tbuckley/cabot-search huggingface dataset:
Abstract 2206: Degradation of hyaluronan in the tumor microenvironment enhances oncolytic reovirus and anti-PD-L1 therapy in a murine syngeneic breast tumor model
Authors: Jisook Lee, Grey A. Wilkinson, Trevor Kimbler, Barbara Blouw, Curtis B. Thompson
Journal: Cancer Research (2020)

Abstract The extracellular matrix (ECM) structure heavily influences tumor growth, invasion and various steps of the cancer-immunity cycle. Hyaluronan (HA), a major component of ECM, is a glycosaminoglycan that accumulates in the tumor microenvironment (TME) of many solid tumor types, and HA accumulation can restrict T cell infiltration and promote immunosuppression. We have demonstrated in preclinical tumor models that enzymatic degradation of TME HA by intravenous PEGylated recombinant human hyaluronidase PH20 (Pegvorhyaluronidase alfa, PEGPH20) facilitates delivery of chemotherapeutics to tumors and enhances efficacy of current immunotherapy strategies including checkpoint inhibitors. In this study, we hypothesized that degradation of HA with PEGPH20 treatment may remodel the TME to improve the efficacy of oncolytic reovirus therapy (pelareorep) and checkpoint blockade therapy. To test this hypothesis, EMT6 murine breast tumor cells, which spontaneously accumulate HA and are sensitive to oncolytic activity of pelareorep were implanted orthotopically into the mammary fat pad of BALB/c mice. In this model, PEGPH20 treatment resulted in a reduction of HA measured by immunohistochemistry and induced tumor growth inhibition (30% TGI). Pelareorep plus anti-PD-L1 treatment also resulted in anti-tumor activity (44% TGI), and flow cytometric analysis of tumor infiltrating immune cells in pelareorep + anti-PD-L1-treated tumors demonstrated a significant increase in the numbers of cytotoxic CD8+ tumor infiltrating lymphocytes (TILs, p=0.0004), a decrease in regulatory T cells (T reg, p&amp;lt;0.0001) and an increase in CD8:Treg ratio (p=0.0018), indicating a robust antitumor immune response. Combination of PEGPH20 with pelareorep + anti-PD-L1 resulted in enhanced anti-tumor activity (71% TGI) compared to either PEGPH20 (30%TGI) or pelareorep + anti-PD-L1 (44% TGI). PEGPH20 in combination with pelareorep + anti-PDL1 also extended survival (median survival time, MST- 30 days, p&amp;lt;0.0001) in comparison with PEGPH20 alone (MST-21 days) or pelareorep + anti-PD-L1 (MST-22 days). Our data demonstrate the potential for matrix modeling through degradation of HA as a strategy to improve oncolytic reovirus + anti-PD-L1 immunotherapy. These findings are consistent with prior preclinical studies and support clinical evaluation of combining PEGPH20 with immune checkpoint inhibitors in HA-accumulating tumors. Citation Format: Jisook Lee, Grey A. Wilkinson, Trevor Kimbler, Barbara Blouw, Curtis B. Thompson. Degradation of hyaluronan in the tumor microenvironment enhances oncolytic reovirus and anti-PD-L1 therapy in a murine syngeneic breast tumor model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2206.
Reduced Mitochondrial Function and Metabolic Dysregulation in Aneurysmal Fibulin-4 Mice.
Authors: I. van der Pluijm, P.M. van Heijningen, A. Ijpma, N. van Vliet, W. Sluiter, E.C. Davis, L.J. Ringuette, D.H.W. Dekkers, S. Ghazi, I. Que, E.L. Kaijzel, L. te Riet, S.I.C. Gabriels, P.G. Mastroberardino, R. van der Linden, M. Vermeij, J.A. Demmers, H. Yanagisawa, R. Kanaar, J. Essers
Journal: Circulation Research (2015)
Abstract 4174: Anticancer activity of a novel small molecule krct-1 through inhibition of Trk-A signaling in breast cancer cells
Authors: Ah-Young Kim, Jae-Sung Kim
Journal: Cancer Research (2020)

Abstract The small molecule krct-1 was synthesized as a structurally novel compound. Krct-1 inhibited cell proliferation and tumor growth of breast cancer. In addition, Krct-1 had a capacity to induce activation of several apoptotic markers and downregulate anti-apoptotic markers in various breast cancer cell lines. Furthermore, Krct-1 increased the radiosensitivity of breast cancer cells by promoting DNA damage responses. By performing the kinase profile analysis, we found that Krct-1 inhibited tropomyosin receptor kinase A (Trk-A) and further demonstrated inhibition of its downstream signaling such as ERK and STAT3 in breast cancer cells. Thus, our results suggest that a novel compound Krct-1 have an antitumor activity through Trk-A regulation in breast cancer. Citation Format: Ah-Young Kim, Jae-Sung Kim. Anticancer activity of a novel small molecule krct-1 through inhibition of Trk-A signaling in breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4174.
EXTUBATION AFTER SURGERY FOR SIMPLE CONGENITAL HEART DEFECTS; STRIDOR AND RE-INTUBATION. A STUDY WITH KIMVENT* MICROCUFF* ENDOTRACHEAL TUBES FOR PEDIATRICS
Authors: R. de Wilde, S. Chaudhry, B.J. Gesink-van der Veer, R. van Brempt
Journal: Intensive Care Medicine (2011)
Abstract 4102: Genome-wide CRISPRa screen reveals new drivers of Enzalutamide resistance in prostate cancer
Authors: Yara Rodriguez, Rajita Vatapalli, Huyin Han, Kenji Unno, Vinay Sagar, Zachary Chalmers, Barbara Lysy, Young A Yoo, Mihai Truica, Sarki Abdulkadir
Journal: Cancer Research (2020)

Abstract Potent anti-androgens such as Enzalutamide (Enza) have been approved for the treatment of mCRPC. Despite initial response, nearly all patients eventually develop resistance to Enza. Although a few mechanisms of Enza resistance have been identified, none have been translated into a clinical benefit for recurrent patients. Our goal is to identify new therapeutic targets to overcome Enza resistance. We performed a genome-wide CRISPR activation screen using deactivated Cas9 (dCas9) fused to VP64 transcriptional activator in the androgen-dependent prostate cancer cell line (LNCaP). We used the Calabrese sgRNA library which targets 18,885 genes using 3 different sgRNAs per gene (56,762 sgRNAs). Cells expressing the gRNA library were treated with Enza (20µM) for 7 weeks to allow for enrichment of potential resistance genes. We identified 10 genes which were targeted by at least 2 sgRNAs with a Fold Change (FC) &amp;gt; 4 in the Enza vs control group. Notably, AR was the most enriched gene. AR up-regulation is one of the main drivers of Enza resistance in patients. Pathway enrichment analysis using all the sgRNAs with FC&amp;gt; 5 revealed an over-representation of the RB1, TP53 and TGF-β pathways. Importantly, these pathways are also known to drive Enza resistance. Our screen also identified new candidate genes that have never been linked to Enza resistance. Interestingly, most of these genes are transcription factors. We validated the screen results in vitro. Further analysis of this target genes in vitro and in vivo will allow us to identify novel genes and potential therapeutic targets for Enza resistance. Citation Format: Yara Rodriguez, Rajita Vatapalli, Huyin Han, Kenji Unno, Vinay Sagar, Zachary Chalmers, Barbara Lysy, Young A Yoo, Mihai Truica, Sarki Abdulkadir. Genome-wide CRISPRa screen reveals new drivers of Enzalutamide resistance in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4102.
Abstract 5912: YTHDF1 amplification associates with clinicopathological featuresand predicts worse survival in breast cancer
Authors: Cheukfai Li, Guochun Zhang, Yulei Wang, Bo Chen, Kai Li, Li Cao, Chongyang Ren, Lingzhu Wen, Minghan Jia, Hsiaopei Mok, Jianguo Lai, Weikai Xiao, Xuerui Li, Ning Liao
Journal: Cancer Research (2020)

Abstract N6-methyladenosine (m6A) is a common RNA modification on eukaryotic mRNA and several m6a regulatory proteins, which plays a crucial part in breast cancer. But the copy number variations (CNVs) for m6a regulatory proteins and their role in pathogenesis and progression in breast cancer is still unclear. By analyzing the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and the cancer genome atlas (TCGA database), we screened CNVs of ten m6A regulatory genes, including YTHDF3, YTHDF1, FTO, YTHDC1, ALKBH5, METTL3, WTAP, METTL14, YTHDF2, YTHDC2. Among them, YTHDF3 and YTHDF1 amplification had higher alteration rates among ten m6A regulatory genes. YTHDF1 and YTHDF3 amplification resulted in higher mRNA expression (P&amp;lt;0.001). We found that YTHDF1 and YTHDF3 amplification presented a high correlation with worse cinlicopathological characteristics and overall survival (OS) in breast cancer patients. COX regression analysis showed YTHDF1 amplification was an independent risk factor for 10-year OS in breast cancer (HR=1.549, 95% CI: 1.408-1.705, P&amp;lt;0.001, Table). Moreover, GSEA analysis revealed the downstream target of YTHDF1 may be related to MYC signaling regulation and T cell differentiation. In conclusion, we illustrated genetic alteration of m6A regulatory genes in breast cancer patients and found significant relationship between YTHDF1 amplification and worse clinical characteristics, indicating it a potential target for breast cancer treatment in epigenetic modification. Univariate and multivariate Cox proportional hazard analysis for 10-year overall survivalUnivariateUnivariateHR95% CIP valueHR95% CIP valueNode status1.7181.566-1.885&amp;lt;0.0011.5491.408-1.705&amp;lt;0.001Tumor Size1.0161.013-1.019&amp;lt;0.001ER status0.6200.530-0.725&amp;lt;0.0010.5260.440-0.629&amp;lt;0.001PR status0.6120.531-0.707&amp;lt;0.001HER2 status1.7471.445-2.112&amp;lt;0.0011.5171.234-1.866&amp;lt;0.001Age1.0241.018-1.030&amp;lt;0.0011.0331.026-1.039&amp;lt;0.001YTHDF11.8111.419-2.313&amp;lt;0.0011.5491.408-1.705&amp;lt;0.001 Citation Format: Cheukfai Li, Guochun Zhang, Yulei Wang, Bo Chen, Kai Li, Li Cao, Chongyang Ren, Lingzhu Wen, Minghan Jia, Hsiaopei Mok, Jianguo Lai, Weikai Xiao, Xuerui Li, Ning Liao. YTHDF1 amplification associates with clinicopathological featuresand predicts worse survival in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5912.
Abstract LB-100: Systematic target prioritization and validation from genome-scale loss-of-function screens in large panels of human cancer cell lines
Authors: Tsukasa Shibue, John M. Krill-Burger, Brenton R. Paolella, Benjamin Gaeta, Adhana Asfaw, Joshua M. Dempster, James M. McFarland, David E. Root, Jesse S. Boehm, Aviad Tsherniak, William C. Hahn, Francisca Vazquez
Journal: Cancer Research (2020)

Abstract Despite its increasing success and revolutionary impact on clinical oncology, Precision Cancer Medicine still has major roadblocks before it becomes applicable to a large proportion of patients. One such roadblock is the limited number of therapeutic targets available. Indeed, for the vast majority of cancer patients, we either do not know what their specific vulnerabilities are or do not have strategies to precisely target their vulnerabilities. In the Cancer Dependency Map Project (DepMap) at the Broad Institute, we aim to overcome these limitations through the use of genome-scale loss-of-function screens in a large panel of cancer cell lines combined with systematic molecular characterization of these cell lines. To date, we have conducted viability screens with genome-wide RNAi and CRISPR/Cas9 libraries on &amp;gt; 800 cell lines, all of which have also been comprehensively profiled with various omics approaches. In order to systematically identify and prioritize potential therapeutic targets, we created an analytical framework that uses a multifaceted approach to score gene dependencies based on the information extracted from screening outcomes, predictive models of sensitivity from all the genetic and molecular information, and the use of priors. To reproducibly validate the nominated targets, we also developed a toolbox of standardized assays that include confirmation of cell viability effects with orthogonal reagents/read-outs and efficient testing for in vivo efficacy across multiple cancer models. Using this approach, we have identified and validated several promising targets, including the WRN DNA helicase that is selectively essential in cancers with microsatellite instability (MSI). The data, framework, and toolbox developed here can inform the nomination and advancement of promising targets for drug development for Precision Cancer Medicine. Citation Format: Tsukasa Shibue, John M. Krill-Burger, Brenton R. Paolella, Benjamin Gaeta, Adhana Asfaw, Joshua M. Dempster, James M. McFarland, David E. Root, Jesse S. Boehm, Aviad Tsherniak, William C. Hahn, Francisca Vazquez. Systematic target prioritization and validation from genome-scale loss-of-function screens in large panels of human cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-100.
Abstract 129: Apoptosis &amp; anti-proliferative nature of Aescin on 7,12 dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis via downregulating Notch signaling
Authors: Hemavardhini Ramadoss, Suresh Kathiresan, Sanjay Gupta
Journal: Cancer Research (2020)

Abstract Worldwide, oral squamous cell carcinoma (OSCC) is the sixth most common cancer &amp; ranked as second most common cancer in India. The most implicated etiologic factors in the development of oral cancer is the use of tobacco, alcohol &amp; also HPV infection. Aescin, a pentacyclic triterpenoid saponin mixtures derived from Aesculus hippocastanum L (horse chestnut) that has been used as traditional herbal medicine, exists the pharmacodynamic properties, anti- edematous, anti-inflammatory &amp; antitumor. The present study, Tumors were induced by applying 0.5% DMBA topically to hamster buccal pouch (HBP) thrice a week for 14 weeks &amp; Aescin was orally administered at a various dose of 40 mg/kg body weight on alternate days of DMBA painting. We observed, reduced the tumor incidence, diminished lipid peroxidation, &amp; elevation of antioxidants, liver marker enzymes by Aescin. Furthermore, aescin induced apoptosis in DMBA induced tumor bearing animals significantly inhibited cell to cell communication of Notch-1, Notch-2 &amp; its ligand &amp; Jagged-1 leads to inhibited expression of the Notch downstream signaling target Hes-1 &amp; Hey-1 analyzed by immunohistochemical analysis. These results clearly suggest that Aescin prevents lipid peroxidation, protects the antioxidant defense system, prohibit the dysplasia &amp; anti-carcinogenic potential. we concluded; the results provide an important new insight of Notch signaling pathway &amp; aescin might be developed as a potential chemo preventive agent for oral cancer. Key words: Oral cancer, aescin, antioxidant, apoptosis, chemopreventive, Notch signaling Citation Format: Hemavardhini Ramadoss, Suresh Kathiresan, Sanjay Gupta. Apoptosis &amp; anti-proliferative nature of Aescin on 7,12 dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis via downregulating Notch signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 129.
Abstract 3794: Mammary cancer stem cells promote an aggressive phenotype in letrozole resistant breast cancer
Authors: Karen Melissa Gallegos, Jankiben Patel, Rashidra R. Walker, A Michael Davidson, Ian R. Davenport, Syreeta L. Tilghman
Journal: Cancer Research (2020)

Abstract Aromatase inhibitors (AI), like letrozole, are the first-line treatment for ER+ breast cancer in post-menopausal women. Despite widespread successful usage of letrozole, resistance to therapy, tumor relapse, and metastasis remain the principal causes of death for breast cancer patients. While there are no cures for AI-resistant breast cancer, previous reports demonstrate AI resistance is associated with hormone independence, increased growth factor signaling, enhanced cellular motility and the epithelial to mesenchymal transition (EMT). Given recent evidence suggesting a convergence of EMT and cancer stem cells (CSC) and their combined implications in endocrine resistance, we hypothesized that breast cancer stem cells contribute to letrozole resistant breast cancer cells by increasing cellular motility. To test this hypothesis, ovariectomized immunocompromised female mice were inoculated in the mammary fat pad with either MCF-7 cells stably transfected with the human aromatase gene that were long term letrozole-treated (LTLT-Ca) or letrozole sensitive, MCF-7 cells stably transfected with the human aromatase gene (AC-1). Afterwards, intratumoral putative CSC marker expression was assessed by immunohistochemistry. Results indicate LTLT-Ca tumors were CD44+/CD24+ while AC-1 tumors were CD44low/CD24low. Both cell lines were cultured either adherently (2D) or as mammospheres (3D) and CD44/CD24 protein expression was assessed by immunoblots. When both cell lines were cultured three dimensionally, they expressed higher levels of CD44 and CD24 compared to their adherent counterparts, with the most robust change occurring within the LTLT-Ca cells. In order to quantitate the breast cancer stem cell activity mammosphere formation assay was performed and LTLT-Ca cells formed mammospheres at a 3.4-fold higher index compared to AC-1 cells. Additionally, we performed targeted gene expression arrays and our results demonstrated decreased expression of genes involved in cell adhesion and tumor suppression (ie., E-cadherin, caveolin 1 and β catenin). Taken together our study demonstrated a strong correlation between AI resistance, increased cancer stem cell expression, an invasive phenotype that may be associated with a poor prognosis. This work was supported by an NIH grant awarded to SL Tilghman (1SC1GM125617). Citation Format: Karen Melissa Gallegos, Jankiben Patel, Rashidra R. Walker, A Michael Davidson, Ian R. Davenport, Syreeta L. Tilghman. Mammary cancer stem cells promote an aggressive phenotype in letrozole resistant breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3794.
tRNA-derived RNA fragments in cancer: current status and future perspectives
Authors: Mengqian Yu, Bingjian Lu, Jisong Zhang, Jinwang Ding, Pengyuan Liu, Yan Lu
Journal: Journal of Hematology & Oncology (2020)

Abstract Non-coding RNAs (ncRNAs) have been the focus of many studies over the last few decades, and their fundamental roles in human diseases have been well established. Transfer RNAs (tRNAs) are housekeeping ncRNAs that deliver amino acids to ribosomes during protein biosynthesis. tRNA fragments (tRFs) are a novel class of small ncRNAs produced through enzymatic cleavage of tRNAs and have been shown to play key regulatory roles similar to microRNAs. Development and application of high-throughput sequencing technologies has provided accumulating evidence of dysregulated tRFs in cancer. Aberrant expression of tRFs has been found to participate in cell proliferation, invasive metastasis, and progression in several human malignancies. These newly identified functional tRFs also have great potential as new biomarkers and therapeutic targets for cancer treatment. In this review, we focus on the major biological functions of tRFs including RNA silencing, translation regulation, and epigenetic regulation; summarize recent research on the roles of tRFs in different types of cancer; and discuss the potential of using tRFs as clinical biomarkers for cancer diagnosis and prognosis and as therapeutic targets for cancer treatment.
Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies
Authors: Haneen Shalabi, Vandana Sachdev, Amita Kulshreshtha, Julia W Cohen, Bonnie Yates, Doug R Rosing, Stanislav Sidenko, Cindy Delbrook, Crystal Mackall, Brandon Wiley, Daniel W Lee, Nirali N Shah
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Chimeric antigen receptor (CAR) T-cell-associated cytokine release syndrome (CRS) may present with tachycardia, hemodynamic instability and reduced cardiac function. Pediatric CAR studies examining cardiac toxicity are limited. Methods We report on cardiac toxicity observed in children and young adults with hematologic malignancies enrolled in a CD19-28ζ CAR T-cell phase I trial ( NCT01593696 ). All patients had a formal baseline echocardiogram. Real-time studies included echocardiograms on intensive care unit (ICU) transfer, and serial troponin and pro-B-type natriuretic peptide (pro-BNP) in the select patients. Results From July 2012 to March 2016, 52 patients, with a median age of 13.4 years (range 4.2–30.3) were treated. CRS developed in 37/52 (71%), which was grade 3–4 CRS in nine patients (17%). The median prior anthracycline exposure was 205 mg/m 2 (range 70–620 mg/m 2 ) in doxorubicin equivalents. The median baseline left ventricle ejection fraction (LVEF) and baseline LV global longitudinal strain (GLS) were 60% (range 50%–70%) and 16.8% (range 14.1%–23.5%, n=37) respectively. The majority, 78% (29/37), of patients had a reduced GLS &lt;19% at baseline, and 6% (3/52) of patients had baseline LVEF &lt;53%. ICU transfers occurred in 21 patients, with nine requiring vasoactive hemodynamic support and three necessitating &gt;1 vasopressor. Six (12%) patients developed cardiac dysfunction (defined by &gt;10% absolute decrease in LVEF or new-onset grade 2 or higher LV dysfunction, per CTCAE v4), among whom 4 had grade 3–4 CRS. Troponin elevations were seen in 4 of 13 patients, all of whom had low LVEF. Pro-BNP was elevated from baseline in 6/7 patients at the onset of CRS, with higher levels correlating with more severe CRS. Cardiac dysfunction fully resolved in all but two patients by day 28 post-CAR. Conclusion Cardiac toxicity related to CD19-28ζ CAR T-cell-associated CRS was generally reversible by day 28 postinfusion. Implementation of more frequent monitoring with formal echocardiograms incorporating systemic analysis of changes in GLS, and cardiac biomarkers (troponin and proBNP) may help to earlier identify those patients at highest risk of severe cardiac systolic dysfunction, facilitating earlier interventions for CRS to potentially mitigate acute cardiac toxicity.