tbuckley/cabot-search huggingface dataset:
Abstract LB-147: EMT transcription factors induce tissue factor expression and pro-coagulant properties, supporting early metastasis of circulating tumor cells
Authors: Morgane Bourcy, Nicolas Skrypek, Erik W. Thompson, Geert Berx, Brett Hollier, Myriam Polette, Christine Gilles
Journal: Cancer Research (2017)

Abstract The presence of circulating tumor cells (CTCs) expressing traits of epithelial-mesenchymal transition (EMT) in cancer patients is increasingly recognized. Recently, we identified a new mechanism by which EMT induces the expression of Tissue Factor (TF, a major cell-associated initiator of coagulation), triggering a local activation of the coagulation cascade that favors the early metastatic colonization of EMT-positive CTCs (Bourcy et al., Cancer Research, 2016). Strengthening the functional contribution of EMT to TF regulation and coagulation, we further accumulated evidence that EMT transcription factors regulate TF expression. Thus, silencing ZEB1 inhibited both EMT-associated TF expression and coagulant activity. EMT-positive cells also exhibited a higher survival/persistence in lungs of mice colonized after intravenous injection, which was diminished by silencing ZEB1. Inversely, triggering de novo expression of Snail in MDA-MB-468 increased TF, coagulant properties and early metastasis in mice. Using TF promoter reporter vectors (mutated at different potential ZEB1 and Snail transcription factors) and CHIP, we further identified a binding region for ZEB1 in the proximal TF promoter encompassing a MCAT box, suggesting that ZEB1 and YAP might interact to regulate TF expression. Ongoing experiments are being performed to verify this hypothesis. We also collected data suggesting that targeting this new EMT/TF axis with anti-EMT drugs may represent an important extension to global anticoagulant strategies against cancer. Citation Format: Morgane Bourcy, Nicolas Skrypek, Erik W. Thompson, Geert Berx, Brett Hollier, Myriam Polette, Christine Gilles. EMT transcription factors induce tissue factor expression and pro-coagulant properties, supporting early metastasis of circulating tumor 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 LB-147. doi:10.1158/1538-7445.AM2017-LB-147
Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes
Authors: Sook Kyung Chang, Ayano C. Kohlgruber, Fumitaka Mizoguchi, Xavier Michelet, Benjamin J. Wolf, Kevin Wei, Pui Y. Lee, Lydia Lynch, Danielle Duquette, Victòria Ceperuelo-Mallafré, Alexander S. Banks, Michael B. Brenner
Journal: Journal of Clinical Investigation (2017)

M2 macrophages, innate lymphoid type 2 cells (ILC2s), eosinophils, Tregs, and invariant NK T cells (iNKT cells) all help to control adipose tissue inflammation, while M1 macrophages, TNF, and other inflammatory cytokines drive inflammation and insulin resistance in obesity. Stromal cells regulate leukocyte responses in lymph nodes, but the role of stromal cells in adipose tissue inflammation is unknown. PDGFRα+ stromal cells are major producers of IL-33 in adipose tissue. Here, we show that mesenchymal cadherin-11 modulates stromal fibroblast function. Cadherin-11-deficient mice displayed increased stromal production of IL-33, with concomitant enhancements in ILC2s and M2 macrophages that helped control adipose tissue inflammation. Higher expression levels of IL-33 in cadherin-11-deficient mice mediated ILC2 activation, resulting in higher IL-13 expression levels and M2 macrophage expansion in adipose tissue. Consistent with reduced adipose tissue inflammation, cadherin-11-deficient mice were protected from obesity-induced glucose intolerance and adipose tissue fibrosis. Importantly, anti-cadherin-11 mAb blockade similarly improved inflammation and glycemic control in obese WT mice. These results suggest that stromal fibroblasts expressing cadherin-11 regulate adipose tissue inflammation and thus highlight cadherin-11 as a potential therapeutic target for the management of obesity.
Abstract 3024: CD4+ outperform CD8+ central memory-derived CAR T cells, mediating persistent antitumor responses and long-term eradication of glioblastoma
Authors: Dongrui Wang, Renate Starr, Brenda Aguilar, Alfonso Brito, Brenda Chang, Aniee Sarkissian, Behnam Badie, Michael E. Barish, Stephen J. Forman, Christine E. Brown
Journal: Cancer Research (2017)

Abstract Purpose: To compare antitumor effector function mediated by CD4+ and CD8+ chimeric antigen receptor (CAR)-T cells targeting IL13 receptor α2 (IL13Rα2) for treatment of glioblastoma (GBM). Experimental Design: CD4+ and CD8+ IL13Rα2-specific CAR-T cells, derived from enriched central memory T cells (Tcm), were evaluated for their antitumor potential both in vitro by recursive challenge with GBM cells and in vivo in established orthotopic GBM xenograft models. Further, GBM-stimulated CD4+ and CD8+ CAR-T cells were examined for their exhaustion- and memory-associated phenotypes at transcriptional and protein levels, which would account for their differential antitumor activity. Results: While CD8+ CAR-T cells mediated robust short-term cytolytic effector function, they became rapidly exhausted and lost antitumor potential after repeated stimulation with tumor cells. CD4+ CAR-T cells, by contrast, persisted and retained effector potency even after repetitive tumor challenge. CD4-mediated cytotoxicity acted through the granzyme B/perforin pathway and was independent of the CD8+ cells. Activated CD4+ CAR-T cells augmented the proliferation of CD8+ cells, but failed to protect the CD8+ cells against stimulation-induced exhaustion. In NSG mice bearing GBM xenografts, CD4+ CAR-T cell treatment led to long-term tumor-free survival, while CD8+ CAR-T cell treated mice showed short-term tumor regression followed by antigen-positive relapse and associated T cell exhaustion. Upon GBM stimulation, CD4+ cells expressed less co-inhibitory receptors and more memory-associated markers than the CD8+ T cell subset. Further, a comprehensive transcriptional analysis revealed that when activated, CD4+ cells retained expression of genes involved in survival- and self-renewal-related pathways, indicating a less exhausted status and a better functional persistence in comparison to the CD8+ cells. Conclusion: We observed a superior anti-GBM activity mediated by CD4+ CAR-T cells over the CD8+ subset, featured by their ability to maintain long-term immune response and reduce stimulation-induced exhaustion. It is thus inferred that the frequency of CD4+ cells could be an important criteria for evaluating the efficacy of CAR-T cells as immunotherapeutic products. Citation Format: Dongrui Wang, Renate Starr, Brenda Aguilar, Alfonso Brito, Brenda Chang, Aniee Sarkissian, Behnam Badie, Michael E. Barish, Stephen J. Forman, Christine E. Brown. CD4+ outperform CD8+ central memory-derived CAR T cells, mediating persistent antitumor responses and long-term eradication of glioblastoma [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 3024. doi:10.1158/1538-7445.AM2017-3024
MRI evaluation of soft tissue sarcomas
Authors: N. Faizi, R. Sharma, S. Sharma, S. Chandrashekhara, N. K. Shukla, A. Malhotra, R. Kumar, S. V. Deo, S. Thulkar
Journal: Journal of Clinical Oncology (2009)

e21523 Background: Althouth soft tissue constitute large part of the body, STS are rare (1% of all neoplasms) and can arise anywhere in the body. Imaging is require to confirm the diagnosis and for staging. We conducted a prospective study to evaluate the role of MRI scan in characterization and staging of the tumor. Methods: This study between 2006 and 2008 included 20 patients with histologically proven soft tissue sarcoma in whom preoperative MRI of the local site was performed and the findings were correlated with the surgical and histopathological findings. Only those patients in whom surgical and histopathological findings were available were included in the study. All MRI were performed on 1.5 T MRI using body and appropriate surface coil. T1W, T2W, and STIR sequences were acquired in axial, coronal, and sagittal planes. Contrast enhanced MRI was performed in four patients. Surgical findings were recorded by the operating surgeon and resected specimens were analyzed by pathologist for assessing extent and histologic typing. All demographic data of the patient, the clinical features, preoperative imaging analysis, operative and histopathological findings were tabulated as per the given proforma. Results: Age of the patients was 16 - 72 years (mean age 44.4 years). Male female ratio was 2.3:1 . Eleven cases were recurrent. Most common histologic type was MFH (30%) while synovial sarcoma was second most common (20%) type of the STS in our study. Eighteen of 20 soft tissue sarcomas were of high grade. Average size on MRI was 9.25 cm (range) and operative size was 9.8 cm (range). Statistically significant agreement existed between MR and operative size. The sensitivity of MRI for individual muscle involvement was 92.3% and specificity was 96.5%. MRI had a sensitivity of 93% and specificity of 100% in predicting fascial involvement. MRI had 100% sensitivity and specificity in showing skin and subcutaneous tissue involvement. MRI had 100% negative predictive value in predicting NV bundle involvement. None of the patients had bone or joint involvement. No distant parenchymal metastases were seen. Specific diagnosis based on MRI image characteristics was suggested in 35% patients. Conclusions: Overall staging accuracy of MRI was 75% in staging of STS when correlated with surgical and histopathological MSKCC staging. No significant financial relationships to disclose.
Abstract 137: FT-1518, a new generation selective and potent mTORC1 and mTORC2 inhibitor: an <i>in vitro</i> and <i>in vivo</i> profile
Authors: Alain C. Mita, Monica M. Mita, Anthony D. William, Khalid Pasha, Chandra Siddamadappa, Kevin Zikaras, Felix T. Garzon
Journal: Cancer Research (2017)

Abstract Mammalian target of rapamycin (mTOR) is a clinically validated target in the treatment of cancer. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2 which regulate cell growth, metabolism, proliferation, and survival. Rapamycin analogues target only the mTORC1 complex but do not affect the mTORC2 complex, which is an important driver for cancer cell growth and survival. The new generation of “Selective” mTOR inhibitors, blocking both mTORC1 and mTORC2 signaling might increase the efficacy and safety while expanding the therapeutic potential of these anticancer agents. Herein we describe FT-1518, a low nanomolar potent, kinase and PI3K sub family selective mTOR inhibitor. FT-1518 not only exhibited high oral bioavailability in preclinical species but has demonstrated excellent microsomal stability with no inhibitory activity towards undesired CYPs. FT-1518 showed high sustained tumor exposure and target Inhibition in a single oral dose xenograft model. FT-1518 depicted very good growth inhibitory activity across a large panel of hematologic and solid tumor cell lines with most activities falling into low nanomolar range. mTOR kinase inhibition in cells, by FT-1518, resulted in more potent inhibition of the mTOR pathway biomarkers (mTORC 1 &amp; 2 biomarkers [pAkt(S473) and pS6(S240/244) or p70 S6K), no inhibition of PI3K biomarker [pAkt(T308)], and improved anti-proliferative activity as compared with rapamycin. FT-1518 exhibited dose-dependent and higher tumor growth inhibition (TGI) in multiple solid tumor xenografts compared with rapalogs and is poised to enter the clinic with a favorable toxicology profile. Citation Format: Alain C. Mita, Monica M. Mita, Anthony D. William, Khalid Pasha, Chandra Siddamadappa, Kevin Zikaras, Felix T. Garzon. FT-1518, a new generation selective and potent mTORC1 and mTORC2 inhibitor: an in vitro and in vivo profile [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 137. doi:10.1158/1538-7445.AM2017-137
Abstract 3350: Cell-free DNA fragmentation patterns analyzed in over 15000 cancer patients reveal changes associated with tumor somatic mutations and result in improved sensitivity and specificity of somatic variant detection
Authors: Diana Abdueva, Helmy Eltoukhy, Darya Chudova, AmirAli Talasaz
Journal: Cancer Research (2017)

Abstract Background: Cell-free DNA (cfDNA) isolated from plasma consists of DNA fragments surviving clearance of dying cells and bloodstream trafficking. In cancer, these fragments carry the footprint of tumor somatic variation as well as its microenvironment. Since genomic distribution of cell free DNA fragments was shown to reflect nucleosomal occupancy in hematopoietic cells, we hypothesized that (a) heterogeneous patterns of cfDNA positioning would be associated with distinct mutations in patient tumors and (b) integration of fragmentation patterns into analysis would allow increased sensitivity and specificity of somatic mutation detection. Methods: cfDNA fragment length and position distributions as well as associated somatic genomic profiles of over 15,000 patients with advanced-stage clinical cancer were determined by a highly accurate, deep-coverage (15,000x) ctDNA NGS test targeting 70 genes (Guardant360). An integrative data analysis of variant-free fragmentomics domain across different driver mutations was performed to identify patterns associated with detected somatic alterations. Results: We discovered distinct classes of fragmentomics subtypes significantly enriched in samples with different genomic subtypes. An independent cohort of samples with known HER2 immunohistochemistry status was interrogated to confirm discovered association between fragmentation patterns and HER2 status. Integrating fragmentomics amplification signature with ERBB2 copy number analysis has resulted in 42% increase in the sensitivity and 7% increase in specificity of detection. Observed lung adenocarcinoma fragmentomics subtypes co-occured with mutually exclusive genomic alterations and previously described intrinsic molecular subtypes of lung cancer. Conclusions: Fragmentomics classification of cancer cfDNA provides independent evidence for observed somatic variation and underlying tumor microenviroment, leading to higher sensitivity and accuracy of variant detection. Citation Format: Diana Abdueva, Helmy Eltoukhy, Darya Chudova, AmirAli Talasaz. Cell-free DNA fragmentation patterns analyzed in over 15000 cancer patients reveal changes associated with tumor somatic mutations and result in improved sensitivity and specificity of somatic variant detection [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 3350. doi:10.1158/1538-7445.AM2017-3350
Abstract 3591: A new method to infer clonal sequences and phylogenies from personal tumor genome profiles
Authors: Sayaka Miura, Karen Gomez, Oscar Murillo, Sudhir Kumar
Journal: Cancer Research (2017)

Abstract Tumor progression involves the evolution of clonal cell populations that mutate and spread in the body. Genetic profiling has revealed the presence of extensive variation in tumor samples from individual patients. However, a tumor sample for genetic profiling is mixture of different clonal cell populations and needs to be decomposed into clonal sequences to infer the evolutionary history of the tumor. Therefore, we have developed a new method, CloneFinder, and show that the clone sequences present in each tumor sample can be accurately inferred from the analysis of multiple tumor sample profiles with our new CloneFinder method. CloneFinder is unique in its use of molecular evolutionary principles to deduce clone sequences at a single-nucleotide resolution along with their frequencies in each sample. It performs better than existing methods, which we found to produce incorrect numbers of clones, clone sequence errors, errors in clonal phylogenies, and biased estimates of cancerous cells in tumors. Application of CloneFinder to a large number of empirical datasets revealed that both early and recently evolved tumors contain ancestral clones at high frequencies. Therefore, our new method provides new insights into the clonal structure of tumors and their evolution within a personal life time. Citation Format: Sayaka Miura, Karen Gomez, Oscar Murillo, Sudhir Kumar. A new method to infer clonal sequences and phylogenies from personal tumor genome profiles [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 3591. doi:10.1158/1538-7445.AM2017-3591
Abstract 3789: Simultaneous visual assessment of RNA and protein expression in circulating tumor cells using the AccuCyte-Cytefinder system
Authors: Arturo B. Ramirez, Sarah B. Crist, Tyler Yeats, Jeffrey L. Werbin, Jackie L. Stilwell, Eric P. Kaldjian
Journal: Cancer Research (2017)

Abstract Background. Circulating tumor cells (CTCs) provide real-time information regarding patient tumor phenotype, including RNA expression. This information may be valuable in guiding care of cancer patients. Simultaneous RNA and protein assessment has been reported previously in large populations of cells. Here, we describe methods to simultaneously evaluate RNA and protein expression on rare single CTCs using the AccuCyte – CyteFinder system (RareCyte). Methods. To establish RNA detection in model CTCs (mCTCs), we used SkBr3 cells spiked into blood and the isolated buffy coat was processed by AccuCyte onto microscope slides. RNAscope® in-situ hybridization (ISH, Advanced Cell Diagnostics) was performed to detect Her2, UBC (positive control) and dapB (negative control) expression in mCTCs. A process to simultaneously stain for RNA and protein was then developed to allow identification of mCTCs by protein expression of cytokeratin (CK) and EpCAM and measurement of gene expression with RNAscope. Various blood collection tubes were tested to measure gene expression, protein expression, and cell recovery up to 48 hours after blood draw. Image analysis software was developed to automatically analyze and count RNA dot number from 40x z-stack images of mCTCs. Finally, clinical samples were stained with the combined RNA/protein assay. Results. Using RNAscope, Her2 and UBC expression could be detected in all SkBr3 cells and was negative in surrounding white blood cells (WBC). Using blood collected into EDTA tubes and processed immediately after spike-in, there were an average of 29 Her2 mRNA dots and 20 UBC dots/cell; negative control dapB gave 1 dot/cell. Using CK and EpCAM expression for mCTCs identification, recovery of mCTCs was over 95%. The RNA/protein assay was compared using blood collected and stored in EDTA, CellSave®, Cell-Free DNA®, Cell-Free RNA®, Cyto-Chex®, and RareCyte BCT tubes. At 48 hours, Cell-Free RNA tubes had the highest number of RNA dots/cell – about half as many dots/cell compared to fresh EDTA samples. Clinical samples were successfully stained with the RNA/protein assay. Conclusions. We have developed a protocol that identifies rare mCTCs using protein staining, and measures RNA expression by RNAscope ISH. This assay may be a useful clinical tool for the real-time investigation of CTC gene expression in cancer patients. Citation Format: Arturo B. Ramirez, Sarah B. Crist, Tyler Yeats, Jeffrey L. Werbin, Jackie L. Stilwell, Eric P. Kaldjian. Simultaneous visual assessment of RNA and protein expression in circulating tumor cells using the AccuCyte-Cytefinder system [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 3789. doi:10.1158/1538-7445.AM2017-3789
Abstract 2133: Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent
Authors: Joseph A. Reddy, Melissa Nelson, Christina Dircksen, Theresa Johnson, Marilynn Vetzel, Spencer Hahn, Longwu Qi, Iontcho Vlahov, Christopher Leamon
Journal: Cancer Research (2017)

Abstract Folate receptor (FR) targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety . This agent was found to be extremely potent with an in vitro IC50 ~ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (300 nmol/kg) using a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. Complete responses were also observed in other FR-positive drug resistant (paclitaxel and cisplatin) models. When evaluated against FR-positive PDX models of ovarian, endometrial and triple negative breast (TNBC) cancers, EC2629 showed significantly greater anti-tumor activity than EC1456 or standard of care (SOC) treatments. Taken together, these studies demonstrated that EC2629 with a distinct DNA reacting mechanism has significant anti-tumor growth activity in numerous models, including those which were drug resistant, thus lending support to our planned clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Melissa Nelson, Christina Dircksen, Theresa Johnson, Marilynn Vetzel, Spencer Hahn, Longwu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent [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 2133. doi:10.1158/1538-7445.AM2017-2133