tbuckley/cabot-search huggingface dataset:
Abstract 33: Epidemiology and clinicopathology of T-cell intravascular lymphoma (TIVL): Making the case for extra-nodal NK-T cell lymphoma-angiotropic type as a provisional entity
Authors: Philip A. Haddad, Kevin Gallagher, Dalia Hammoud
Journal: Cancer Research (2020)

Abstract TIVL is a rare and often aggressive NK/T-cell lymphoma characterized by the presence of neoplastic lymphocytes that are restricted to the lumen of small vessels. It comprises 8-10% of all IVL. By the time a diagnosis is made, TIVL tends to be widely disseminated across multiple extra-nodal sites with frequent catastrophic consequences. In order to study the demographic characteristics, presentation and progression patterns, survival, and prognostic factors, we constructed a database that pooled cases between 1986 and 2019. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinical factors on survival. A total of 81 patients with confirmed TIVL were identified. The median age was 53 (17-87) years with a peak incidence between ages 50 and 60. There was a slight male predominance with a male to female ratio of 1.5. Comprising 43% of reported cases, Asians were the most afflicted ethnic group. Skin (71%) was the most common site involved with TIVL followed by CNS (23%), and pulmonary and bone marrow involvement (8% each). The median overall survival of the whole group was 7 months. Sex and age did not seem to affect survival rates. When compared to supportive care, chemotherapy significantly improved survival (HR:0.15, p&amp;lt;0.0001). Skin only involvement had the highest survival rates whereas CNS and pulmonary involvement had the worst. When skin only involvement was associated with constitutional symptoms survival rates significantly declined. In a multivariate analysis, skin only involvement (HR:0.43, p=0.009) and not receiving treatment (HR:3.45, p=0.001) continued to have a significant association with survival. CD56+, CD30-, and TCR clonality each seems to adversely impact survival. However, they were of borderline non-statistical significance. Only the detection of EBER in the sample was found to significantly impact survival in a negative manner (p=0.016). Our results indicate that TIVL is an NK/T cell entity with distinct angiotropic pathology and aggressive clinical behavior and often poor outcomes. TIVL's B-cell counterpart is already recognized by the WHO lymphoma classification as a separate B-cell entity. It is our hope that these results serve as the basis for establishing Extra-Nodal NK/T Cell Lymphoma-Angiotropic Type as a provisional entity in order to further study and characterize this rare disease. Citation Format: Philip A. Haddad, Kevin Gallagher, Dalia Hammoud. Epidemiology and clinicopathology of T-cell intravascular lymphoma (TIVL): Making the case for extra-nodal NK-T cell lymphoma-angiotropic type as a provisional entity [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 33.
Abstract 707: Combinatorial assessment of ctDNA release and mutational burden predicts clinical outcome from anti-PD-(L)1 therapies in non-small-cell lung cancer
Authors: Wenfeng Fang, Yuxiang Ma, Jiani C. Yin, Huaqiang Zhou, Fufeng Wang, Hua Bao, Ao Wang, Xue Wu, Shaodong Hong, Yunpeng Yang, Yan Huang, Hongyun Zhao, Yang W. Shao, Li Zhang
Journal: Cancer Research (2020)

Abstract Background: Blood-based detection of circulating tumor DNA (ctDNA) is a non-invasive and clinical accessible source of biomarkers that enables selection of non-small-cell lung cancer (NSCLC) patients for treatment with anti-PD-(L)1 therapies. However, new approaches are necessary to improve enrichment of responders. Patients and Methods: Pretreatment plasma ctDNA from 97 advanced-stage NSCLC patients who underwent anti-PD-(L)1 therapy from December 2015 to August 2017, with matched tissue samples from 66 patients, were profiled using a targeted next-generation sequencing (NGS) panel (Geneseeq) encompassing 422 cancer-relevant genes. External validation was performed using two large randomized trials, POPLAR and OAK. Results: In the 72 patients with adequate ctDNA release (maximum somatic allele frequency, MSAF ≥2%), high blood tumor mutational burden (bTMB) was associated with significantly prolonged median PFS (110 vs 60 days, HR=0.54 [95%CI, 0.31-0.92]; log-rank p = 0.02) and a trend towards improved DCB (34.8% vs 22.5%, p=0.39). While a high concordance was observed between bTMB and tTMB (Spearman's ρ= 0.71), the greatest progression-free survival (PFS) improvement was achieved with concomitantly high bTMB and tTMB (mPFS, 156 vs 59 days, HR=0.47 [95%CI, 0.24-0.91], log-rank p=0.02). Remarkably, the subset of patients with low ctDNA release (MSAF&amp;lt;2%), and consequently non-evaluable bTMB, derived similar PFS benefit as those with high bTMB. The additive predictive value of MSAF and bTMB was externally validated by results from the two large randomized trials. Conclusions: Our findings validated panel-assessed bTMB as a promising biomarker that demonstrated added value over tissue testing alone for benefit with anti-PD-(L)-1 therapies. Our findings also provided the first clinical evidence suggesting that matched tissue and blood testing might be necessary to refine the predictive value of TMB. Moreover, we identified low ctDNA MSAF as an important and robust predictor of improved immunotherapy outcome. Citation Format: Wenfeng Fang, Yuxiang Ma, Jiani C. Yin, Huaqiang Zhou, Fufeng Wang, Hua Bao, Ao Wang, Xue Wu, Shaodong Hong, Yunpeng Yang, Yan Huang, Hongyun Zhao, Yang W. Shao, Li Zhang. Combinatorial assessment of ctDNA release and mutational burden predicts clinical outcome from anti-PD-(L)1 therapies in non-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 707.
Abstract 5726: A-to-I RNA deaminase deregulation in pre-leukemia stem cell evolution
Authors: Qingfei Jiang, Frida Holm, Jane Isquith, Adam Mark, Cayla Mason, Eduardo Reynoso, Isabella Morris, Wenxue Ma, Raymond Diep, Jessica Pham, Chanond Nasamran, Guorong Xu, Roman Sasik, Sara Brin Rosenthal, Amanda Birmingham, Leslie Crews, Gabriel Pineda, Thomas Whisenant, Kathleen Fisch, Catriona Jamieson
Journal: Cancer Research (2020)

Abstract While inflammation induced ADAR1 RNA deaminases protect the human genome from retroviral integration, deregulation promotes therapeutic resistance in many malignancies. However, the combinatorial role of these deaminases in pre-leukemia stem cell (pre-LSC) evolution to therapy resistant LSC had not been elucidated. Thus, we performed whole genome sequencing (WGS) analysis of 43 CD34+pre-leukemic myeloproliferative neoplasm (MPN) samples compared with matched saliva and non-MPN controls andwhole transcriptome sequencing (RNA-seq) analysis of 113 FACS-purified hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) from MPN, acute myeloid leukemia (AML) and healthy young and aged samples. During MPN progression, inflammation-driven ADAR1 isoform p150 upregulation corresponded with increased Adenosine-to-Inosine (A-to-I) transitions in both MPN stem and progenitor populations. We identified unique A-to-I editing events in coding regions that are associated with either normal stem progenitors or with MPN progenitors. In addition, STAT3 transcript hyper-editing leads to STAT3beta splice isoform expression. Moreover, lentiviral ADAR1p150 overexpression enhanced replating as well as beta-catenin activation, which was reversed by lentiviral shRNA ADAR1 knockdown. In summary, innate immune deaminase deregulation fuels pre-LSC evolution to LSC and may represent a vital LSC therapeutic vulnerability. Citation Format: Qingfei Jiang, Frida Holm, Jane Isquith, Adam Mark, Cayla Mason, Eduardo Reynoso, Isabella Morris, Wenxue Ma, Raymond Diep, Jessica Pham, Chanond Nasamran, Guorong Xu, Roman Sasik, Sara Brin Rosenthal, Amanda Birmingham, Leslie Crews, Gabriel Pineda, Thomas Whisenant, Kathleen Fisch, Catriona Jamieson. A-to-I RNA deaminase deregulation in pre-leukemia stem cell evolution [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 5726.
Abstract 2518: Function of microRNA-10a in cholangiocarcinoma
Authors: Matthieu Spriet, Cody Wehrkamp, Brandon Henslee, Ashley Mohr, Steve Kachman, Justin Mott
Journal: Cancer Research (2020)

Abstract Cholangiocarcinoma, a primary liver cancer of the bile ducts, effects 6,000 patients yearly and incidence has been growing consistently over the past 15 years. Current therapies for cholangiocarcinoma are not curative and patient survival is less than 1 year after diagnosis. Strides toward new treatment rest on better understanding tumor biology. The expression of microRNAs in cholangiocarcinoma cells was analyzed by RNAseq after knockdown of fibroblast growth factor receptor 4 (FGFR4) to identify potential microRNAs regulated by FGFR4. Caspase activity was used to evaluate miR-10a roles in anti-apoptotic signaling. Cell scratch assays were used to test cell migration and cell counting was used to determine proliferation. Quantitative real time PCR was used to measure miR-10a levels in cholangiocarcinoma cell lines Mz-ChA-1, HUCCT-1 and KMCH after FGFR4 knockdown with siRNA. Potential target proteins of miR-10a were evaluated by western blot. Preliminary data showed dozens of microRNAs (miRs) in cholangiocarcinoma cells were modulated by FGFR4 knockdown. Treatment with siRNA to FGFR4 caused increased sensitivity to TRAIL-induced apoptosis, and also reduced miR-10a expression in Mz-ChA-1, HuCCT-1, and KMCH cell lines. Importantly, apoptosis sensitization was reversed by restoring miR-10a expression in cells. miR-10a helped regulate both cell proliferation and cell migration in cholangiocarcinoma cells. When miR-10a was increased in cholangiocarcinoma cells, migration and proliferation increased. When miR-10a was decreased these effects also decreased. Protein targets of miR-10a included the MAP Kinase-related proteins MLK-1 &amp; TAK-1. Other protein targets such as PHLDA1 &amp; AKTIP were also identified. Notably, microRNA binding prediction programs did not include MLK-1 as a target, though our sequence analysis shows multiple stable binding sites. MLK-1 showed the most dramatic response to miR-10a. We investigated the role miR-10a plays for cholangiocarcinoma and the mechanism through which this pathway is regulated. Data supports miR-10a as a key player in cell survival, proliferation and migration. We have identified a set of proteins that are regulated by miR-10a in cholangiocarcinoma cells. Looking forward, identification of the function of these proteins will help elucidate how miR-10a functions in cholangiocarcinoma progression. Citation Format: Matthieu Spriet, Cody Wehrkamp, Brandon Henslee, Ashley Mohr, Steve Kachman, Justin Mott. Function of microRNA-10a in cholangiocarcinoma [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 2518.
Abstract 4841: Functional genome-wide screening identifies triple-negative breast cancer cell cycle-dependent vulnerability driven by genomic gain of death effector domain-containing protein
Authors: Yingjia Ni, Keon R. Schmidt, Barnes A. Werner, Jenna K. Koenig, Ian H. Guldner, Patricia M. Schnepp, Xuejuan Tan, Lan Jiang, Misha Host, Longhua Sun, Erin N. Howe, Junmin Wu, Laurie E. Littlepage, Harikrishna Nakshatri, Siyuan Zhang
Journal: Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC) persists as a clinical challenge, with targeted therapeutic options remaining limited for the subtype due to few targetable tumor-specific vulnerabilities. While basal-like TNBC tumors express epidermal growth factor receptor (EGFR), the target of multiple clinically efficacious therapies, TNBC showed little to no response to anti-EGFR therapy in clinical trials. Using a genome-wide synthetic lethal pooled barcoded shRNA screen, we identified Death Effector Domain-containing protein (DEDD), upregulated in over 60% of TNBC tumors, as a driver of mitogen-independent G1/S cell cycle transition in TNBC under EGFR inhibition. This cell cycle role of DEDD depends on cytoplasmic localization and is independent of nuclear DEDD, which maintains roles in apoptosis. Cytosolic DEDD promotes G1/S transition through direct interaction with Rb family proteins, encouraging their degradation. Further, DEDD interacts with heat shock 71kDa protein 8 (HSC70) to augment cyclin D1 expression and drive transition to S phase. These interactions of overexpressed cytosolic DEDD with the G1/S checkpoint mechanism present a vulnerability of TNBC to cell cycle inhibition. Frequent Rb-loss in TNBC has prevented clinical testing of CDK4/6 inhibitors in TNBC, however. Yet, we found TNBC with DEDD overexpression to be sensitive to a combination of CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo, independent of Rb status. This novel vulnerability presented by DEDD overexpression in TNBC suggests promising therapeutic potential for CDK4/6 inhibitor use in combinatorial regimens. Citation Format: Yingjia Ni, Keon R. Schmidt, Barnes A. Werner, Jenna K. Koenig, Ian H. Guldner, Patricia M. Schnepp, Xuejuan Tan, Lan Jiang, Misha Host, Longhua Sun, Erin N. Howe, Junmin Wu, Laurie E. Littlepage, Harikrishna Nakshatri, Siyuan Zhang. Functional genome-wide screening identifies triple-negative breast cancer cell cycle-dependent vulnerability driven by genomic gain of death effector domain-containing protein [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 4841.
Abstract 5042: Targeting the ERK5 and ERK1/2 pathways simultaneously induces mesenchymal to epithelial transition in TNBC
Authors: Akshita Bhatt, Thomas Wright, Van Barnes, Suravi Chakrabarty, Patrick Flaherty, Matthew Burow, Jane Cavanaugh
Journal: Cancer Research (2020)

Abstract Extracellular signal-regulated kinase (ERK) 5, a member of mitogen activated protein kinase (MAPK) family, is an emerging target in cancer therapeutics. Activation of ERK5 via overexpression induces EMT and hormone-independent growth of breast cancer. EMT leads to the loss of cell polarity, downregulation of E-cadherin, and upregulation of mesenchymal markers snail, zinc-finger E-box binding homeobox (ZEB1), and vimentin. EMT is also associated with drug resistance. Although ERK1/2 and ERK5 activation is known to mediate EMT, the effect of ERK1/2 and ERK5 inhibition on mesenchymal to epithelial transition (MET), the reverse of EMT, is poorly understood in cancer.Triple negative breast cancer (TNBC) cells have a mesenchymal phenotype and show poor sensitivity to chemotherapy agents. The loss of estrogen, progesterone hormone receptors and human epidermal growth factor receptors (HER2) contributes to the aggressive state of the disease and lack of targeted therapy. Activation of the intracellular signaling pathways such as the MAPK pathway mediates tumorigenesis in TNBCs. MEK1/2 inhibitors have been successful clinical drug candidates; however, there is emerging evidence that the activation of the MEK5-ERK5 pathway mediates resistance to the MEK1/2 inhibitors in several BRAF and KRAS-mutant cancers. The effect of MEK1/2 inhibition on MEK5-mediated EMT, cell survival, and migration in TNBC is less well understood. Therefore, we hypothesize that dual inhibition of the ERK1/2 and ERK5 pathways is a relevant strategy to target TNBCs.In the present study, the effect of dual ERK1/2 and ERK5 inhibition on MET, cell viability, migration, and anchorage-independent growth was evaluated in TNBC. ERK1/2 and ERK5 activities were modulated via pharmacological inhibitors and molecular tools. Cell morphology and protein expression of EMT markers E-cadherin, ZEB1, snail, and vimentin were evaluated. XMD8-92, an ERK5 inhibitor was found to synergize with doxorubicin in lung and cervical cancer cells. Therefore, the effect of dual ERK1/2 and ERK5 on doxorubicin sensitivity was evaluated. Citation Format: Akshita Bhatt, Thomas Wright, Van Barnes, Suravi Chakrabarty, Patrick Flaherty, Matthew Burow, Jane Cavanaugh. Targeting the ERK5 and ERK1/2 pathways simultaneously induces mesenchymal to epithelial transition in TNBC [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 5042.
Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL
Authors: Yaqi Zhao, Ibrahim Aldoss, Chunxu Qu, Jeremy Chase Crawford, Zhaohui Gu, Emma K. Allen, Anthony E. Zamora, Thomas B. Alexander, Jeremy Wang, Hiroaki Goto, Toshihiko Imamura, Koshi Akahane, Guido Marcucci, Anthony S. Stein, Ravi Bhatia, Paul G. Thomas, Stephen J. Forman, Charles G. Mullighan, Kathryn G. Roberts
Journal: Blood (2020)
Abstract 980: Maligant ascites microenvironment skews M2/M1 macrophage polarization in ovarian cancer during peritoneal metastasis
Authors: Huogang Wang, Mingo MH Yung, Arvin FS Chen, Hextan YS Ngan, David W. Chan
Journal: Cancer Research (2020)

Abstract Advanced ovarian cancers with peritoneal metastases are usually accompanied with metastatic recurrence and high mortality. Macrophages, as a primary cell population in the tumor microenvironment, can be active and polarized into heterogeneous tumor-associated macrophages (TAMs). Clinical evidence indicates that a high M2/M1 ratio of TAMs are commonly found in malignant ascites microenvironment (MAM), and is attributed to a poor prognosis in advanced ovarian cancers. However, the molecular mechanisms of macrophage polarization in MAM remain elusive. Here, we report that MAM could modulate Hippo and/or Wnt signaling cascades in facilitating M2 macrophage polarization. In this study, we firstly evidenced the heterogeneity macrophage populations in cancerous omental tissues and ascites cancer cell spheroids of ovarian cancers by multiplex immunohistochemical, flow cytometry and immunofluorescent analyses. Consistently, in vitro polarization model demonstrated that co-cultured monocyte (THP-1 and U937) with omentum conditioned medium (OCM) or ascites significantly led to more CD206+ M2 macrophage than CD86+ M1 macrophage or M2/M1 ratio. Quantitative RT-PCR (qPCR) analysis showed that TAM-related genes: CCL2, IL6, and IL10 genes were significantly upregulated in OCM treated macrophage. Intriguingly, OCM treated macrophage could significantly promotes ovarian cancer cell migratory capacities. Importantly, RNA-seq analysis identified Hippo and Wnt signaling cascades may play important roles in macrophage polarization in malignant OCM and ascites. Further investigations of these pathways in M2/M1 macrophage polarization in MAM are warranted. Citation Format: Huogang Wang, Mingo MH Yung, Arvin FS Chen, Hextan YS Ngan, David W. Chan. Maligant ascites microenvironment skews M2/M1 macrophage polarization in ovarian cancer during peritoneal 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 980.
Abstract 4820: Novel protein AX-295aa encoded by circAX promotes gastric carcinogenesis by activating Wnt pathway
Authors: Yin Peng, Xiaojing Zhang, Shiqi Deng, Jieqiong He, Wangchun Chen, Xiaohui Zhu, Yuan Yuan, Xianling Feng, Xinmin Fan, Zhe Jin
Journal: Cancer Research (2020)

Abstract Recently, traditionally non-encoding circRNA has been shown to encode a new protein to play an important role in oncogenesis. Based on the sequencing data and bioinformatics analysis, circAX was screened as an oncogenic circRNA encoding AX-295aa in gastric cancer. CircAX is highly expressed in gastric cancer and associated with lymph node metastasis. We found that circAX promotes GC cell proliferation and migration and it encodes a novel protein AX-295aa. AX-295aa interacts with APC and competitively inhibits AXIN1 binding to APC. It enhances β-catenin nuclear translocation and activates Wnt signaling pathway to promote the carcinogenesis and development of gastric cancer. The study reveals a new regulatory mechanism of circAX and clarify the mechanism by which circAX promotes gastric carcinogenesis. It will ultimately provide novel circRNA molecular markers for early diagnosis and targets for more effective treatment of gastric cancer. Citation Format: Yin Peng, Xiaojing Zhang, Shiqi Deng, Jieqiong He, Wangchun Chen, Xiaohui Zhu, Yuan Yuan, Xianling Feng, Xinmin Fan, Zhe Jin. Novel protein AX-295aa encoded by circAX promotes gastric carcinogenesis by activating Wnt pathway [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 4820.
Abstract 314: Micropatterning supported method for cancer spheroid assays under flow and high throughput CAR-T cell potency assay with single cell resolution
Authors: Elias Horn, Miriam Balles, Angelika J. Fischbeck, Jan Schwarz, Dane A. Thyssen, David W. Drell, Elfriede Noessner, Roman Zantl
Journal: Cancer Research (2020)

Abstract Tumor spheroids, organoids, and cell culture models demand defined cell-cell and cell-matrix interactions, ideally with specific cell attachment on adhesion sites for multicellular spheroids or single cells. Our bioinert based micropatterning technology allows for the creation of adhesion spots while the surrounding passivated area is biologically inert, not interfering with the assay.We use this micro-patterning of adhesion ligands on highly passivated surfaces to generate homogenously distributed spheroids within a microfluidic channel system which can be perfused. Spheroids can either be directly generated by a simple injection of a large number of cells and a self-sorting process or by the addition of pre-formed spheroids, which will bind to the patterned adhesion sites. Perfusion of the spheroid chip enables the homogenous supply of all spheroids with nutrients and oxygen, and also the application of a defined shear stress, metabolite analysis together with toxicological screenings or even co-culture of multiple spheroid types. Applying a flow increases the overall spheroid growth, but condenses the cell aggregate, as well as influences the drug triggered protein expression response towards a more in vivo-like reaction.We also use this technique to generate arrays of homogenously distributed single cancer cells to evaluate cytotoxic T cell activity on a single cell level. By optical analysis combined with machine-learning based image processing of cell / spheroid arrays we obtained efficient label-free analysis of each cancer cell - T cell interaction over time. Citation Format: Elias Horn, Miriam Balles, Angelika J. Fischbeck, Jan Schwarz, Dane A. Thyssen, David W. Drell, Elfriede Noessner, Roman Zantl. Micropatterning supported method for cancer spheroid assays under flow and high throughput CAR-T cell potency assay with single cell resolution [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 314.