tbuckley/cabot-search huggingface dataset:
Abstract 1622: The role of the CCL-2 on lymphopenia-induced myeloid derived suppressor cells
Authors: Pasquale P. Innamarato, Amy Weber, Shari Pilon-Thomas
Journal: Cancer Research (2017)

Abstract The induction of lymphopenia prompts the expansion of CD11b+Ly6ChiLy6G- monocytic MDSCs (M-MDSCs) and CD11b+Ly6C+Ly6G+ polymorphonuclear MDSCs (PMN-MDSCs). Patients receiving adoptive cell therapy (ACT) require nonmyeloablative chemotherapy to induce lymphopenia and support anti-tumor immunity. However, the role of MDSCs in the setting of ACT is not fully understood. As high levels of CCL-2 can be measured in lymphopenic mice, in this study we investigate the role of CCL-2 in the expansion and function of lymphopenia-induced MDSCs using CCR2KO mouse models. Lymphopenia was induced in melanoma-bearing C57BL/6 (WT) and CCR2KO mice by 600rad of total body irradiation or combination therapy with cyclophosphamide and fludarabine. We first evaluated the percentages of splenic MDSCs in WT and CCR2KO mice after the induction of lymphopenia. At day 14, the expansion of total MDSCs were similar in WT (279% of normal) and CCR2KO (241% of normal). However, the mean percentages of M-MDSCs (3.5%) and PMN-MDSCs (30.3%) in CCR2KO mice were altered compared to M-MDSCs (22.2%) and PMN-MDSCs (21.7%) in WT mice. In addition, M-MDSCs in B16 tumors grown in CCR2KO mice were decreased compared to intratumoral M-MDSCs in WT mice (p&amp;lt;0.001). In contrast, the percentages of M-MDSCs and PMN-MDSCs were unchanged in the bone marrow (BM). To investigate the suppressive capacity of lymphopenia-induced MDSCs, OVA antigen-specific CD8+ T cells were co-cultured with OVA peptide in the presence of MDSCs purified from the spleens of CCR2KO and WT mice. Both CCR2KO and WT MDSCs potently suppressed T cell proliferation as measured by 3H thymidine incorporation. CCR2KO and WT MDSCs had significant arginase activity and production of nitrites. To investigate the efficacy of ACT, B16 tumor-bearing CCR2KO and WT mice were lymphodepleted and gp100 antigen-specific Thy1.2+CD8+ T cells were adoptively transferred followed by 3 days of IL-2 treatment. We found that donor T cell tumor infiltration was similar and no difference in tumor growth was observed between CCR2KO and WT mice. Collectively, these results suggest that the role of CCL-2 is important for the egress of lymphopenia-induced M-MDSCs from the BM, but has no effect on the expansion or function of PMN-MDSCs in the setting of lymphopenia. These data suggest that factors besides CCL-2 play an important role in the expansion and function of MDSCs after the induction of lymphopenia. Citation Format: Pasquale P. Innamarato, Amy Weber, Shari Pilon-Thomas. The role of the CCL-2 on lymphopenia-induced myeloid derived suppressor cells [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 1622. doi:10.1158/1538-7445.AM2017-1622
Abstract 5096: Targeted ablation of essential oncogenes in rhabdomyosarcoma with CRISPR/Cas9 gene therapy
Authors: Michael Phelps, Heechang Yang, Eleanor Chen
Journal: Cancer Research (2017)

Abstract Targeted therapy seeks to exploit unique vulnerabilities in cancer cells not present in normal tissue. The development of effective therapies targeting essential tumor proteins has had significant challenges particularly for tumor oncogenes many of which have proven “undruggable”. Targeting these critical tumor oncogenes has been one of the foremost challenges in cancer research. Current sequencing technology facilitates rapid identification of novel cancer mutations yet there are no effective therapeutic strategies aimed at targeting essential cancer genes at the genome level. To overcome the challenges associated with targeting “undruggable” cancer proteins, we have employed high efficiency CRISPR/Cas9 genome editing technology to destroy cancer cells by directly targeting the genomic DNA of essential cancer genes. We used pediatric rhabdomyosarcoma to demonstrate the potential of CRISPR/Cas9 gene therapy in solid tumor preclinical xenograft mouse models. Rhabdomyosarcoma is an aggressive pediatric sarcoma characterized by myogenic differentiation arrest. The two major subtypes of rhabdomyosarcoma (RMS), embryonal (ERMS) and alveolar (ARMS) are defined largely by either activation of the RAS pathway (ERMS) or the presence of a fusion oncogene between PAX3 and FOXO1 (ARMS). CRISPR/Cas9 was first used to target critical exons in the activated RAS or PAX3/FOXO1 oncogenes unique to each RMS subtype, using inducible or viral CRISPR delivery systems. Targeting these essential genes resulted in significant regression of tumor xenografts due to a combination of cell death and differentiation. By precisely targeting the activating mutations in the RAS oncogene or the fusion site in the PAX3/FOXO1 fusion gene we further demonstrate that tumor-specific CRISPR/Cas9-mediated gene therapy can also be achieved. This strategy disrupts the essential cancer oncogenes with minimal impact to normal cells that do not harbor the unique cancer mutations. Our results highlight the utility of exploiting essential cancer genetic mutations for personalized therapy. This novel approach to cancer therapy provides a potential alternative strategy for targeting “undruggable” oncogenes while establishing a foundation for further development of CRISPR/Cas9 gene therapy for cancer treatment Citation Format: Michael Phelps, Heechang Yang, Eleanor Chen. Targeted ablation of essential oncogenes in rhabdomyosarcoma with CRISPR/Cas9 gene therapy [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 5096. doi:10.1158/1538-7445.AM2017-5096
Exercise for Patients With Hypertrophic Cardiomyopathy—Reply
Authors: Sara Saberi, Matthew Wheeler, Sharlene M. Day
Journal: JAMA (2017)

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TRIOC: A randomised parallel group double-blind phase II study to assess the activity of MVA-5T4 vaccine versus placebo in patients with relapsed asymptomatic epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Authors: Agnieszka Michael, Rosemary Lord, Geoff Hall, Louise Hanna, Anjana Anand, Axel Walther, Shibani Nicum, Andrew R. Clamp, Rebecca Sophie Kristeleit, Alan Hackshaw, Gita Parmar, Yen Ngai, Laura Farrelly, Sharadah Essapen, Iain A. McNeish, Richard Harrop, Jonathan A. Ledermann
Journal: Journal of Clinical Oncology (2016)

TPS5604 Background: Ovarian cancer is the second most common gynaecological malignancy in the Western world. The majority of patients present in an advanced stage and the survival rates are still poor. There is extensive evidence that ovarian cancer is under immune surveillance. Patients who develop CA-125 relapse and do not have clinical symptoms will often have a low volume disease on the CT scan and are ideally suited for immune-based strategies as they do not benefit from chemotherapy. 5T4 is an oncofetal tumour antigen (TAA) which is expressed on the cell surface and has been identified as a promising target for immunotherapy and has high expression in ovarian cancer. Methods: This is a phase II randomised, controlled double-blind multicentre study of a highly attenuated Modified Vaccinia Ankara virus containing the gene encoding for the human TAA, 5T4 (MVA-5T4) in women with relapsed asymptomatic ovarian cancer compared to placebo. The overall aim of the trial is to assess the effectiveness of MVA-5T4 in extending time to progression in asymptomatic relapsed ovarian cancer patients. The primary efficacy endpoint is RECIST-defined progression at 25 weeks. The secondary endpoints include progression free survival defined by immune related response criteria, safety, quality of life, overall survival, immune and exploratory biomarkers. The aim is to detect a progression rate of 50% in the MVA-5T4 arm as compared to 70% in the placebo group. Based on a direct comparison of proportions, 80% power and one-sided test of statistical significance of 20%, the sample size for the study has been set at 75 patients. Patients are randomised to MVA-5T4 or placebo and receive 12 intradermal injections of MVA-5T4, the first 2- once a week followed by injection after 2 weeks, then 3 injections every 3 weeks followed by 6-weekly injections. The inclusion criteria include women who completed cytoreductive surgery and chemotherapy and relapsed with asymptomatic low volume disease detectable on the CT or with CA125 only. 45 out of 75 patients have been recruited. Clinical Trial Information NCT01556841 CR UK endorsed – ref A15045 Clinical trial information: NCT01556841.
Abstract 270: Trends in colorectal cancer survival in Arab World, 1990-2009
Authors: Zoubida Zaidi, Mokhtar Hamdi Cherif
Journal: Cancer Research (2017)

Abstract Introduction: Cancer survival is a key measure of the effectiveness of health-care systems. Globally, colon and rectum cancer ranked third for cancer incidence and fourth for cancer death in 2013. For developed countries it ranked second for incidence and mortality, and in developing countries it ranked fourth for both incidence and mortality. An increasing trend in incidence is reported from various registries of Arab world, Kuwait and Saudi Arabia present the highest incidences worldwide. Objective: To describe the trends of the survival of colorectal cancer patients diagnosed in Arab countries. Material and Methods: This report is a summary of the two survival figures of CONCORD study 1 (1990-1994) and CONCORD study 2 (1995-2009). Individual colon and rectum tumour records were submitted by 06 population-based cancer registries in Arab countries (Jordan, Saoudi Arabia, Qatar, Algeria, Lybia and Tunisia) for 9050 patients (15-99 years) diagnosed during 1990-2009 and followed up to 31 December 2009 . Estimated five-year net survival, adjusted for background mortality by single year of age, sex, calendar year in each country. Results : For patients diagnosed during the period 2005-2009, the age-standardized five-years net survivals were respectively higher 68,2% for colon cancer and 77,8% for rectum cancer in Qatar and the lowest rate for rectal cancer 21% in Jordan, between 1995-1999 and 2005-2009, Survival increased in Algeria, but this trend is less reliable Conclusions: Comparison of population-based cancer survival CONCORD study showed very wide variations in survival from colorectal cancer in Arab world. Cancer survival research is being used to formulate cancer control and the need to implement effective strategies of primary prevention. Note: This abstract was not presented at the meeting. Citation Format: Zoubida Zaidi, Mokhtar Hamdi Cherif. Trends in colorectal cancer survival in Arab World, 1990-2009 [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 270. doi:10.1158/1538-7445.AM2017-270
Simulation of Lipid-Lowering Therapy Intensification in a Population With Atherosclerotic Cardiovascular Disease
Authors: Christopher P. Cannon, Irfan Khan, Alexa C. Klimchak, Matthew R. Reynolds, Robert J. Sanchez, William J. Sasiela
Journal: JAMA Cardiology (2017)

<h3>Importance</h3> In patients with atherosclerotic cardiovascular disease (ASCVD), guidelines recommend optimizing statin treatment, and consensus pathways suggest use of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with persistently elevated low-density lipoprotein cholesterol (LDL-C) levels despite use of statins. Recent trials have provided evidence of benefit in reduction of cardiovascular events with these agents. <h3>Objective</h3> To estimate the percentage of patients with ASCVD who would require a PCSK9 inhibitor when oral lipid-lowering therapy (LLT) is intensified first. <h3>Design, Setting, and Participants</h3> This simulation model study used a large administrative database of US medical and pharmacy claims to identify a cohort of 105 269 patients with ASCVD enrolled from January 1, 2012, through December 31, 2013, who met the inclusion criteria (database cohort). Patients were sampled with replacement (bootstrapping) to match the US epidemiologic distribution and entered into a Monte Carlo simulation (simulation cohort) that applied stepwise treatment intensification algorithms in those with LDL-C levels of at least 70 mg/dL. All patients not initially receiving a statin were given atorvastatin, 20 mg, and the following LLT intensification steps were applied: uptitration to atorvastatin, 80 mg; add-on ezetimibe therapy; add-on alirocumab therapy, 75 mg (a PCSK9 inhibitor); and uptitration to alirocumab, 150 mg. Sensitivity analyses included evolocumab as a PCSK9 inhibitor. Efficacy was estimated from published studies and incorporated patient-level variation. Data were analyzed from December 2015 to May 2017. <h3>Exposures</h3> Treatment intensification strategies with LLT. <h3>Main Outcomes and Measures</h3> Use of LLT among the population with ASCVD and distributions of LDL-C levels under various treatment intensification scenarios. <h3>Results</h3> Inclusion criteria were met by 105 269 individuals in the database cohort (57.2% male and 42.8% female; mean [SD] age, 65.1 [12.1] years). In the simulation cohort (1 million patients; 54.8% male and 45.2% female; mean [SD] age, 66.4 [12.2] years), before treatment intensification, 51.5% used statin monotherapy and 1.7% used statins plus ezetimibe. Only 25.2% achieved an LDL-C level of less than 70 mg/dL. After treatment intensification, 99.3% could achieve an LDL-C level of less than 70 mg/dL, including 67.3% with statin monotherapy, 18.7% with statins plus ezetimibe, and 14% with add-on PCSK9 inhibitor. <h3>Conclusions and Relevance</h3> Large gaps exist between recommendations and current practice regarding LLT in the population with ASCVD. In our model that assumes no LLT intolerance and full adherence, intensification of oral LLT could achieve an LDL-C level of less than 70 mg/dL in most patients, with only a modest percentage requiring a PCSK9 inhibitor.
Abstract 4789: A novel MIF signaling pathway drives the malignant character of pancreatic cancer by targeting NR3C2
Authors: Shouhui Yang, Peijun He, Liming Wang, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Katsuhiko Yanaga, Tadashi Uwagawa, Abhay R. Satoskar, Jochen Gaedcke, Markus Bernhardt, B. Michael Ghadimi, Matthias M Gaida, Frank Bergmann, Jens Werner, Thomas Ried, Nader Hanna, H. Richard Alexander, S. Perwez Hussain
Journal: Cancer Research (2017)

Abstract Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and noncoding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally, and clinically characterized using cell lines, a genetically engineered mouse model, and PDAC patient cohorts. Here, we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b that targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. In addition, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof of principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management. Citation Format: Shouhui Yang, Peijun He, Liming Wang, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Katsuhiko Yanaga, Tadashi Uwagawa, Abhay R. Satoskar, Jochen Gaedcke, Markus Bernhardt, B. Michael Ghadimi, Matthias M Gaida, Frank Bergmann, Jens Werner, Thomas Ried, Nader Hanna, H. Richard Alexander, S. Perwez Hussain. A novel MIF signaling pathway drives the malignant character of pancreatic cancer by targeting NR3C2 [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 4789. doi:10.1158/1538-7445.AM2017-4789
Abstract 2062: Inhibition of STAT3 overcomes gemcitabine resistance in pancreatic cancer cells
Authors: Chi-Wei Chen, Ruiqin Wu, Yunxiao Meng, Wenge Zhu
Journal: Cancer Research (2017)

Abstract Gemcitabine is used as the first line treatment of pancreatic ductal adenocarcinoma (PDAC), however, either innate or acquired resistance to gemcitabine limit its therapeutic efficacy. In this study, several DNA damage agents including DNA repair inhibitors, and kinase inhibitors were examined for suppression of cell growth of gemcitabine resistant cells. The results show that most of these compounds are cross-resistant to gemcitabine-resistant pancreatic cells. By using STRING protein network database, we found that STAT3 signaling pathway plays a connectional role to link targeted proteins we tested. Interestingly, gemcitabine-resistant pancreatic cells have higher level of phosphor-STAT3 (pSTAT3) and are more sensitive to STAT3 inhibitor, S3I-201. Furthermore, combined S3I-201 with gemcitabine synergically suppresses the growth of both cell lines in vitro. We also confirmed the therapeutic efficacy of combined treatments using xenografted model. Taken together, inhibition of STAT3 overcomes gemcitabine resistance in pancreatic cancer cells. This study may provide us with a new approach to treat pancreatic cancer as well as gemcitabine resistance of pancreatic cancer. Citation Format: Chi-Wei Chen, Ruiqin Wu, Yunxiao Meng, Wenge Zhu. Inhibition of STAT3 overcomes gemcitabine resistance in pancreatic cancer cells [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 2062. doi:10.1158/1538-7445.AM2017-2062
Abstract 1941: Cell surface vimentin is a novel marker for CTC detection in neuroblastoma
Authors: Izhar S. Batth, Heming Li, Giselle Saulnier Sholler, Shulin Li
Journal: Cancer Research (2017)

Abstract Among children in the United States, brain cancers now account for most number of cancer-related deaths. Neuroblastomas (NB) and sarcomas account for 13% of all childhood cancers in the United States. Despite significant progress yielding increased 5-year survival, 1250 deaths are expected this year from childhood cancers and cancer incidence has been steadily increasing. One of the key contributors to cancer mortality is tumor metastasis. It is generally believed that CTCs are shed into the circulation from primary tumors and contain unique driver mutations enabling their aggressive phenotype. However, detection of CTCs from NB is difficult as there is no direct method. Our lab has developed a monoclonal antibody targeting vimentin on the cells’ surface. Cell surface vimentin (CSV) is only observed in tumor cells; it remains intracellular in normal cells. We have published data demonstrating the superior specificity and sensitivity of our approach in breast, colon, and prostate cancer. Here, we report direct CTC detection in NB using our CSV mAb. As part of our collaborative effort analyzing NB blood samples from a multicenter Phase II trial, we present novel discoveries regarding treatment of NB with difluoromethylornithine (DFMO) and its effects on CTC release into the circulation in patients under remission. Among our observations, approximately ~1/3 patients have low or no CTCs while ~1/4 with high numbers of CTC are responding to DFMO treatment. Remaining patients show oscillating CTC numbers. Further, treatment with DFMO showed a statistically significant decline in CTCs after the beginning of therapy. Ongoing work including whole genome analysis can possibly reveal new insight into CTCs’ entering the circulation. These data demonstrate that our CTC capture using CSV is a novel and unique approach for detection in NB. Citation Format: Izhar S. Batth, Heming Li, Giselle Saulnier Sholler, Shulin Li. Cell surface vimentin is a novel marker for CTC detection in neuroblastoma [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 1941. doi:10.1158/1538-7445.AM2017-1941