tbuckley/cabot-search huggingface dataset:
Abstract LB-067: Cargocytes: A novel cell therapy platform to drive anti-tumor immunity
Authors: Richard L. Klemke, Huawei Wang, Bei Liu, Christina Alarcon, Felicia Watson
Journal: Cancer Research (2019)

Abstract Adoptive cell therapy has emerged as a powerful new tool to treat cancer and other diseases. However, the clinical utility of many cell-based therapies is limited by inadequate production of therapeutic factors, production of unwanted factors, unwanted engraftment into the tumor, and poor controllability resulting in poor pharmacokinetics. Genetic and bioengineering strategies can overcome many limitations, but modification of genomic DNA or the introduction of new genetic material into therapeutic cells raises substantial safety concerns, ultimately making FDA approval difficult. To address these limitations, we developed a novel platform for cell-based therapies in which any cell type, including immortalized cells, can be extensively engineered and loaded with therapeutic cargo, and then rendered safe for patient administration through removal of the nucleus. Enucleated cells (Cargocytes) retain many desired biologic functions (endogenous and engineered), such as viability up to 72 hours, retention of cell surface markers/proteins, secretion of bioactive molecules, robust in vitro and in vivo chemotaxis, and delivery of a wide range of cancer-fighting cargos. Using this technology, we demonstrate that Cargocytes derived from hTERT-immortalized mesenchymal stem cells (hTERT MSCs) and engineered to express therapeutic levels of IL-12 can potently activate an anti-tumor immune response in a preclinical mouse model of triple negative breast cancer. hTERT MSC-derived Cargocytes robustly delivered IL-12 to the tumor with definable pharmacokinetics, activated known IL-12 biomarkers, and induced infiltration of tumor-fighting immune cells that inhibited tumor growth and improved animal survival. In addition, co-administration of Cargocytes secreting IL-12 and anti-PD-L1 antibodies further improved animal survival without notable adverse events. Collectively, our findings indicate that Cargocytes provide a new means to deliver powerful immunomodulatory biologics to malignant tumors in a safe and controllable manner. The genetic tractability and excellent safety profile of the Cargoycte platform enables bioengineering of a wide range of designer therapeutics derived from genetically modified cells, immortalized stem cells, and even cancer cells, each with improved clinically relevant functions. Citation Format: Richard L. Klemke, Huawei Wang, Bei Liu, Christina Alarcon, Felicia Watson. Cargocytes: A novel cell therapy platform to drive anti-tumor immunity [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 LB-067.
Long-Term Survival and Late Deaths After Hematopoietic Stem Cell Transplantation for Primary Immunodeficiency Diseases and Inborn Errors of Metabolism.
Authors: Mary Eapen, Kwang Woo Ahn, Paul Orchard, Morton Jerome Cowan, Stella M. Davies, Anders Fasth, Anna Hassebroek, Mouhab F. Ayas, Carmem Bonfim, Tracey O'Brien, Thomas Gross, Mary M. Horowitz, Mitchell Horwitz, Edwin M. Horwitz, Neena Kapoor, Joanne Kurtzberg, Navneet S. Majhail, Olle Ringden, Paul Szabolcs, Paul A. Veys, K. Scott Baker
Journal: Blood (2009)
Abstract 3519: High-throughput unbiased microwell-based single-cell CNV detection reveals tumor clonal subtypes in hepatocellular carcinoma
Authors: Liang Wu, Yuzhou Wang, Miaomiao Jiang, Shiping Liu
Journal: Cancer Research (2019)

Abstract Single-cell genomics is critical for understanding cellular heterogeneity in cancer, but existing DNA amplification and library preparation methods are expensive and introduce coverage bias during sample pre-amplification. Based on a massively parallel 5184-microwell chip, we developed a high-throughput unbiased single-cell DNA library preparation approach up to 1800 cells for copy number variation (CNV) detection, which provides a comprehensive, scalable solution for revealing genome heterogeneity. Compared with existing methods, it is more efficient and cost-effective to construct a barcoded-single-cell library without pre-amplification in 2 days. Besides, it has significantly lower Median Absolute Pairwise Difference (MAPD:0.17±0.004) values which are used to evaluate the amplification biases and noises, than using MDA (multiple displacement amplification) method (MAPD: 0.79±0.23) or MALBAC (multiple annealing and looping-based amplification cycles) approach (MAPD : 0.24±0.002). We further successfully applied this approach to obtain single-cell CNV information of more than 500 cells from a tumor sample of hepatocellular carcinoma in one run. Using the unsupervised clustering, we identified at least two clonal subpopulations with a multitude of non-integer alterations across the genome. Overall, this is an unbiased, effective, high-throughput and low cost approach to figure out tumor heterogeneity and understand clonal evolution in tumor at the single-cell level. Citation Format: Liang Wu, Yuzhou Wang, Miaomiao Jiang, Shiping Liu. High-throughput unbiased microwell-based single-cell CNV detection reveals tumor clonal subtypes in hepatocellular carcinoma [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 3519.
Re: Fabian Lohaus, Klaus Zöphel, Steffen Löck, et al. Can Local Ablative Radiotherapy Revert Castration-resistant Prostate Cancer to an Earlier Stage of Disease? Eur Urol 2019;75:548–51
Authors: Piet R. Dirix, Carole Mercier, Luc Y. Dirix
Journal: European Urology (2019)
Abstract 5302: Interplay of Parkin, a 'tumor suppressor’ in metabolic deregulation of cancer
Authors: Zafar I. Bhat, Khalid Imtiyaz, M. Moshahid Rizvi
Journal: Cancer Research (2019)

Abstract Cancer is a disease of uncontrolled proliferation which initially arises as a result of dysregulation in some gene candidates responsible for maintaining a normal cellular state. Some genes are suppressed with a concomitant increase in the expression of certain dormant ones. The former group constitutes the tumor suppressors while as the later- the oncogenes. Parkin a PARK 2 gene product is a potent tumor suppressor, has been well reported to be down regulated in many cancer types. Besides its tumor suppressor role, it regulates the redox state of the cell and recently it was reported to be an important factor in TP53 (a master tumor suppressor protein) mediated tumor suppression provides a clue about the role of Parkin in metabolic deregulation- an emerging hallmark of cancer! To this end, here we present that how Parkin is regulated under different environmental conditions and how it governs metabolic plasticity- glycolytic phenotype and hence cellular migration. To conclude, the results show that Parkin differentially regulates metabolism by modulating certain potent marker candidates responsible for Warburg effect and associated carcinogenesis. [MMA Rizvi is the corresponding author for this work.] Note: This abstract was not presented at the meeting. Citation Format: Zafar I. Bhat, Khalid Imtiyaz, M. Moshahid Rizvi. Interplay of Parkin, a 'tumor suppressor’ in metabolic deregulation of 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 5302.
Abstract 4792: Azetidine functionalized small-molecules potently inhibit STAT3 signaling and block tumor growth in human breast cancer xenografts
Authors: Peibin Yue, Francisco Lopez-Tapia, Wenzhen Fu, Christine Brotherton-Pleiss, Marcus Tius, James Turkson
Journal: Cancer Research (2019)

Abstract The development of inhibitors of Signal transducer and activator of transcription (STAT) 3 for clinical application has faced significant challenges and to date there are no suitable STAT3 small molecule inhibitors in the clinic. We report a novel class of azetidine-based small molecules that potently and preferentially inhibit STAT3 DNA-binding activity in vitro, with IC50 of 300-800 nM, compared to IC50 of 17 μM or higher against STAT1 DNA-binding activity. In the human breast cancer MDA-MB-231 and MDA-MB-468 cells treated with the azetidine compounds, including H182, constitutive STAT3 DNA-binding activity and tyrosine phosphorylation were strongly inhibited in both time- and dose-dependent manner. By contrast, the azetidine compounds showed little effects on EGF-induced STAT1 activity, Ras-Raf-MEK-ERK or other STAT3-independent signaling pathways, or on other SH2 domain-containing proteins. Furthermore, H182 and other azetidine compounds strongly inhibited viability, anchorage-dependent and -independent growth, and colony survival of the human breast cancer cells, with IC50 of 1.0 - 1.9 μM, compared to the IC50 of 3.8 - 8.1 μM against the viability and growth of the immortalized breast epithelial MCF-10A cells. The migration of breast cancer cells in vitrowere similarly inhibited by treatment with low concentrations of H182 for 18 h, without changes in viable cell number. Analysis of STAT3 downstream genes show that the expression of VEGF and survivin were significantly suppressed in breast cancer cells treated with the azetidine compounds. In vivo evaluation of antitumor efficacy shows H182 inhibited growth of human breast tumor xenografts. Studies together identify the azetidine-functionalized small molecules as potential candidate compounds for clinical development as novel therapeutic agents for human breast and other cancers that harbor aberrantly-active STAT3. Citation Format: Peibin Yue, Francisco Lopez-Tapia, Wenzhen Fu, Christine Brotherton-Pleiss, Marcus Tius, James Turkson. Azetidine functionalized small-molecules potently inhibit STAT3 signaling and block tumor growth in human breast cancer xenografts [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 4792.
Abstract 3966: Combined Rho-kinase inhibition and immunogenic cell death triggers and propagates immunity against cancer
Authors: In-San Kim, Gi Beom Kim, Gi-Hoon Nam, Yeonsun Hong
Journal: Cancer Research (2019)

Abstract Activation of T-cell immune response is critical for the therapeutic efficacy of cancer immunotherapy. Current immunotherapies have shown remarkable clinical success against several cancers; however, significant responses remain restricted to a minority of patients. Here, we show a therapeutic strategy that combines enhancing the phagocytic activity of antigen-presenting cells with immunogenic cell death to trigger efficient antitumour immunity. Rho-kinase (ROCK) blockade increases cancer cell phagocytosis and induces antitumour immunity through enhancement of T-cell priming by dendritic cells (DCs), leading to suppression of tumour growth in syngeneic tumour models. Combining ROCK blockade with immunogenic chemotherapy leads to increased DC maturation and synergistic CD8+ cytotoxic T-cell priming and infiltration into tumours. This therapeutic strategy effectively suppresses tumour growth and improves overall survival in a genetic MMTV/Neu tumour model. Collectively, these results suggest that boosting intrinsic cancer immunity using immunogenic killing and enhanced phagocytosis is a promising therapeutic strategy for cancer immunotherapy. Citation Format: In-San Kim, Gi Beom Kim, Gi-Hoon Nam, Yeonsun Hong. Combined Rho-kinase inhibition and immunogenic cell death triggers and propagates immunity against 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 3966.
Abstract LB-259: FGFR- and EGFR-driven SHP2 activation displays differential sensitivity to allosteric SHP2 inhibition
Authors: Huaixiang Hao, Hengyu Lu, Chen Liu, Matthew LaMarche, Jeffrey A. Engelman, Peter S. Hammerman, Giordano Caponigro
Journal: Cancer Research (2019)

Abstract Introduction: The non-receptor protein tyrosine phosphatase SHP2 mediates RAS activation downstream of various receptor tyrosine kinases (RTKs). Cancer cell lines dependent on RTK signaling are generally sensitive to SHP2 genetic knockdown but differ widely in their sensitivity to allosteric SHP2 inhibitors such as SHP099. A recent report suggested that FGFR can drive resistance to MAPK inhibitors independently of SHP2. We sought to understand the molecular basis of differential sensitivity to allosteric SHP2 inhibitors when SHP2 is activated by different RTKs, particularly FGFR versus EGFR. Experimental procedures: We profiled a panel of cancer cell lines driven by various wild-type FGFR activation (receptor amplification or autocrine ligand mediated) for their sensitivity to SHP099 and characterized MAPK pathway inhibition at various time points and SHP099 doses, in comparison with EGFR-driven cell lines. We also compared the inhibitory effects of SHP099 on FGFR- and EGFR-mediated pathway feedback activation in response to MEK inhibitor treatment. Results: We find FGFR-driven cell lines are often more resistant to SHP099 compared to EGFR-driven cell lines. Those SHP099-resistant FGFR-driven cell lines were sensitive to SHP2 knockdown and SHP099 inhibited p-ERK in those cells at earlier time points. However, p-ERK quickly rebounded after SHP099 treatment, which was not observed with FGFR inhibitors and can be attenuated with high concentrations of SHP099. Consistently, FGFR-driven MAPK pathway feedback activation following treatment with MEK inhibitor was also more resistant to SHP099 compared to EGFR-driven feedback activation. Additional studies are being performed in isogenic cell lines for direct comparison. Conclusions: Our findings suggest that many FGFR-driven cell lines are dependent on SHP2 but are intrinsically resistant to allosteric SHP2 inhibition, compared to EGFR-driven cell lines. FGFR-driven cells tend to have a quick p-ERK rebound following initial pathway inhibition by SHP099, which is mediated by the feedback activation of FGFR. The feedback activated FGFR likely efficiently promotes the open conformation of SHP2 and causes resistance to allosteric SHP2 inhibitors. For certain FGFR-driven cancers, SHP2 inhibitor combinations such as with MAPK inhibitors might be needed for sustained efficacy. Citation Format: Huaixiang Hao, Hengyu Lu, Chen Liu, Matthew LaMarche, Jeffrey A. Engelman, Peter S. Hammerman, Giordano Caponigro. FGFR- and EGFR-driven SHP2 activation displays differential sensitivity to allosteric SHP2 inhibition [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 LB-259.
Abstract 3075: Antitumor activity of M8891, a potent and reversible inhibitor of methionine aminopeptidase 2
Authors: Manja Friese-Hamim, Olga Bogatyrova, Maria J. Ortiz, Dirk Wienke, Timo Heinrich, Felix Rohdich, Klaus Duecker, Christoph Schultes, Bayard Huck, Frank T. Zenke, Andree Blaukat
Journal: Cancer Research (2019)

Abstract N-terminal cleavage of methionine by methionine aminopeptidases is a crucial step in the maturation of proteins during protein biosynthesis. MetAP2, one of the two methionine aminopeptidases expressed in mammalian cells, has been identified as the target of the highly potent and irreversible inhibitor fumagillin to which antiangiogenic and antitumoral properties have been ascribed. This and other findings support the rationale to develop MetAP2 inhibitors for cancer therapy. The fumagillin derivative TNP-470 has been evaluated in several clinical trials, but development was discontinued following demonstration of unfavorable pharmacokinetics and side effects likely attributed to the reactivity of the compound. We have developed M8891, an orally bioavailable, potent, and reversible inhibitor of MetAP2. M8891 inhibited growth of primary endothelial cells as well as patient-derived tumor cells and demonstrated antiangiogenic and antitumoral activity in mouse models. Accumulation of an unprocessed MetAP2 substrate, methionylated elongation factor 1 α, Met-EF1a, was observed upon treatment with M8891 in vitro as well as in vivo confirming that MetAP2 can be effectively inhibited with this compound. In combination with sunitinib, M8891 demonstrated strong and durable antitumor activity in a cohort of patient-derived renal cancer xenografts at well-tolerated exposure levels. Predictive biomarker hypotheses generated from CRISPR sensitivity/resistance screens as well as analyses of molecular profiling data from PDX tumors are currently being evaluated in further nonclinical studies. A dose-escalation phase 1 study in patients with advanced solid tumors is currently ongoing. Citation Format: Manja Friese-Hamim, Olga Bogatyrova, Maria J. Ortiz, Dirk Wienke, Timo Heinrich, Felix Rohdich, Klaus Duecker, Christoph Schultes, Bayard Huck, Frank T. Zenke, Andree Blaukat. Antitumor activity of M8891, a potent and reversible inhibitor of methionine aminopeptidase 2 [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 3075.
Abstract 4370: Knockdown of PKM2 induces autophagic cell death via Akt/mTOR pathway in human prostate cancer cells
Authors: Prasanta Dey, Amit Kundu, Byung Mu Lee, Hyung Sik Kim
Journal: Cancer Research (2019)

Abstract Pyruvate kinase M2 (PKM2) is crucial for aerobic glycolysis that is highly expressed in the various cancer tissues. Although high expression of PKM2 is observed in prostate tumor tissues, its functional role against affecting cancer metabolism is not clearly understood. Herein, we investigate its role in regulating autophagy and its associated pathways. In the current study, various PKM2-siRNA constructs were used to knockdown the PKM2 expression and observed its cellular pathways on autophagy. Cell viability was significantly reduced in PKM2-siRNA transfected prostate cancer cells, DU145. Acridine orange staining and immunoblotting analysis showed that downregulation of PKM2 markedly increased autophagy cell death. In addition, immunoblotting analysis exhibited the blocking the protein kinase B (Akt) and mTOR1 pathways, which subsequently down-regulated the expression of glycolytic enzymes lactate dehydrogenase A (LDHA) and Glucose transporter 1 (GLUT1). To the best of our knowledge, this is the first study that inhibition of PKM2 changes in cancer cell metabolism and induces autophagy, thus, providing new perspectives into the mechanism of its anticancer activity against prostate cancer, DU145. Citation Format: Prasanta Dey, Amit Kundu, Byung Mu Lee, Hyung Sik Kim. Knockdown of PKM2 induces autophagic cell death via Akt/mTOR pathway in human prostate cancer cells [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 4370.
Access to care and patient satisfaction for surgically-treated breast cancer
Authors: G. A. Porter, J. M. Murdoch, K. M. Inglis, P. J. Veugelers
Journal: Journal of Clinical Oncology (2007)

17010 Background: Although recent studies have described timeliness of breast cancer (BC) care and its impact on outcomes, there is little data on patient perception of timeliness. This study examined the association between clinicodemographic factors, timeliness and patient satisfaction for surgically-treated BC patients across defined intervals of diagnosis (Dx) and treatment. Methods: All patients undergoing surgery for primary BC within a single Health District over 24 months were enrolled in a prospective consecutive cohort study. A comprehensive, standardized method of ascertaining specific time intervals, including a patient interview, was used to quantify the timeliness of presentation, Dx and treatment. A validated satisfaction questionnaire was applied to patients 2 weeks after surgery, and following chemotherapy. Multiple linear regression, using the natural logarithm of the time interval as the dependant variable, was performed to examine the association of factors and satisfaction with specific time intervals. Results: Among the 519 patients in the study, 317 (61%) were screen-detected and 202 (39%) presented symptomatically. Complete satisfaction questionnaire responses were obtained in 348 (67%). The median time intervals in days (interquartile range) were: abnormal screen to Dx - 33 (21–48); symptoms to Dx 44 (23–97); Dx to surgery - 31 (22–43); surgery to adjuvant chemotherapy 63 (49–73). On multivariate analysis, the interval from presentation (either abnormal mammogram or symptoms) to Dx was 33% longer for screen-detected patients (p&lt;0.0001) and 38% longer for patients where more than one diagnostic test was performed (p=0.009). Moderate correlation was identified between patient satisfaction and both the intervals from presentation to Dx (r 2 =0.212;p&lt;0.0001) and from Dx to surgery (r 2 =0.262;p&lt;0.0001). Controlling for the length of these intervals, younger women (p=0.01) and those with a Dx made via screening (p=0.004) had significantly lower satisfaction scores. Conclusions: The timeliness of care for BC involves several defined components; variations in the relatively short interval from Dx to surgery appeared to have most impact on patient satisfaction. Younger women and those diagnosed via screening were less satisfied with their access to timely care. No significant financial relationships to disclose.