tbuckley/cabot-search huggingface dataset:
Abstract LB-256: PDGFRβ blockade bypasses resistance to combined MEK1/2-JAK2 inhibition in triple-negative breast cancer via intratumoral CD8+ T-cells infiltration
Authors: Murugan Kalimutho, Kum Kum Khanna
Journal: Cancer Research (2019)

Abstract Despite the increasing progress in breast cancer research, currently there is no targeted therapy available for TNBC. Here, we demonstrated a novel resistance mechanism mediated by PDGFRβ in TNBC cells. We showed that TNBC cells exposed to JAK2 or MEK1/2 inhibitors promote PDGFRβ upregulation. Using publically available databases, we found that basal-like breast cancer patients expressing high PDGFRβ exhibit poor relapse-free survival. We found that JAK2 overexpression controls PDGFRβ protein degradation. Blockade of PDGFRβ with JAK2 and MEK1/2 inhibitors significantly impacted the CD44+/CD24- stem-cell-like cells and the growth of basal-like breast cancer xenografts in vivo through intratumoral CD8+ T cells in a manner that is reversed by anti-CD8 antibody treatment. Together, these findings reveal a novel regulatory role of JAK2-mediated PDGFRβ proteolysis and provide an example of a PDGFRβ-mediated resistance mechanism upon JAK2 and MEK1/2 inhibition in TNBC. Citation Format: Murugan Kalimutho, Kum Kum Khanna. PDGFRβ blockade bypasses resistance to combined MEK1/2-JAK2 inhibition in triple-negative breast cancer via intratumoral CD8+ T-cells infiltration [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-256.
Abstract 15409: Differences in 1-Year Mortality Risk Between Survivors of ST-Segment Elevation and Non ST-Segment Elevation ACS: Insights From the EPICOR Study
Authors: Hector Bueno, Stuart Pocock, Muriel Licour, Jesús Medina, Lin Zhang, Lieven Annemans, Nicolas Danchin, Frans Van de Werf
Journal: Circulation (2013)

Background: Patients with NSTEACS show lower short-term mortality and similar or worse long-term prognosis than STEMI patients. Contemporary information on difference in prognosis between these 2 p...
Abstract 1428: Allogeneic CRISPR/Cas9 gene-edited CAR-T cells targeting CD33 show potent preclinical activity against AML cells
Authors: Brigid McEwan, Zinkal Padalia, Ashley Porras, Jason Sagert, Jonathan A. Terrett, Tony Ho, Demetrios Kalaitzidis
Journal: Cancer Research (2019)

Abstract Acute myelogenous leukemia (AML) has a high mortality rate and remains difficult to treat, making new treatment approaches critical. Chimeric antigen receptor T (CAR-T) cell therapies have shown impressive clinical responses in B-cell neoplasia. However, comparable successes have not been reported to date in myeloid malignancies, potentially due to difficulty in manufacturing efficacious CAR-T cells from AML patients and lack of a suitable tumor antigen for AML. To address these issues, we have developed allogeneic CAR-T cells from healthy donors targeting the CD33/Siglec-3 antigen, a protein expressed on most AML cells and subpopulations in the majority of AML patients at presentation and relapse. Allogeneic anti-CD33 CAR-T cells were produced from healthy donor-derived T cells using CRISPR/Cas9 gene editing. In these cells, the TRAC locus was disrupted to reduce the risk of graft versus host disease (GvHD). At the same time, a CAR construct targeting CD33 was inserted site-specifically into the TRAC locus. In addition, the beta-2-microglobulin locus was disrupted to prevent clearance of the allogeneic CAR-T cells by the host immune system. These allogeneic anti-CD33 CAR-T cells showed potent effector activity in vitro against human AML-derived cell lines, as measured by both tumor cell lysis and effector cytokine secretion. The allogeneic anti-CD33 CAR-T cells also potently reduced AML tumors in vivo in xenograft mouse models. Citation Format: Brigid McEwan, Zinkal Padalia, Ashley Porras, Jason Sagert, Jonathan A. Terrett, Tony Ho, Demetrios Kalaitzidis. Allogeneic CRISPR/Cas9 gene-edited CAR-T cells targeting CD33 show potent preclinical activity against AML 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 1428.
Abstract 198: The T3R domain of thrombospondin-1 delays tumor growth and improves tumor response to chemotherapy by remodeling the tumor vasculature
Authors: Denise Pinessi, Andrea Resovi, Lavinia Morosi, Patrizia Borsotti, Alexander Berndt, Raffaella Giavazzi, Massimo Zucchetti, Giulia Taraboletti
Journal: Cancer Research (2019)

Abstract The disorganized and inefficient nature of the tumor vasculature affects the delivery and activity of antineoplastic treatments. Certain antiangiogenic agents induce a transient normalization of tumor vessels, hence representing a promising strategy to improve the delivery and efficacy of cytotoxic therapy. Our previous studies demonstrated the antiangiogenic activity of the type III repeats (T3R) domain of thrombospondin-1 (TSP-1), a major endogenous inhibitor of angiogenesis. Aim of this study was to investigate the role of the T3R domain in tumor growth and tumor response to chemotherapy. Ectopic tumor cell expression of T3R delayed in vivo growth in two tumor models, the human ovarian carcinoma A2780-1A9 and endometrial adenocarcinoma HEC-1B. This was associated with vascular remodeling, decreased cell proliferation and increased apoptosis. T3R was active in preventing tumor growth also when expressed by the host cells (rather than the tumor cells), following pretreatment of mice with adeno-associated virus (rAAV)-T3R before tumor cell implantation. Expression of T3R also resulted in improved tumor response to paclitaxel (PTX 10 mg/kg Q4x3, i.v.) and cisplatin (DDP 4 mg/kg Q4x3, i.v.). Through the pharmacokinetic study, conducted by HPLC and MALDI imaging mass spectrometry analysis, a higher concentration and a more homogeneous drug distribution were observed in tumors expressing T3R 4h after a single administration of PTX (60 mg/kg, i.v.). This was associated with a marked reorganization of the tumor vasculature that presented decreased vessel area and vessel diameter and increased number of CD31-positive vessels. These findings indicate the ability of T3R to reduce tumor growth and improve tumor response to chemotherapy through the remodeling of tumor vasculature. This sets the basis for the development of new therapeutic strategies based on T3R to be used in combination therapies. Supported by AIRC. DP is recipient of the AIRC fellowship “Lina e Giovanni Giasini” Citation Format: Denise Pinessi, Andrea Resovi, Lavinia Morosi, Patrizia Borsotti, Alexander Berndt, Raffaella Giavazzi, Massimo Zucchetti, Giulia Taraboletti. The T3R domain of thrombospondin-1 delays tumor growth and improves tumor response to chemotherapy by remodeling the tumor vasculature [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 198.
Abstract 471: Tumor clonal status predicts clinical outcomes of non-small-cell lung cancer
Authors: Eun Young Kim, Sanghoon Lee, Arum Kim, Tae Hee Kim, Yoon Soo Chang
Journal: Cancer Research (2019)

Abstract Background: Intratumoral heterogeneity is a major cause of resistance to therapeutic agents and treatment failure. In this study, we evaluated clonal status, which reflects intratumoral heterogeneity, in non-small-cell lung cancer (NSCLC) and we discussed its clinical implications. Materials and Methods: Targeted sequencing was performed using a customized panel comprising 70 solid tumor-associated genes on samples obtained from 99 lung adenocarcinoma cases. In parallel, TCGA-LUAD cases with clinical information were extracted from the GDC data portal for validation. Clonal status was identified from the allele frequency of the mutated gene using the Maftools package. Results: We found no significant relationships with stage between the total number of mutations or the number of variants when classified according to the variant effect predictor. There was a positive correlation between the maximum primary tumor diameter and the number of clones (σ=0.2318, P-value = 0.0339). Additionally, the number of clones increased with stage (p-value= 0.0220, Kruskal-Wallis chi-squared test). Disease-free survival (DFS) was significantly shorter among cases wherein tumors comprised two or more clones than among cases in which tumors were comprised of only one clone (P-value = 0.008, Log-rank test). A multivariate model that controlled for total number of mutations, tumor stage, sex, age, and smoking indicated that the number of clones was an independent determinant of DFS. Conclusions: Number of clones comprising the primary lesion was positively correlated with tumor size and stage, and was an independent factor affecting clinical outcome, indicating that a description of tumor clonality may be required for next-generation sequencing. Citation Format: Eun Young Kim, Sanghoon Lee, Arum Kim, Tae Hee Kim, Yoon Soo Chang. Tumor clonal status predicts clinical outcomes of non-small-cell lung 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 471.
Unsound Evaluations of Medical Machine Translation Risk Patient Health and Confidentiality—Reply
Authors: Elaine C. Khoong, Alicia Fernandez
Journal: JAMA Internal Medicine (2019)

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Reasons for chemotherapy discontinuation and end of life in gastro-intestinal cancers: a multicentric prospective AGEO study
Authors: L. Palmieri, O. Dubreuil, V. Hautefeuille, J. Bachet, I. Trouilloud, C. Locher, R. Coriat, F. Moryoussef, B. Landi, G. Perkins, S. Doat
Journal: Annals of Oncology (2019)
Abstract 18505: Atrial Fibrillation Ablation May Suppress Systemic Inflammatory Activation by Inhibiting Thioredoxin Interacting Protein Expression
Authors: Vincent Jk Goh, Christopher Woolley, Alex Awford, Nathan Procter, Cher-Rin Chong, Saifei Liu, Yuliy Y Chirkov, John Ty Hii, John D Horowitz
Journal: Circulation (2016)

Introduction: Atrial fibrillation (AF) is characterized by inflammatory activation and impaired tissue responsiveness to nitric oxide (NO). Both these processes may contribute to perpetuation of AF...
Abstract 12043: Transplant Benefit Associated with Increasing Risk of Wait-list Mortality in Patients Listed for Heart Transplantation in the United States
Authors: Tajinder P Singh, Carly Milliren, Christopher S Almond, Dionne Graham
Journal: Circulation (2012)

The sickest patients among those listed for a heart transplant (HT) are also at higher risk of post-transplant mortality making it difficult to determine which patients may benefit most from HT. We...
Efficacy of Cidofovir in Treatment of BK Virus Induced Hemorrhagic Cystitis in Post Allogeneic Hematopoietic Cell Transplant Recipients
Authors: Eric Anthony Coomes, Amanda Jacques, Fotios V. Michelis, Dennis (Dong-Hwong) Kim, Santhosh Thyagu, Auro Viswabandya, Jeff H. Lipton, Hans A. Messner, Uday Deotare
Journal: Blood (2017)
Abstract LB-018: Orally active small molecule PD-L1 inhibitor demonstrating similar efficacy as Durvalumab in human knock-in MC38 model
Authors: Yuguang Wang, Nong Zhang, Feilan Wang, Qiang Zhao, Zenggang Li
Journal: Cancer Research (2019)

Abstract Cancer immunotherapy with PD-1/PD-L1 antibody drugs has made tremendous progress in clinical application. It was also recognized by the scientific community with awarding of the 2018 Nobel Price. However, the discovery of orally active, small molecule drugs targeting PD-1/PD-L1 pathway remains highly challenging. We wish to report for the first time the similar efficacy as measured by TGI between small molecule inhibitor Max-10181 and Durvalumab in the head to head test of human PD-L1 knock-in MC38 cell line in human PD-1 knock-in mice. In addition, we would also like to report the superior efficacy of Max-10181 to mouse anti-PD-1 Ab in PD-L1 expression low syngeneic mouse 4T1 model. Our data indicated that small molecule drugs may have different dependency of PD-L1 expression level. As a result, they may have different therapeutic application in clinics. Furthermore, the data related to the mechanistic aspect of these observed results will also be discussed. Citation Format: Yuguang Wang, Nong Zhang, Feilan Wang, Qiang Zhao, Zenggang Li. Orally active small molecule PD-L1 inhibitor demonstrating similar efficacy as Durvalumab in human knock-in MC38 model [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-018.
Abstract 1146: [18F]FPyGal: A novel ß-galactosidase specific PET tracer for <i>in vivo</i> imaging of tumor senescence
Authors: Marcel A. Krueger, Jonathan M. Cotton, Benyuan Zhou, Katharina Wolter, Johannes Schwenck, Anna Kuehn, Kerstin Fuchs, Andreas Maurer, Christian La Fougere, Lars Zender, Bernd J. Pichler
Journal: Cancer Research (2019)

Abstract Senescence influences treatment outcome in cancer. Therefore it is of great interest to develop a diagnostic tool to detect senescent cells in cancer patients. Here we describe the evaluation of the PET tracer FPyGal for non-invasive imaging of ß-galactosidase as a surrogate marker for senescence. In vitro, we induced senescence in HCT116 cells by doxorubicin, in a liver progenitor cell line by p53-reactivation and in two liver carcinoma cell lines by a ribosomal checkpoint inhibitor (RCI). The cells were then incubated with FPyGal and tracer uptake was determined in a gamma-counter. For in vivo testing, the described cell lines were injected s.c. in mice. The tumor bearing mice were then treated appropriately to induce senescence. PET/MR scans were performed after i.v. injection of FPyGal for assessment of tracer uptake in the tumors. Ex vivo autoradiographies and X-Gal stainings were prepared to correlate intratumoral distribution of ⇓-galactosidase activity and tracer uptake. After toxicology studies, a pilot first-in-man study was performed in a cancer patient treated with Alisertib. Compared to the respective control cells, in vitro tracer uptake was significantly increased in all four cellular models tested. The strongest increase was observed in one of the liver carcinoma cell lines with a &amp;gt;3-fold increase in senescent cells. FPyGal tracer uptake increased in control HCT116 tumors from 1.1 to 1.7%ID/cc in senescent cells in in vivo PET/MRI studies and in the HRas model from 0.9 to 1.5 %ID/cc. In one of the liver tumor models we could observe a 2-fold increase in treated mice. Ex vivo ⇓-galactosidase staining and IHC of tumor tissue confirmed induction of senescence. Autoradiography and X-Gal staining showed an intratumoral correlation of ⇓-gal activity and FPyGal uptake. The compound passed the toxicology tests. A first patient study revealed high and heterogeneous tracer uptake in a liver metastasis. FPyGal shows increased in vitro and in vivo uptake in senescent cells and tumors. No toxicity of the compound could be detected and a first-in-man study showed promising results. Clinical trials including histological cross-validation are currently being prepared. Citation Format: Marcel A. Krueger, Jonathan M. Cotton, Benyuan Zhou, Katharina Wolter, Johannes Schwenck, Anna Kuehn, Kerstin Fuchs, Andreas Maurer, Christian La Fougere, Lars Zender, Bernd J. Pichler. [18F]FPyGal: A novel ß-galactosidase specific PET tracer for in vivo imaging of tumor senescence [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 1146.
Abstract 4289: ERK3 negatively regulates IL-6/STAT3 signaling via SOCS3 in cancer cells
Authors: Astha Shakya, Minyi Chen, Michael Markey, Weiwen Long
Journal: Cancer Research (2019)

Abstract Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen activated protein kinase (MAPK) which is dysregulated in several cancers including lung cancer, breast cancer and melanoma. It has a single Ser-Glu-Gly (SEG) phospho-acceptor motif in its activation loop, instead of the Thr-Xaa-Tyr (TXY) motif conserved in the classical MAPKs. Moreover, compared to the conventional MAPKs, much less is known about the targets of ERK3 signaling. Hence, to elucidate the ERK3-regulated genes and pathways, we performed gene microarray analyses of both A549 lung cancer cells and A375 melanoma cells after treatment with either a siRNA specifically targeting ERK3 or a non-targeting control siRNA. Interestingly, IL-6 target genes were found to be highly upregulated upon ERK3 knockdown. Interleukin-6 (IL-6) is a pleiotropic cytokine which signals via the JAK/STAT3 pathway. Phosphorylation of STAT3 at Tyrosine 705 (Y705) by JAK activates STAT3 in response to IL-6 stimulation. IL-6 signaling is negatively regulated by a feedback inhibitor SOCS3 (Suppressor of cytokine signaling 3), which binds to and inhibits JAK kinase activity. Interestingly, we noted that ERK3 interacts with SOCS3 from a published Yeast-two-hybrid screening. We validated the interaction between ERK3 and SOCS3 by co-immunoprecipitation assay. In addition, we found that ERK3 downregulates the phosphorylation of STAT3 at Y705. In line with its negative regulation of oncogenic STAT3 activity, ERK3 inhibits melanoma cell growth, migration/invasion and colony formation in soft agar. Taken together, we have revealed a novel role for ERK3 in suppressing IL-6/STAT3 signaling via SOCS3 in cancer cells. Citation Format: Astha Shakya, Minyi Chen, Michael Markey, Weiwen Long. ERK3 negatively regulates IL-6/STAT3 signaling via SOCS3 in 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 4289.
DNA damage response gene alterations are associated with high tumor mutational burden and clinical benefit from programmed death 1 axis inhibition in non-small cell lung cancer.
Authors: Biagio Ricciuti, Michael L. Cheng, Gonzalo Recondo, Mizuki Nishino, Renato Umeton, Lynette M. Sholl, Mark M. Awad
Journal: Journal of Clinical Oncology (2019)

9077 Background: DNA damage response (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with benefit from immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. Methods: Clinicopathologic and genomic data were collected from patients (pts) with advanced NSCLC at the Dana-Farber Cancer Institute treated with PD-(L)1 inhibitors. Targeted next-generation sequencing (NGS) by OncoPanel was used to determine DDR gene mutation status and TMB. DDR positive (DDRpos) cases were defined as those with pathogenic DDR alterations (per COSMIC and ClinVar databases). DDR negative (DDRneg) cases were defined as either DDR wild-type or those with non-pathogenic DDR alterations. Results: Of 468 pts with successful NGS who received ICIs, 242 (51.7%) were identified as having any DDR alteration. Of them, 74 (15.8% in the entire cohort) were defined as DDRpos with pathogenic alterations in the following genes: ATM (41.9%), MLH1/MSH2/MSH6 (18.9%), BRCA1/2 (16.2%), CHEK1/2 (9.4%), FANC genes (9.4%), BAP1 (5.4%), RAD genes (5.4%), ERCC4/6 (4.0%), POLE (2.7%), ATR (2.7%). DDRpos and DDRneg groups were balanced in terms of age, performance status, gender, histology, oncogenic driver mutation, smoking status, ICI line, baseline brain metastases. The median TMB was significantly higher in the DDRpos group compared to the DDRneg group (12.1 vs 9.8 mutations/megabase, P = 0.007). No difference in median PD-L1 tumor proportion score was observed between groups (30% vs 25%, P = 0.33). Compared to DDRneg pts (N = 394), DDRpos pts had a significantly higher objective response rate (31.1% vs 19.1%, P = 0.03), and longer median progression-free survival (4.3 vs 2.6 months, HR: 0.71 [95%CI: 0.53-0.95], P = 0.02) and overall survival (16.3 vs 9.8 months, HR: 0.63 [95%CI: 0.45-0.89], P = 0.009) with PD-(L)1 therapy. Conclusions: Pathogenic DDR alterations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes in NSCLC pts treated with PD-1 axis inhibition.
A genetics-led approach defines the drug target landscape of 30 immune-related traits
Authors: Hai Fang, Hans De Wolf, Bogdan Knezevic, Katie L. Burnham, Julie Osgood, Anna Sanniti, Alicia Lledó Lara, Silva Kasela, Stephane De Cesco, Jörg K. Wegner, Lahiru Handunnetthi, Fiona E. McCann, Liye Chen, Takuya Sekine, Paul E. Brennan, Brian D. Marsden, David Damerell, Chris A. O’Callaghan, Chas Bountra, Paul Bowness, Yvonne Sundström, Lili Milani, Louise Berg, Hinrich W. Göhlmann, Pieter J. Peeters, Benjamin P. Fairfax, Michael Sundström, Julian C. Knight
Journal: Nature Genetics (2019)
Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12
Authors: Orr-El Weizman, Eric Song, Nicholas M. Adams, Andrew D. Hildreth, Luke Riggan, Chirag Krishna, Oscar A. Aguilar, Christina S. Leslie, James R. Carlyle, Joseph C. Sun, Timothy E. O’Sullivan
Journal: Nature Immunology (2019)