibitory compounds. This study has generated preliminary evidence that voltage-gated sodium channels (VGSCs) may indeed be potential targets for treating metastatic MTC. The results may be translated to future studies focused on controlling metastasis through specified drug treatment in MTC, leading to the limitation of cancer progression by means of targeting VGSCs. Citation Format: Paras Ahuja, Rachael Guenter, Jaden Cowan, Yazen Shihab, Jason Whitt, Herbert Chen, Sadanandan Velu, Renata Jaskula-Sztul. Inhibiting voltage-gated sodium channel activity in medullary thyroid cancer using small molecule compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2001.
Both CD4+CD25+Foxp3+ Regulatory T Cells and CD3-CD56+ NK Cells Affect the Response of Newly Diagnosed Chronic Myeloid Leukemia Patients to Treatment with a Tyrosine Kinase Inhibitor
Authors: Fumihito Tajima, Koji Adachi, Takaya Nishio, Hiroshi Mochida, Toshio Kawatani, Junji Suzumiya
Journal: Blood (2017)
Abstract 4575: IL17 signaling modulates tumor microenvironment in pancreatic cancer
Authors: Yu Zhang, Erick Marcelo Riquelme Sanchez, Michelle Annabel Zoltan, Florencia McAllister
Journal: Cancer Research (2019)

Abstract Pancreatic cancer is the one of the most devastating malignancies and the 5-years survival remains below 10% for decades. The pancreatic tumor microenvironment is very complex with tumor cells surrounded by a dense fibro-inflammatory stroma with fibroblasts and immune-suppressive cells which are known to play a pivotal role in the whole process of tumorigenesis, and contributing to the lack of responses to most therapies. We have previously described that IL17, a cytokine secreted from immune cells recruited to the pancreas in response to Kras and inflammation, is involved in the initiation and development of pancreatic premalignant lesions, in part by promoting stemness on the oncogenic epithelium. In this study, we aim to dissect the role of IL17 on the stroma in established pancreatic adenocarcinoma. To this end, we blocked the IL17 signaling pathway with monoclonal antibodies and also used a parallel genetic approach which consisted in IL17RA deletion from the cancer cells using CRISPR-Cas9. RNA sequencing analysis, flow cytometry, immunohistochemistry, and opal-multiplex immunofluorescence were performed on tumors and cellular compartments. We uncovered that neutrophils recruitment was the main pathway altered by IL-17. Using flow cytometry, IHC and opal-multiplex we found that Gr1+ cells were significantly modulated by Il17 in the tumor microenvironment, as not only the numbers of these cells were altered but also their spatial distribution with respect to CD8+T cells, which may contribute to the generation and maintenance of the immunosuppressive microenvironment that characterizes pancreatic cancer. Moreover, we found that reactive oxygen species (ROS) level was also evidently downregulated by IL17 signaling blockage.Therefore, we conclude that IL17 plays an important role in remodeling the pancreatic cancer immunosuppressive tumor microenvironment. Citation Format: Yu Zhang, Erick Marcelo Riquelme Sanchez, Michelle Annabel Zoltan, Florencia McAllister. IL17 signaling modulates tumor microenvironment in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4575.
Abstract 3092: Activation of evolutionarily young transposable elements and the host innate immune system are linked to clinical response to 5-azacitidine
Authors: Hitoshi Ohtani, Andreas D. Ørskov, Alexandra S. Helbo, Linn Gillberg, Minmin Liu, Wanding Zhou, Johanna Ungerstedt, Eva Hellstrom-Lindberg, Weili Sun, Gangning Liang, Peter A. Jones, Kirsten Grønbæk
Journal: Cancer Research (2019)

Abstract The DNA methyltransferase inhibitors 5-azacitidine (AZA) and 5-aza-2-deoxycytidine (DAC) have been approved for the treatment of higher-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). A more comprehensive understanding of the molecular changes in patients treated with AZA is needed to help explain why only about 50% of these patients have clinical responses. We examined gene expression profiles in a total of 150 RNA samples taken before, during and after treatment with AZA, in three cohorts of patients with hematological cancers (40 patients total; 15 non-responders, 25 responders). We show that activation of the innate immune system is linked to clinical response to AZA treatment. We also measured the induced expression of transposable elements (TEs) to determine whether this was a potential trigger for the immune response. Both responders and non-responders showed robust upregulation of TEs however responders showed the statistically significant upregulation of specific classes of evolutionarily young transposable elements (TEs). These include short and long nuclear elements (SINEs and LINEs) and endogenous retroviruses (ERVs). Moreover, the upregulation of type I interferon signaling pathway genes in responders was significantly higher than non-responders, but not cancer testis antigens (CTAs) or tumor suppressor genes with the exception of CDKN2A and CDKN2B. Therefore, we suggest that induction of specific subsets of silenced evolutionarily young TEs may be a key to the success of epigenetic therapy in hematological cancer patients. Citation Format: Hitoshi Ohtani, Andreas D. Ørskov, Alexandra S. Helbo, Linn Gillberg, Minmin Liu, Wanding Zhou, Johanna Ungerstedt, Eva Hellstrom-Lindberg, Weili Sun, Gangning Liang, Peter A. Jones, Kirsten Grønbæk. Activation of evolutionarily young transposable elements and the host innate immune system are linked to clinical response to 5-azacitidine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3092.
BMA is set to sue government over “discriminating” pension scheme
Authors: Elisabeth Mahase
Journal: BMJ (2019)

More than a dozen doctors are taking legal action against the government, claiming that they were discriminated against when they were forced to transfer to the 2015 NHS pension scheme while older doctors were allowed to stay in the previous scheme, which was deemed to be better.

The move, led by the BMA’s legal team, follows a threat of legal action earlier this year. In March the BMA called on the government to agree that the 2015 …
Abstract 437: Increasing Cardiac Fatty Acid Oxidation Protects Against High Fat Diet Induced Cardiomyopathy in Mice
Authors: Dan Shao, Nathan Roe, Loreta D Tomasi, Alyssa N Braun, Ana Mattos, Stephen Kolwicz, Rong Tian
Journal: Circulation Research (2016)

In the obese and diabetic heart, an imbalance between fatty acid uptake and fatty acid oxidation (FAO) promotes the development of cardiac lipotoxicity. We previously showed that cardiac specific deletion of acetyl CoA carboxylase 2 (ACC2) was effective in increasing myocardial FAO while maintaining normal cardiac function and energetics. In this study, we tested the hypothesis that ACC2 deletion in an adult heart would prevent the cardiac lipotoxic phenotype in a mouse model of diet-induced obesity. ACC2 flox/flox (CON) and ACC2 flox/flox-MerCreMer+ (iKO) after tamoxifen injection were subjected to a high fat diet (HFD) for 24 weeks. HFD induced similar body weight gain and glucose intolerance in CON and iKO. In isolated Langendorff-perfused heart experiments, HFD feeding increased FAO 1.6-fold in CON mice which was increased to 2.5-fold in iKO mice compared with CON on chow diet. Fractional shortening was significantly decreased in CON-HFD (32.8±2.8% vs. 39.2±3.2%, p&lt; 0.05, n=5-6), but preserved in iKO-HFD mice (42.8±2.3%, vs. 38.5±1.4%, n=6), compared to respective chow fed controls. Diastolic function, assessed by E’/A’ ratio using tissue Doppler imaging, was significantly decreased in CON-HFD mice (1.11±0.08 vs. 0.91±0.09, p&lt;0.05 n=5-6), while no difference was observed in iKO-HFD compared to iKO-chow (1.10±0.03 vs. 1.09±0.04, n=6). Heart weight /Tibia length ratio was significantly higher in CON than iKO mice after HFD feeding (7.19±0.22 vs. 6.47±0.28, p&lt;0.05, n=6). Furthermore, HFD induced mitochondria super complex II, III and V instability, which was attenuated in iKO-HFD mice. These data indicate that elevated myocardial FAO per se does not cause the development of cardiac dysfunction in obese animals. In fact, enhancing FAO via ACC2 deletion prevents HFD induced cardiac dysfunction and attenuates pathological hypertrophy. These effects may be mediated, in part, by maintenance of mitochondrial integrity. Taken together, our findings suggest that promoting cardiac FAO is an effective strategy to resist the development of cardiac lipotoxicity during diet-induced obesity.
SGNBCMA-001: A phase 1 study of SEA-BCMA, a non-fucosylated monoclonal antibody, in subjects with relapsed or refractory multiple myeloma.
Authors: Al-Ola A. Abdallah, James Edward Hoffman, Mark A. Schroeder, Celine Jacquemont, Hong Li, Yinghui Wang, Heather Van Epps, Mary S. Campbell
Journal: Journal of Clinical Oncology (2019)

TPS8054 Background: Despite recent advances in treatment, multiple myeloma (MM) remains incurable in most patients. The standard of care for MM includes combinations of agents with different mechansims of action, e.g. proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies, alkylating agents, and corticosteroids. Sequential lines of treatment typically yield shorter durations of disease control with each subsequent relapse. Frail patients face a particularly high unmet need, given the toxicity profiles of many agents. SEA-BCMA is a humanized non-fucosylated IgG1 monoclonal antibody targeting BCMA, a plasma cell-specific protein that is expressed on MM cells of most patients. Based on preclinical data, SEA-BCMA displays enhanced antibody dependent cellular cytotoxicity through increased FcγRIII binding, antibody dependent cellular phagocytosis, and blocking of BCMA-mediated pro-survival and proliferative signaling. SEA-BCMA is active at 0.03 mg/kg in xenograft models and does not cause adverse effects in preclinical models, supporting clinical investigation for MM. Methods: This is a phase 1, open-label, multicenter, dose-escalation study to evaluate the safety, tolerability, and antitumor activity of SEA-BCMA in adults with relapsed/refractory MM. Enrollment began in November 2018 for adults aged ≥18 years with histologically confirmed MM, Eastern Cooperative Oncology Group performance status of ≤1, and no other therapeutic options available. Prior therapies must include a PI, an IMiD, and an anti-CD38 antibody. Prior receipt of BCMA targeted agents is prohibited. BCMA expression is not required for study entry, but will be tested retrospectively. Dose-escalation is being conducted in ~25 subjects using the modified toxicity probability interval method. During dose-expansion, ~40 subjects will be treated at the maximum tolerated or optimal dose. Responses are assessed per the 2016 International Myeloma Working Group criteria. Biomarker and pharmacokinetic evaluations will be performed on peripheral blood and bone marrow. Clinical trial information: NCT03582033.
Survivorship Bias in Analyses of Immune Checkpoint Inhibitor Trials
Authors: Sarah C. Conner, Ludovic Trinquart
Journal: JAMA Oncology (2019)

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