tbuckley/cabot-search huggingface dataset:
Abstract 5328: RNF12 inhibits the proliferation of hepatocellular carcinoma through c-Myc and p21
Authors: Meng Nie, Yongsheng Huang, Lin Wang
Journal: Cancer Research (2017)

Abstract Purpose: RNF12/RLIM, a RING E3 ubiquitin ligase, plays an important role in the epigenetic regulation of sex-specific nurturing tissues in female mice. Recently, a few studies demonstrated a correlation between RNF12 and the proliferation of multiple cancers. The role of RNF12 in hepatocellular carcinoma is incompletely understood. The purpose of this study is to investigate the effect of RNF12 on the proliferation of human hepatocellular carcinoma cells. RNF12 is also known to interact with a number of nuclear proteins, including CLIM, HDAC2, and Smad4. We also explored whether c-Myc and p21, an oncogene and tumor suppressor essential to liver tumorigenesis, were affected by RNF12. Methods: Immunohistochemistry of RNF12 and c-Myc was performed on surgically dissected human hepatocellular carcinoma tissues. The soft-agar cloning, flow cytometry and Transwell invasion assays were carried out to investigate the role of RNF12 in SK-Hep1 cell proliferation, cell cycle and invasiveness. Real-time quantitative PCR and Western blotting were used to examine the mRNA and protein levels of RNF12 and related proteins in SK-Hep1 cells. Results: We found that the level of RNF12 was lower in hepatocellular carcinoma, compared with the surrounding non-cancerous tissues, while the c-Myc expression was higher. Using a SK-Hep1 cell line stably expressing RNF12, we showed that RNF12 over-expression inhibited cell proliferation and induced cell cycle arrest at G1 phase. Furthermore, we showed that RNF12 over-expression decreased the level of oncoprotein c-Myc, while not much affecting its mRNA level. Co-immunoprecipitation demonstrated that RNF12 and c-Myc associated with each other, suggesting a direct protein-protein interaction. RNF12 over-expression also markedly increased the mRNA and protein levels of p21, a tumor suppressor and the downstream target of p53, c-Myc and many other cancer-related regulators. Consistently, silencing of RNF12 reduced p21 mRNA and protein levels and increased c-Myc protein. Conclusion: Our study demonstrated reduced expression of RNF12 in hepatocellular carcinoma, and RNF12 over-expression inhibited the proliferation and cell cycle progression of SK-Hep1 cells. Mechanistically, RNF12 may directly regulate the level of c-Myc, similarly as other transcription factors such as CLIM and Smad4. The mechanisms underlying the increased expression of p21 is being investigated. Taken together, RNF12 may serve as a tumor suppressor in hepatocellular carcinoma, partly through oncoprotein c-Myc and tumor suppressor p21. Note: This abstract was not presented at the meeting. Citation Format: Meng Nie, Yongsheng Huang, Lin Wang. RNF12 inhibits the proliferation of hepatocellular carcinoma through c-Myc and p21 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5328. doi:10.1158/1538-7445.AM2017-5328
Abstract 1892: Small molecule NSC59984 prevents cancer cell migration and invasion
Authors: Shengliang Zhang, Jessica Wagner, Lanlan Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2017)

Abstract Tumor metastasis is one of the main mechanisms leading to mortality of cancer patients. Searching for new therapeutic strategies to prevent tumor metastasis is one of the anti-tumor approaches in cancer therapy. Cell migration and invasion are crucial initial steps in the complex process and progression of tumor metastasis. Mutant p53 has been known as an important factor associated to cancer cell migration. Therefore, targeting mutant p53 is a potential strategy to avoid tumor metastatic spread. We previously reported an anti-tumor small molecule, NSC59984 which degrades mutant p53 and restores p53 pathway via activation of p73. Here we demonstrate that NSC59984 inhibits cancer cell migration and invasion. Treatment with NSC59984 partially attenuates cell migration in various cancer cells based on the scratch assay and Boyden chamber assay. The effect of NSC59984 on cell migration is partially blocked by knockdown of p73, a member of the p53 family, suggesting that restoration of p53 pathway signaling via p73 is required for NSC59984-inhibition of cell migration in cancer cells. We found that NSC59984 induces ERK2-dependent p53 restoration and mutant p53 degradation. To examine the role of ERK2 in the cell migration, ERK2 signaling is blocked by U0126 treatment in cancer cells. The effect of NSC59984 on cancer cell migration is partially inhibited by U0126 treatment, suggesting that NSC59984 inhibits cancer cell migration partially dependent on ERK1/2 pathway signaling in cancer cells. In addition, the gelatin degradation assay shows that NSC59984 inhibits cancer cell invasion. Consistent to the in vitro assays, NSC59984 decreases tumor invasion of xenograft tumors as compared to the xenograft tumors treated with DMSO as control. Our results, taken together, suggest that NSC59984 not only suppresses tumor growth, but also inhibits cancer cell migration and invasion. Our findings provide the potential administration of p53-restoring compound NSC59984 in cancer therapy by blocking tumor metastasis. Citation Format: Shengliang Zhang, Jessica Wagner, Lanlan Zhou, Wafik S. El-Deiry. Small molecule NSC59984 prevents cancer cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1892. doi:10.1158/1538-7445.AM2017-1892
Abstract 15386: Hospitalizations and Other Healthcare Resource Utilization Among Patients With Deep Vein Thrombosis Treated With Rivaroxaban versus Low-Molecular-Weight Heparin and Warfarin in the Outpatient Setting
Authors: Steven Deitelzweig, François Laliberté, Monika Raut, Guillaume Germain, Brahim K Bookhart, William H Olson, Jeffrey Schein, Patrick Lefebvre
Journal: Circulation (2015)

Introduction: Compared with low-molecular-weight heparin (LMWH) and warfarin, the oral anticoagulant rivaroxaban has advantages such as simplified care that may lead to less healthcare resource utilization (HRU). Objective: To compare HRU (hospitalization, emergency room [ER], and outpatient [OP] visit) among deep vein thrombosis (DVT) patients who received rivaroxaban or LMWH/warfarin in the outpatient setting. Methods: A retrospective matched-cohort analysis was conducted using the Truven Health Analytic MarketScan Claims database from 1/2011-12/2013. Adult patients with a primary diagnosis of DVT during an OP/ER visit after November 02, 2012, and who initiated treatment on the same day with rivaroxaban or LMWH/warfarin were identified. Patients were observed within 1, 2, 3, and 4 weeks after their DVT diagnosis. Mean number of all-cause and VTE (DVT or PE)-related hospitalizations and other HRU were evaluated using Lin’s method. Results: All of the 512 rivaroxaban patients were well-matched with LMWH/warfarin patients. Mean all-cause number of hospitalizations was significantly lower for rivaroxaban compared to LMWH/warfarin users within 1 week (0.012 vs 0.032; P=0.044) and 2 weeks (0.022 vs 0.048; P=0.040), and numerically lower within 3 weeks (0.038 vs 0.061; P=0.112) and 4 weeks (0.045 vs 0.078; P=0.058). Corresponding mean number of VTE-related hospitalizations was significantly lower for rivaroxaban within 1 week (0.008 vs 0.028; P=0.020) and 2 weeks (0.016 vs 0.042; P=0.020), numerically lower within 3 weeks (0.030 vs 0.052; P=0.074), and significantly lower within 4 weeks (0.034 vs 0.068; P=0.036). Corresponding all-cause OP visits were significantly lower for rivaroxaban users, while ER visits were similar between cohorts (Table 1). Conclusion: DVT patients treated with rivaroxaban following an OP/ER visits had significantly fewer hospitalizations and outpatient visits during the first weeks compared to matched LMWH/warfarin users.
Abstract SY33-01: Targeting metabolism to enhance immunotherapy
Authors: Jonathan D. Powell, Robert Leone, Judd Englert, Rana Rais, Barbara Slusher
Journal: Cancer Research (2017)

Abstract The extraordinary proliferative capacity of cancer necessitates specialized metabolic programming on the part of cancer cells. Indeed, this specialized metabolism not only facilitates growth but also creates a hypoxic, acidic, nutrient-deprived tumor microenvironment able to thwart immune destruction. We hypothesized that by targeting tumor metabolism we could not only slow down tumor growth but also “condition” tumors to be more susceptible to immunotherapy. Inherent to the specialized metabolism of tumors is a markedly increased requirement for glutamine. To this end we have devised a novel glutamine antagonist that is delivered as an inert prodrug that is converted to the active drug by enzymatic activity, which is enriched in tumors. In syngeneic mouse models of cancer our prodrug (JHU-083) markedly inhibited tumor growth, leading to cure of mice after only 14 days of monotherapy. Importantly, targeting glutamine metabolism led to a decreased extracellular acidification rate (ECAR), decreased hypoxia, and increased nutrient availability. Furthermore, we observed decreases in MDSC and fibrocytes with a concomitant increase in inflammatory (TNF-producing) tumor-associated macrophages (TAMs). Likewise, there was an increase in the CD8:Treg ratio and in some tumors a decrease in PDL1 expression on both tumors and infiltrating immune cells. Most importantly, JHU-083 markedly enhanced the efficacy of immunotherapy in the form of checkpoint blockade, adoptive cellular therapy (ACT), and A2aR blockade. Overall our studies define a novel compound for targeting metabolism as a means of enhancing immunotherapy for cancer. Citation Format: Jonathan D. Powell, Robert Leone, Judd Englert, Rana Rais, Barbara Slusher. Targeting metabolism to enhance immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY33-01. doi:10.1158/1538-7445.AM2017-SY33-01
Abstract 1611: Intravesical BCG induces CD4 T Cell expansion in an immune competent model of bladder cancer
Authors: Max Kates, Thomas Nirschl, Nikolai Sopko, Noah Hahn, David McConkey, Alex Baras, Charles Drake, Trintiy Bivalacqua
Journal: Cancer Research (2017)

Abstract Intravesical BCG Immunotherapy is the standard of care in treating non-muscle invasive bladder cancer (NMIBC), yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. While prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Fischer 344 rats aged 7 weeks received 1.5mg/kg N-Nitroso-N-methylurea (MNU) every other week for 6 weeks (4 doses). Bladder dysplasia began by week 8 and by week 16 the majority of rats had a NMIBC phenotype. Beginning week 8 following the first MNU dose, rats were intravesically administered 0.3ml of BCG (Tice), cisplatin (1mg/ml), Mitomycin C (2mg/ml), MMC+ BCG, or saline (n=10 for all groups) weekly for 6 total doses. Animals were sacrificed at week 16, and bladders were processed for histopathology and digested into single cell suspensions for flow cytometry. Whole transcriptome expression profiling was then performed on sorted CD4 and CD8 cells of post-BCG tumors vs untreated tumors to assess T cell differentiation after BCG. Our data demonstrate that cancer progression in the MNU rat model of bladder cancer is characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. By contrast, treatment with intravesical BCG leads to a large, transient rise in the CD4+ T cell population in the urothelium, and is both more effective and immunogenic compared to intravesical chemotherapy. Interestingly, whole transcriptome expression profiling of post-treatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that while BCG induces T cell recruitment to the bladder, the T cell phenotype does not markedly change, implying that combining T cell activating agents with BCG might improve clinical activity. Citation Format: Max Kates, Thomas Nirschl, Nikolai Sopko, Noah Hahn, David McConkey, Alex Baras, Charles Drake, Trintiy Bivalacqua. Intravesical BCG induces CD4 T Cell expansion in an immune competent model of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1611. doi:10.1158/1538-7445.AM2017-1611
Abstract 2989: Expression of immune checkpoints proteins and their prognostic relevance in prostate cancer
Authors: Claudia Hube-Magg, Cornelia Schroeder, Ronald Simon, Martina Kluth, Till Krech, Franziska Büscheck, Frank Jacobsen, Doris Höflmayer, Lars Budäus, Hartwig Huland, Markus Graefen, Guido Sauter, Thorsten Schlomm
Journal: Cancer Research (2017)

Abstract Immune checkpoint proteins including programmed death ligand 1, 2 (PD-L1, PD-L2) and B7-H3 play important roles for immune evasion in many cancer types. PD-L1 is an established therapeutic target in lung cancer and in a growing number of other indications. The clinical success of PD-L1 inhibitors has accelerated the development of drugs also targeting PD-L2 and B7-H3. In prostate cancer, studies on the prevalence and clinical relevance of these proteins have been inconclusive. Here, we performed immunohistochemical analysis of PD-L1, PD-L2 and B7-H3 in our large prostate cancer prognosis tissue microarray (TMA) containing tissue samples from more than 17,000 patients. Normal prostate glands were negative for PD-L1 and B7-H3, but positive for PD-L2. We found that 47% of 12,808 interpretable cancers showed B7-H3 expression, and 92% of 9,463 cancers showed PD-L2 expression, while expression of PD-L1 was virtually absent (0.2% of 17,392 tumors) in epithelial cells. Stroma cells and immune cells were entirely negative for PD-L1 and B7-H3, while some faint staining of lymphocytes was occasionally observed for PD-L2. In cancers, PD-L2 and B7-H3 staining had different prognostic impact, which depended on the ERG status: B7-H3 expression was linked to young patient age, advanced stage, high Gleason grade, lymph node metastasis (p&amp;lt;0.0001 each), presence of PTEN deletion (p&amp;lt;0.0001), and poor prognosis in ERG negative cancers (p&amp;lt;0.0001), while PD-L2 expression was linked to beneficial tumor features and good prognosis exclusively in tumors with ERG fusion (p&amp;lt;0.0001). In a multivariate analysis including pT stage, Gleason grade, nodal stage, resection margin and preoperative PSA level, B7-H3 expression was an independent prognostic factor (p=0.0004). In summary, the results of our study identify a subset of young patients with ERG negative aggressive prostate cancers that might benefit from anti-B7-H3 therapy in the future. PD-L2 expression appears to protect tumors from progression and does not seem to be suitable as a potential target in prostate cancer. PD-L1 expression is extremely rare in this disease, suggesting that only few prostate cancer patients might benefit from PD-L1 inhibitors. Citation Format: Claudia Hube-Magg, Cornelia Schroeder, Ronald Simon, Martina Kluth, Till Krech, Franziska Büscheck, Frank Jacobsen, Doris Höflmayer, Lars Budäus, Hartwig Huland, Markus Graefen, Guido Sauter, Thorsten Schlomm. Expression of immune checkpoints proteins and their prognostic relevance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2989. doi:10.1158/1538-7445.AM2017-2989
Abstract 3640: Novel humanized anti-Sialyl-Tn, anti-CD3 bispecific antibodies demonstrate tumor and T-cell specificity for immune activation at the tumor site
Authors: David A. Eavarone, Jillian Prendergast, Patricia E. Rao, Jenna Stein, Jeff Behrens, Daniel T. Dransfield
Journal: Cancer Research (2017)

Abstract Tumor-associated carbohydrate antigens (TACAs) historically have been challenging targets for antibody therapeutics. Sialyl-Tn (STn) is a cancer specific antigen that is expressed on the surface of carcinomas including ovarian, colon, prostate, and pancreatic tumors but is rarely present in normal tissue. STn expression has been linked to innate immune suppression, a chemoresistant phenotype, metastasis, and poor prognosis. Previous attempts to target this antigen in the clinic with synthetic glycan vaccines proved safe but lacked efficacy. We have developed humanized bispecific antibodies targeting STn and CD3 for T-cell recruitment and activation at the tumor site. These bispecific antibodies were selected for optimal tumor targeting using our glycan microarray that enriches for candidates whose binding is protein-independent and glycan specific. STn-selective binding was demonstrated. Current lead candidates exhibited low nanomolar EC50 binding in flow cytometric assays against both STn expressing tumor cells and T cells. Quantification of T-cell activation and T-cell induced tumor killing in vitro provides a basis for the further clinical development of these bispecific antibody candidates. Citation Format: David A. Eavarone, Jillian Prendergast, Patricia E. Rao, Jenna Stein, Jeff Behrens, Daniel T. Dransfield. Novel humanized anti-Sialyl-Tn, anti-CD3 bispecific antibodies demonstrate tumor and T-cell specificity for immune activation at the tumor site [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3640. doi:10.1158/1538-7445.AM2017-3640
Abstract 24: HMBD001, a novel anti-ErbB3 antibody with a unique mechanism of action, effectively inhibits tumor growth in pre-clinical models of ErbB3+ solid tumors
Authors: Jerome D. Boyd-Kirkup, Dipti Thakkar, Piers J. Ingram
Journal: Cancer Research (2017)

Abstract Gastric cancer is the second highest cause of cancer mortality in Asia. Over-expression of ErbB3, a cell surface RTK, occurs in ~60% of mGC patients where it is significantly associated with poorer survival. Ligand binding to ErbB3 triggers heterodimerization and downstream signaling through Akt. Neutralizing antibodies that inhibit ligand binding show poor efficacy in clinical trials, likely due to high levels of ligand independent activation in many tumor types. Directly inhibiting heterodimerization could be more effective, however, current methods of antibody isolation offer limited control over the site of antibody binding and, therefore, mechanism of action, requiring extensive screening of antibodies and posing significant challenges to identifying suitable candidates for therapeutic development. Hummingbird Bioscience has used its proprietary Rational Antibody Development Platform for the design and development of novel therapeutic antibodies against ErbB3. Computational sequence and structural analyses predicted highly specific surface epitopes, with strong antigenicity and good safety profiles, where antibody binding would inhibit dimerization. Subsequently, Hummingbird’s directed evolution mouse immunization strategy efficiently isolated monoclonal antibodies that bound with low nM (Kd &amp;lt; 5nM) affinity to these epitopes on native folded ErbB3. Furthermore, these mAbs showed ELISA cross-reactivity to ErbB3 in model organisms (mouse, rat, monkey) but no binding to other EGFR family proteins. Antibody HMBD001 was found to strongly inhibit the phosphorylation of ErbB3 and decrease downstream signaling through the Akt pathway (90% decrease in p-ErbB3 and 60% decrease in p-AKT observed at 24 hrs) resulting in the inhibition of tumor cell proliferation in models of ErbB3+ gastric cancer (over 90% inhibition of NCI-N87 proliferation after 5 days) and breast cancer (up to 85% inhibition of BT474 proliferation after 5 days). In mouse NCI-N87 gastric cancer CDX models, weekly doses of HMBD001 achieved greater than 90% inhibition of tumor growth (at 25 days) with no observable adverse toxicity. The first in-human trial of HMBD001 is planned for 2018. Citation Format: Jerome D. Boyd-Kirkup, Dipti Thakkar, Piers J. Ingram. HMBD001, a novel anti-ErbB3 antibody with a unique mechanism of action, effectively inhibits tumor growth in pre-clinical models of ErbB3+ solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 24. doi:10.1158/1538-7445.AM2017-24
Bone marrow involvement in mantle cell lymphoma: An immunophenotyping analysis with clinicopathologic correlation from a tertiary care center in North India.
Authors: CHANDAN KRUSHNA DAS, Lalit Kumar, Ajay Gogia, Reena Kaushal
Journal: Journal of Clinical Oncology (2016)

e19073 Background: Mantle cell lymphoma (MCL) is an aggressive lymphoma with significant bone marrow (BM) involvement which ranges from 40% to 80%. The aim of the study was to analyze the prevalence and clinical significance of bone marrow involvement in a series of patients with MCL and correlate with morphologic finding. Methods: We retrospectively analyzed 51 consecutive patients who were treated at our institute for Mantle cell lymphoma. Leukemic involvement was assessed by conventional morphology and multicolor flow cytometry (MFC) in BM samples. In addition, fluorescent in situ hybridization was performed to confirm the diagnosis. The overall survival (OS) and progression-free survival (PFS) were measured from the time of diagnosis Results: On evaluation, the evidence of bone marrow involvement was found in 63% by morphology and MFC. Other extra nodal involvement was present in 50% patients with BM involvement. Ninety nine percentage of patients were cyclinD1 positive. CD5-ve CD23+ve MCL constitute around 5% each. The median age at diagnosis was 57 year (29-80). The absolute lymphocyte ratio at diagnosis was 24089mm3+/-72078(780-72078). The response rate to chemotherapy in patients with BM involvement was 66% and was lower than patients without BM involvement. With a median follow up of 19 months (2.5-75), PFS at 1 and 2 years was 41% and 17%, and overall survival (OS) 55% and 26%, respectively. Conclusions: Bone marrow involvement detected by MFC was found to be in more than half of the patients with MCL. The IHC immunophenotypic correlated with flow cytometric analysis. Bone marrow involvement associated with high LDH, high circulating lymphocyte count had poor response rate to chemotherapy and a shorter overall survival.