tbuckley/cabot-search huggingface dataset:
Thrombosis and Inflammation Are Coupled by a Common Thioredoxin Reductase Pathway Downstream of the P2×7 Receptor.
Authors: Andrea S Rothmeier, Christian Furlan-Freguia, Brian G. Petrich, Patrizia Marchese, Zaverio M. Ruggeri, Mark H. Ginsberg, Wolfram Ruf
Journal: Blood (2012)
Abstract 3536: Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model
Authors: Marc T. Abrams, Junyan Tao, Shanthi Ganesh, Wendy Cyr, Bo Ying, Martin Koser, Rokhand Arvan, Girish Chopda, Hank Dudek, Cheng Lai, Weimin Wang, Bob Brown, Satdarshan Monga
Journal: Cancer Research (2015)

Abstract Hepatoblastoma (HB), the commonest pediatric liver tumor is frequently associated with an N-terminal deletion in the CTNNB1 gene, which encodes stable β-catenin and promotes nuclear localization and transactivation activity. In 80% of patients, nuclear localization of β-catenin and Yes Associated Protein (YAP), a Hippo-related transactivator, is seen together. Further, stable hepatic co-expression of Δ90-CTNNB1 and active-YAP in mice causes rapid and aggressive HB. Dicer-substrate siRNAs (DsiRNAs) are potent RNA interference (RNAi) triggers that that are efficacious in preclinical tumor models of diverse origin, and are currently under clinical evaluation. To determine if CTNNB1-targeting DsiRNAs have potential as a therapy in HB, we encapsulated this oligonucleotide payload into lipid nanoparticles (LNPs), and systemically administered into mice bearing CTNNB1/YAP-induced HB. The LNP platform used, termed EnCore (because of its specific Envelope and Core lipid components), enables high encapsulation efficiency, long-term stability, and consistent analytical criteria. Downstream of LNP-mediated DsiRNA delivery, both qPCR and in situ hybridization were used to visualize changes in CTNNB1 expression in both tumor and normal liver. Robust and specific silencing of CTNNB1 mRNA was achieved in the tumors. The distribution of mRNA knockdown within each tumor nodule suggests efficient extravasation and internalization of the LNP and its payload into the tumor parenchyma, in contrast to previous reports of vascular-channel limited nanoparticle accumulation in tumors. Intriguingly, a “liver-centric” LNP formulation, which delivers cargo efficiently to a normal liver due to rapid hepatic extraction and apolipoprotein-mediated internalization, was inactive in the tumors. Further evaluation demonstrated efficacy of β-catenin targeting in this model. In conclusion, we report a highly relevant modality of RNAi delivery in a mouse model of hepatoblastoma to target a classically-undruggable oncogene. Citation Format: Marc T. Abrams, Junyan Tao, Shanthi Ganesh, Wendy Cyr, Bo Ying, Martin Koser, Rokhand Arvan, Girish Chopda, Hank Dudek, Cheng Lai, Weimin Wang, Bob Brown, Satdarshan Monga. Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3536. doi:10.1158/1538-7445.AM2015-3536
Decrease of Mortality during Deferiprone Treatments: Results from A Large Randomised Cohort of Thalassemia Major Patients Under the Auspices of the Italian Society for Thalassemia and Hemoglobinopathies
Authors: Aurelio Maggio, Angela Vitrano, Marcello Capra, Liana Cuccia, Francesco Gagliardotto, Aldo Filosa, Carmelo Magnano, Michele Rizzo, Vincenzo Caruso, Calogera Gerardi, Crocetta Argento, Saveria Campisi, Rosario Cantella, Francesca Commendatore, Domenico Giuseppe D’Ascola, Carmelo Fidone, Angela Ciancio, Marika Galati, Gaetano Giuffrida, Giovanni Giugno, Turi Lombardo, Luciano Prossomariti, Roberto Malizia, Anna Meo, Gaetano Roccamo, Maria Antonietta Romeo, Pietro Violi, Paolo Rigano, Paolo Cianciulli
Journal: Blood (2008)
285. Exploring On-Target Hematopoietic Toxicity With Highly Potent, High Affinity FRβ-Specific CAR T Cells for AML
Authors: Rachel C. Lynn, Mathilde Poussin, Yang Feng, Keith Schutsky, Anna Kalota, Philip S. Low, Dimiter S. Dimitrov, Daniel J. Powell
Journal: Molecular Therapy (2015)

On-target, off-tumor recognition of antigen in normal tissues is one of the largest safety concerns in chimeric antigen receptor (CAR) T cell therapy. Careful assessment of target protein expression by flow cytometry or IHC can provide helpful data for prediction of potential toxicity. However, high affinity reagents should be carefully chosen in order to assure the most sensitive and thorough investigation of target antigen levels, which may be low in normal tissues. We are currently optimizing our folate receptor beta (FRβ)-directed CAR T cell platform for acute myeloid leukemia (AML) and have isolated a high affinity antibody single-chain-variable fragment (scFv) for production of CAR T cells. The high affinity (m923, 2.48nM KD) CAR T cells exhibited greatly enhanced reactivity against FRβ(+) AML in vitro and in vivo compared to previously generated lower affinity (m909, 54.3nM KD) FRβ-specific CAR T cells. However, higher affinity reagents pose the potential for increased risk of toxicity directed against normal tissues. To most accurately predict m923 CAR T cell toxicity, we utilized high affinity m923 IgG for analysis of FRβ expression in normal hematopoietic tissues by flow cytometry. We were able to detect high levels of FRβ in peripheral blood monocytes as well as low levels in myeloid-lineage bone marrow progenitor cells which were non-detectable using m909 IgG. Notably, CD34(+) bone marrow hematopoietic stem cells (HSCs) displayed very low expression of FRβ and m923 CAR T cells did not inhibit HSC colony formation in classic CFU assays. We next examined the ability of m923 CAR T cells to target whole bone marrow populations. Upon co-culture, m923 CAR T cells were able to eliminate FRβ(+) myeloid progenitors while sparing neighboring FRβ(-) bone marrow cells. We hypothesized that, because high affinity FRβ-specific CAR T cells did not impact bone marrow HSCs and non-myeloid-committed progenitors, short-term treatment with CAR T cells may allow for tumor clearance, following which any affected myeloid populations could be reconstituted from healthy HSCs. Therefore, we investigated transient expression via mRNA electroporation of the m923 CAR platform. mRNA-CAR T cells retained effective anti-tumor activity. Our results highlight the importance of antibody affinity for assessment of target protein during CAR development. In addition, we report a highly potent, high affinity FRβ-specific CAR T cell platform that does not target HSCs, and, when delivered transiently through mRNA electroporation, could allow for AML tumor destruction while providing a decreased risk for long-term myeloid toxicity.
Abstract 2583: Refinement of inhibitors of the KRAS-signaling naocluster protein, CNKSR1, that block oncogenic KRAS signaling and growth
Authors: D. Lynn Kirkpatrick, Martin Indarte, Mike Scott, Assael Madrigal, Geoffrey Grandjean, Garth Powis
Journal: Cancer Research (2015)

Abstract Introduction: KRAS, the predominant form of mutated RAS (mut-KRAS), is found in ∼25% of patient tumors across many cancer types and plays a critical role in driving tumor growth and resistance to therapy. CNKSR1 (connector enhancer of kinase suppressor of Ras 1) a protein associated with KRAS in the RAS membrane signaling nanocluster and we have shown it is critical for mut-KRAS but not wild type (wt)-KRAS signaling and cell proliferation. CNKSR1 is a multi-domain protein with a pleckstrin homology (PH) domain, which we have exploited to discover inhibitors that selectively inhibit mut-KRAS tumor growth. The initial leads identified were found to inhibit mut-KRAS signaling and growth of mut-KRAS isogenic NSCLC cell lines (IC50 ∼ 30 μM) and compound refinement provided PHT-7390 and 7391 (IC50 5 to 10 μM). Importantly, they did not block the growth of wt-KRAS cell lines at concentrations up to 100 μM. In mice the agents had antitumor activity againsta mut-KRAS xenograft model and improved the activity of EGFR inhibitors without observable toxicity, but had poor pharmacokinetic properties.Methods: PHusis has used its in silico computational modeling of the PH-domain of CNK1 to optimize its lead inhibitors to improve potency and pharmacokinetic properties. In silico compound refinement has been paired with surface plasmon resonance spectroscopy (SPR) and in vitro cell line screening to provide the latest panel of highly potent CNK1 inhibitors that are moving toward late preclinical development. Results: A panel of analogues of PHT-7390 and 7391 were synthesized with the aim of improving potency and pharmacokinetic properties. This structural optimization yielded several analogues with up to 100 fold greater potency than PHT-7390 to mut-KRAS NSCLC lines (IC50 10-100 nM) while retaining the differential in effect against wt-KRAS lines without activity up to 100 μM. Target engagement studies have shown that the agents inhibit mut-KRAS signaling in similar fashion as KRAS knockdown with siRNA, confirming on target effects in cells. Pharmacokinetic properties were also improved and agents have moved to clinical candidate selection. Conclusion: Potent and specific inhibitors of CNK1 PH-domain with improved pharmacokinetics have been identified. These novel PH-domain inhibitors now provide a therapeutic potential for patients with oncogenic KRAS for which there is currently no effective therapy. Citation Format: D. Lynn Kirkpatrick, Martin Indarte, Mike Scott, Assael Madrigal, Geoffrey Grandjean, Garth Powis. Refinement of inhibitors of the KRAS-signaling naocluster protein, CNKSR1, that block oncogenic KRAS signaling and growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2583. doi:10.1158/1538-7445.AM2015-2583
Peripheral Tolerance to PR1 Is Maintained After Uptake of Soluble Proteinas-3 and Neutrophil Elastase
Authors: Gheath Alatrash, Yoko Ono, Anna Sergeeva, Pariya Sukhumalchandra, Mao Zhang, Kathryn Quintanilla, Paul Armistead, Hong He, Tania Rodriguez-Cruz, Karen Clise-Dwyer, Eric Wieder, Greg Lizee, Sijie Lu, Jeffrey J. Molldrem
Journal: Blood (2010)
Abstract B69: Tuft cell signaling can induce pancreatic inflammation and promote pancreatic ductal adenocarcinoma
Authors: Megan T. Hoffman, Shan Gao, Howard Crawford
Journal: Cancer Research (2016)

Abstract The tuft cell is a chemosensory cell type that can interpret signals from luminal surfaces throughout the body in order to activate downstream effectors. One clear effector pathway of the tuft cell promotes a type-two immune response in the intestine after parasitic infection, suggesting that this cell population has the ability to communicate with the immune system. Furthermore, tuft cells have also been shown to activate sensory nerve fibers to lead to the production of a neuroinflammatory signal in the nasal epithelium. Therefore, tuft cells can promote effector inflammatory responses through direct immune cell signaling and through sensory nerve fibers. Pancreatic ductal adenocarcinoma (PDA) is characterized by a robust stromal reaction, a large component of which is composed of an immune response. It has been previously studied that this inflammatory response can function to promote both the initiation and progression of PDA. One mechanism by which inflammatory cells can be recruited to the pancreas is through neuroinflammatory pathways. Work with collaborators has shown that pancreatic sensory neurons are required for the progression of PDA, as ablation of this cell type significantly prolongs survival. Interestingly, tuft cells in the metaplastic pancreas have been shown to appear during transdifferentiation and progression to PDA. These tuft cells also possess key signaling elements that have the potential to mediate the response to extracellular signals, such as α-gustducin and TRPM5. Metaplastic tuft cells also produce the proteins necessary to make or release prostaglandins, acetylcholine and ATP, all of which can stimulate either a direct immunomodulatory signal or activate sensory nerve fibers. This leads us to hypothesize that tuft cells are a key mediator of signals to the stromal immune compartment and to sensory neurons in order to promote a robust immune response. In order to answer this question we are using chemosensory knockout animals to ablate critical signaling components of the chemosensory cascade to study the progression of PDA. Citation Format: Megan T. Hoffman, Shan Gao, Howard Crawford.{Authors}. Tuft cell signaling can induce pancreatic inflammation and promote pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B69.
Abstract 2418: A comparison of NVP-AUY-922 (AUY) and Geldenamycin (G) in human tumor primary culture microspheroids
Authors: Robert Alan Nagourney, Paula J. Bernard, Federico Francisco, Meghan Cule, Ryan Wexler, Steven S. Evans
Journal: Cancer Research (2015)

Abstract Introduction: Molecular chaperone heat shock protein 90 (HSP 90) maintains the stability and function of client proteins essential for malignant transformation. The ansamycin Geldenamycin (G) and its derivative 17-AAG are potent HSP90 inhibitors with activity observed in human tumors. The resorcinol-based HSP90 inhibitor AUY offers advantages with regard to solubility &amp; DT-diaphorase independence. To evaluate and compare the activity of AUY &amp; G we conducted ex vivo analysis of programmed cell death (EVA/PCD™) on microspheroids isolated from fresh human tumor specimens. Methods: The EVA/PCD™ method as previously reported (Nagourney, RA Anticancer Res. 2012) isolates microspheroids of desired size by mechanical &amp; enzymatic disaggregation followed by precise density centrifugation. Drug activity is measured by delayed loss of membrane integrity &amp; ATP content (luciferase). Lethal concentration (LC50) values are interpolated from 5-point dose response curves and compared by modified Z-Score. Concentrations ranges for AUY were 6.25-100 uM and for G 1.25-20 uM. Results: AUY and G activity compared in 22 parallel analyses by Pearson Moment revealed a correlation coefficient R = 0.59 (p &amp;lt;0.005). Activities for AUY &amp; G by disease were generally similar favoring Heme &amp;gt;Sarcoma &amp;gt;Melanoma &amp;gt;Ovary&amp;gt;NSCLC&amp;gt;Breast. ERBB2 (+) breast appeared more sensitive as did several EGFr mutation (+) NSCLC specimens. Metachronous assays conducted in 3 EGFr (+) NSCLC pts revealed activity for G following Erlotinib failure. Additional studies with AUY alone and in combination are underway. Conclusions: i) HSP-90 inhibitors are active in human tumor primary cultures ii) AUY and G activity correlate iii) HSP90 inhibitor activities reveal disease &amp; patient-specific profiles iv) EVA/PCD™ analyses could facilitate the development of clinical strategies for the use of HSP90 inhibitors. Supported by The Vanguard Cancer Foundation &amp; The Nagourney Institute. NVP-AUY-922 was the kind gift of Novartis AG. Citation Format: Robert Alan Nagourney, Paula J. Bernard, Federico Francisco, Meghan Cule, Ryan Wexler, Steven S. Evans. A comparison of NVP-AUY-922 (AUY) and Geldenamycin (G) in human tumor primary culture microspheroids. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2418. doi:10.1158/1538-7445.AM2015-2418
Investigation of predictive biomarkers for R1507, an anti-IGF1R antibody, in patients with advanced non-small cell lung cancer with progression after first-line chemotherapy.
Authors: K. Habben, P. Delmar, C. M. Brownstein, W. Koehler, K. Kuenkele, O. Splesis, S. S. Ramalingam, J. A. Engelman, D. Chen
Journal: Journal of Clinical Oncology (2011)

7584 Background: R1507 is a monoclonal antibody which specifically inhibits IGF-IR. NO21160 was a randomized, placebo controlled phase II trial of two doses and schedules of R1507 + erlotinib as second/third-line therapy for advanced non-small cell lung cancer. The primary endpoint, comparison of PFS rate at 12 weeks, was not met (HR=0.99 for 16 mg q3W and 1.17 for 9 mg qW) in an unselected patient population. A panel of biomarkers were analyzed in an attempt to identify potential predictive markers and define a subset of the patients who may be more likely to benefit from the investigational drug. Methods: Candidate biomarkers of potential prognostic or predictive significance such as IGF-1R, free IGF1, total IGF, IGFBP-3, pAKT, PTEN, EGFR and Kras, were analyzed in archival tumor tissues collected at diagnosis and in the blood samples collected at the baseline by IHC, ELISA, qRE-PCR and mutation analysis, as appropriate. Correlation between PFS rate at 12 weeks and marker values were investigated. Results: The median IGF1R membrane H–score was 64 (range 0-300). A significantly higher PFS rate was observed in the high (>median) free IGF-1 level patients between the 16 mg/kg regimen and placebo (46% vs. 18%. HR=3.94, CI 95% 1.2-13.6). Somatic mutations of Kras gene, analyzed in 127 available tumor DNA samples, were detected in 6 (15%), 16 (36%) and 11 (26%) patients in placebo, 9 mg/kg and 16 mg/kg arms, respectively. 12.5% and 36.4% of patients with the Kras mutations in the R1507 arms, in comparison with 0% of the 6 Kras mutant patients in the placebo arm, was progression free by week 12. Within either R1507 treatment arm, however, Kras mutant and wild-type patients showed a similar PFS rate (OR=0.88). No significant impact on the treatment was observed when the PFS rates of patient subgroups defined by other biomarkers, including IGF1R level, were compared within each treatment arm and between placebo and treatment arms. Conclusions: Higher free serum IGF-1 level appears to correlate with a higher PFS rate at 12 weeks with 16 mg/kg dose of R1507. Patients with mutant Kras may be more likely to benefit from R1507+ elotinib than elotinib alone.
Abstract 3168: A role for tumor-derived CCL2 in directing leukocyte infiltration and stromal heterogeneity in pancreatic ductal adenocarcinoma
Authors: Graham M. Tooker, Whitney L. Gladney, Gregory Beatty
Journal: Cancer Research (2015)

Abstract Tumor heterogeneity within solid tumors is a recognized barrier to the efficacy of standard therapies. In pancreatic ductal adenocarcinoma (PDAC) the microenvironment is characterized by varying degrees of cytokine/chemokine production, stromal extracellular matrix, and immune cell infiltrates (Hezel et al. 2006). To investigate stromal phenotypical differences in PDAC, we have used the KrasG12D-; Trp53R172H; Pdx-1 Cre (KPC) genetically engineered mouse model which recapitulates tumor heterogeneity seen in human PDAC (Hingorani et al. 2005). Gross histological analysis of KPC tumors allowed us to stratify tumors into 2 broad groups: stromal and non-stromal. We found that stromal tumors were comprised of a significant macrophage infiltrate, whereas non-stromal tumors were generally void of macrophages. We modeled this stromal heterogeneity using tumor cell lines derived from KPC tumors. We found that, when implanted under the skin of wild-type mice, some cell lines produced stromal tumors rich in macrophages, while others formed non-stromal tumors with few macrophages within the microenvironment. Supernatant cultured from these KPC tumor cell lines in vitro revealed elevated CCL2 production, specifically in cell lines from stromal tumors. As CCL2 is a known chemo-attractant for monocytes, we hypothesized that tumor-derived CCL2 contributes to monocyte recruitment and stromal heterogeneity within the tumor microenvironment. To test this hypothesis, we have used an in vitro trans-well migration assay. With this assay, we found that more bone marrow derived cells migrate toward supernatant from stromal tumors relative to non-stromal tumors. This finding was lost in the presence of a CCL2 inhibitor. Ongoing studies are examining a role for tumor-derived CCL2 in regulating tumor-associated stroma in PDAC. Our findings suggest the importance of tumor-immune cell interactions in defining stromal heterogeneity and may offer insight into mechanisms that regulate the stromal compartment in human PDAC. Citation Format: Graham M. Tooker, Whitney L. Gladney, Gregory Beatty. A role for tumor-derived CCL2 in directing leukocyte infiltration and stromal heterogeneity in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3168. doi:10.1158/1538-7445.AM2015-3168
Winter Solstice 2016
Authors: Carol Snyder Halberstadt
Journal: JAMA (2016)

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Ruxolitinib Therapy in Myelofibrosis: Analysis of 241 Patients Treated in Compassionate Use (French “ATU” program) by the French Intergroup of Myeloproliferative Neoplasms (FIM).
Authors: Annalisa Andreoli, Jerome Rey, Charles Dauriac, Raoul Herbrecht, Franck E. Nicolini, Christian Recher, Philippe Rousselot, Jacques Delaunay, Bernard Drenou, Dana Ranta, Laurence Legros, Martine Delain, Pascale Cony-Makhoul, Jean-François Viallard, Sorin Visanica, Sophie Lefort, Brigitte Dupriez, Valérie Coiteux, Denis Guyotat, Borhane Slama, Khaled Benabed, Jean-Loup Demory, Stephane Giraudier, Damien Roos-Weil, Laurence Sanhes, Anne Quinquenel, Pascal Lenain, Valérie Ugo, Jean-Jacques Kiladjian, Lydia Roy
Journal: Blood (2012)