tbuckley/cabot-search huggingface dataset:
Abstract 1059: Targeting IDH1/2 mutant cancers with unique combinations of DNA repair inhibitors
Authors: Amrita D. Sule, Ranjini Sundaram, Ranjit Bindra
Journal: Cancer Research (2020)

Abstract Mutations in the Isocitrate Dehydrogenase-1 and -2 (IDH1/2) genes occur in the vast majority of solid tumors including low-grade and secondary high-grade gliomas. These neomorphic mutations occur early on in gliomagenesis leading to the production of 2-Hydroxyglutarate (2HG). 2HG has been implicated in tumorigenesis via inhibiting α-ketoglutarate (αKG)-dependent dioxygenases. Our group recently demonstrated that the production of 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state of “BRCAness”. We initially found that mutant IDH1/2-induced BRCAness confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, a finding which now has been replicated by multiple independent laboratories. Although IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML) cells, multiple other tumor types have subsequently been shown to harbor these mutations. Current clinical trials are testing the efficacy of PARP inhibitors as a monotherapy, as well as in combination with other DNA repair inhibitors. Here, we demonstrate that novel combinations of DNA repair inhibitors can be utilized to synergistically target IDH1/2-mutant glioma cells. In particular, we demonstrate potent synergy with ATRi and PARPis, a finding which was validated in multiple structurally unique drugs within these classes. We have shown that in an in vivo flank model bearing IDH1 R132H mutation, AZD6738 (ATRi) and Olaparib (PARPi) combination treatment reduces the tumor burden significantly relative to monotherapy and vehicle. As this combination is active in BRCA1/2-mutant cancers, in particular after the emergence of PARPi resistance, these data suggest are consistent with an underlying HR defect in IDH1/2-mutant gliomas. These preclinical investigations will provide a blueprint for future clinical trials combining PARP and ATR inhibitors in the treatment of IDH1/2 mutant cancers. Citation Format: Amrita D. Sule, Ranjini Sundaram, Ranjit Bindra. Targeting IDH1/2 mutant cancers with unique combinations of DNA repair inhibitors [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 1059.
Impact of Tricuspid Regurgitation on Clinical Outcomes
Authors: Rebecca T. Hahn, Federico Asch, Neil J. Weissman, Paul Grayburn, Saibal Kar, Scott Lim, Ori Ben-Yehuda, Bahira Shahim, Shmuel Chen, Mengdan Liu, Bjorn Redfors, Diego Medvedofsky, Rishi Puri, Samir Kapadia, Anna Sannino, JoAnn Lindenfeld, William T. Abraham, Michael J. Mack, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2020)
Abstract 5086: The aged tumor microenvironment promotes melanoma metabolic plasticity and therapy
Authors: Gretchen Marie Alicea, Vito W. Rebecca, Aaron Goldman, Mitchell Fane, Reeti Behera, Marie Webster, Brett Ecker, Ian Blair, David Speicher, Zachary Schug, Ashani Weeraratna
Journal: Cancer Research (2020)

Abstract “Aged” melanoma patients (&amp;gt;55 years old) have poorer prognosis and reduced response rates to targeted therapy relative to “young” patients (&amp;lt;40 years old). Here, we report an altered metabolic landscape in the aged tumor microenvironment (TME) as critical for melanoma aggressiveness. Aged fibroblasts uptake high levels of glucose compared to their young counterparts, which fuels lipid production. Melanoma cells cultured in an aged TME in vitro or in vivo display elevated intracellular lipid levels and increased metastatic potential relative to melanoma cells in a young TME. Further, lipidomics reveal an elevated lipid profile (i.e., triglycerides, ceramides, and cholesterol) preferentially secreted by aged fibroblasts relative to young. In turn, we show that melanoma cells adaptively increase extracellular fatty acid scavenging via the lipid transporter FATP2 in the lipid rich aged TME. Melanoma cells cultured in the aged TME also display an increased oxygen consumption rate (OCR) relative to those grown in young TME, which could be ablated when fatty acid transport into the mitochondria is blocked with etomixir. Notably, melanoma cells in the aged TME treated with BRAFi/MEKi in combination with a FATP2 inhibitor display decreased OCR relative to BRAFi/MEKi inhibitor alone, which paralleled the increased overall survival of aged mice treated with BRAFi/MEKi/FATP2i relative to either agent alone. To rule out off-target effects of the FATP2 inhibitor, we used a doxycycline inducible system for FATP2 knockdown in melanoma cells and reproduced the abrogation of tumor growth and extension of survival in aged immune-competent mice when combined with BRAFi/MEK therapy. Additionally, elevated FATP2 levels correlate with worse response in human patients. We hypothesize the aged TME triggers adaptive metabolic plasticity of melanoma cells critical for therapy escape. Citation Format: Gretchen Marie Alicea, Vito W. Rebecca, Aaron Goldman, Mitchell Fane, Reeti Behera, Marie Webster, Brett Ecker, Ian Blair, David Speicher, Zachary Schug, Ashani Weeraratna. The aged tumor microenvironment promotes melanoma metabolic plasticity and therapy [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 5086.
Abstract 4493: Enhancer reprogramming contributes to anti-PD1 resistance in melanoma
Authors: Mayinuer Maitituoheti, Ming Tang, Christopher J. Terranova, Emily Keung, Katarzyna J. Tomczak, Jennifer Wargo, Kunal Rai
Journal: Cancer Research (2020)

Abstract Immune checkpoint blockade therapy has improved clinical responses and long-term survival benefit for patients with advanced melanoma, however the response rate is modest and a large fraction of treated patients do not experience clinical benefits. Therefore, there is tremendous need to identify combination strategies to improve responses and to overcome resistance to therapy. Emerging data suggest that epigenetic drugs can improve the responses to immunotherapy. However, we have limited understanding of epigenetic mechanisms that characterize responses to Immune checkpoint blockade therapy. Therefore, we generated comprehensive epigenomic landscapes of 36 samples from anti PD-1 treated metastatic melanoma patients by profiling 6 histone markers. To determine correlation of epigenetic features with gene expression, we generated RNA-Access data for 12 matched samples. We determined chromatin states using ChromHMM and ChromHMM profiling consolidated using Epilogos. Analysis of chromatin state differences and associated individual mark profiles with response rate suggested that pre-treatment samples from anti PD-1 non-responsive patients contain higher active enhancer state (enriched for H3K27Ac) compared to responsive patients. Many of these enhancers targeted key regulators of pathways that are shown to mediate resistance to immune checkpoint blockade therapy. Importantly, aberrant expression of these genes correlated well with enhancer gains. Inhibition of enhancers with bromodomain inhibitor along with anti PD-1 significantly decreased the tumor volume by increased T cell infiltration. Together, these findings reveal that enhancer gains on key oncogenes associate with poor response to Immune checkpoint therapy which could be potentially used for stratifying responder and resistant lesions. Citation Format: Mayinuer Maitituoheti, Ming Tang, Christopher J. Terranova, Emily Keung, Katarzyna J. Tomczak, Jennifer Wargo, Kunal Rai. Enhancer reprogramming contributes to anti-PD1 resistance in melanoma [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 4493.
TCT-431 Socioeconomic disparities in access for Watchman device insertion in patients with atrial fibrillation and at elevated risk of bleeding.
Authors: Daniel Kupsky, Dee Dee Wang, Marvin Eng, Neil Gheewala, Asaad Nakhle, Fawaz Georgie, Rajan Shah, Meredith Mahan, Adam Greenbaum, William O'Neill
Journal: Journal of the American College of Cardiology (2017)
Abstract 3006: Anticancer and multidrug resistance-reversing activities of novel antimicrobial peptides
Authors: Qiu-Xu Teng, Zi-Ning Lei, Xiaofang Luo, Jing-Quan Wang, Zuodong Qin, John N. Wurpel, Zhe-Sheng Chen
Journal: Cancer Research (2020)

Abstract Cancer is a growing concern in public health problems worldwide. Although the development of advanced chemotherapies has already partly reduced the cancer death rate and improved patients' prognosis, the phenomenon of multidrug resistance (MDR), which impairs the efficacy of a serial structure-unrelated anticancer agent, casts a large shadow over the bright future of chemotherapies. MDR has various mechanisms to induce acquired drug resistance of cancer cells after a relatively long period of chemotherapy. One of the most common causes of MDR is the expression of ATP-binding cassette (ABC) transporters, which act as efflux pumps on cancer cell membranes and transport anticancer drugs out of cancer cells thereby reducing the intracellular drug concentration. The growing resistance of cancer cells to current anticancer drugs leads to the urgent need to develop anticancer drugs with a new mechanism of action. Over the past decade, antimicrobial peptides have entered the view of scientists as a new generation of anticancer drugs. In this study, the anticancer effects and the reversal activities against ABC transporter mediated MDR of four novel antimicrobial peptides were investigated. The results showed that, at non-toxic concentrations in vitro, peptides #7, #14, #22, and #24 significantly sensitized ABCB1- and ABCC1-overexpressing cell lines, including both drug-selected MDR cancer cell lines and ABCB1 or ABCC1 gene transfected HEK293 cell lines, to the substrate anticancer drugs paclitaxel and vincristine. Among the antimicrobial peptide compounds, #14 and #24 with the most potent reversal ability were selected for further investigation. These peptides increased the intracellular accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells and that of [3H]-vincristine in ABCC1 overexpressing cells by suppressing the efflux function of ABCB1 and ABCC1 transporters, without causing alteration in the expression levels and localization patterns of ABCB1 and ABCC1 in overexpressing cells. Furthermore, the results of the ATPase assay showed that both two peptides stimulated ABCB1 ATPase activity. Taken together, these results demonstrated that peptide #14 and #24 reverse ABCB1- and ABCC1-mediated MDR through blocking the function of ABCB1 and ABCC1 without affecting the transporters' expression and cellular localization, which suggests that antimicrobial peptides may be used as a novel prospective cancer therapeutic strategy in the combination with traditional anticancer agents. Citation Format: Qiu-Xu Teng, Zi-Ning Lei, Xiaofang Luo, Jing-Quan Wang, Zuodong Qin, John N. Wurpel, Zhe-Sheng Chen. Anticancer and multidrug resistance-reversing activities of novel antimicrobial peptides [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 3006.
Abstract 4687: Oncogenic role of the transcription factor YY1 and its target Survivin in non-Hodgkin's lymphoma
Authors: Silvia Vivarelli, Luca Falzone, Saverio Candido, Benjamin Bonavida, Massimo Libra
Journal: Cancer Research (2020)

Abstract Objective Yin Yang 1 (YY1) is a transcription factor with a dual role in cancer genesis. Hematological malignancies, including non-Hodgkin lymphomas (NHL), are often characterized by a frequent development of resistance to therapy and a high rate of tumor recurrence. Our previous observations showed that YY1 is overexpressed in hematological tumors. The aim of this study was to investigate the functional role of YY1 in anti-cancer therapy induced cell death and to identify YY1 downstream resistant factors. Experimental Designs The NHL Raji cell line was used as a cellular model. The expression of YY1 was assessed by q-PCR and WB. YY1 knock-down (KD) was achieved using retroviral shRNA. Viability was measured by both the MTT assay and the Trypan Blue live/dead cell count. Cell death was induced following Vincristine and Doxorubicin treatments. The following analyses were used in this study: the JASPAR database, the Encyclopedia of DNA Elements (ENCODE) and the Cancer Genome Atlas (TCGA) datasets relative to NHL patients have been analyzed to assess the expression levels of YY1 and apoptotic genes, according to tumor stages and patients' clinical-pathological features. Results Silencing of YY1 in Raji cells resulted in increased sensitivity to both Vincristine and Doxorubicin treatments and augmented apoptosis. Jaspar analysis identified several potential YY1 transcriptional targets involved in cellular death regulation. As a result of q-PCR screening and validation, Survivin has been identified as a potential YY1 target, as it was significantly downregulated following YY1 KD. Bioinformatic analysis of deposited Chip-Seq databases in ENCODE revealed that YY1 is able to target Survivin transcriptional regulatory regions in different cancer cell lines, as well as in normal B lymphocytes. The TCGA-deposited datasets identified specific clusters of YY1 expression significantly correlated with Survivin. Conclusions Our findings demonstrated that (1) YY1 silencing resulted in the sensitization of Raji tumor cells to drug-induced apoptosis (2) q-PCR-mediated screening of putative YY1 targets led to the identification of Survivin as a potential YY1 target, as when YY1 was KD, Survivin levels were strongly downregulated (3) YY1 might be positively regulating Survivin expression (4) Survivin could be a potential target of YY1 in NHL and (5) YY1 and Survivin in NHL may represent two novel diagnostic and prognostic biomarkers to assess patients' response to chemotherapy. Citation Format: Silvia Vivarelli, Luca Falzone, Saverio Candido, Benjamin Bonavida, Massimo Libra. Oncogenic role of the transcription factor YY1 and its target Survivin in non-Hodgkin's lymphoma [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 4687.
Abstract 2656: Myeloid derived Wnt5a influences the immune-dynamics of melanoma tumor microenvironment
Authors: Stephen Douglass, Mitchell Fane, Emilio Sanseviero, Dmitry Gabrilovich, Ashani Weeraratna
Journal: Cancer Research (2020)

Abstract Despite breakthroughs in targeted therapies and immunotherapies, over 75% of patients either do not respond to therapy, or relapse. This may be due in part to changes in their tumor microenvironment (TME). Wnt5A is a glycoprotein that has been shown to influence melanoma phenotype, promoting a slow-cycling, but more invasive cancer. Wnt5A was thought to be produced from tumor cells and fibroblasts in the TME. However, our data now suggest that unique pathologically induced myeloid derived suppressor cells (MDSCs) produce a major proportion of Wnt5A in the TME which is taken up by melanoma cells to increase invasiveness. This finding highlights the diverse roles that MDSCs play in melanoma, going beyond immunosuppression. We created novel transgenic animals with MDSC specific knockdown of Wnt5A and demonstrate a clear decrease in the Wnt5A expression within the TME. Wnt5A deficient MDSCs caused an increase in CD8+ T-cells in peripheral blood and decreased tumoral MDSCs and Tregs. Tumor infiltrating lymphocytes also had significantly decreased PD-1 expression suggesting a less exhausted phenotype, and increased ratios of effector T-cells to immunosuppressive cells resulting in a more immunogenic TME. Wnt5A promotes a switch from proliferative to an invasive melanoma cell state. Myeloid specific Wnt5A knockdown caused decreased lung metastasis and significantly increased tumor growth in vivo, with the lack of MDSC infiltration negatively correlating to tumor volume. Tumor infiltrating MDSCs from control animals had a strong positive correlation with Tregs, whereas, this was completely ablated in animals with Wnt5A-negative MDSCs. Overall, our data suggests that while MDSCs contribute to an immunosuppressive and less immunogenic environment, they may have an additional function as the major source of Wnt5A in the tumor microenvironment. These two functions likely synergize to drive a highly metastatic and therapy-resistant phenotype altering immunogenicity. Citation Format: Stephen Douglass, Mitchell Fane, Emilio Sanseviero, Dmitry Gabrilovich, Ashani Weeraratna. Myeloid derived Wnt5a influences the immune-dynamics of melanoma tumor microenvironment [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 2656.
Abstract 6528: Anti-PD-1 induces the endocytosis of the co-receptor from the surface of T-cells: Nivolumab is more effective than Pembrolizumab
Authors: Elham Ben Saad, Andres Oroya, Christopher E. Rudd
Journal: Cancer Research (2020)

Abstract Immune checkpoint blockade (ICB) has revolutionized the treatment of cancer. Present models show that anti-PD-1 operates simply by blocking co-receptor binding to its ligand PD-L1. Surprisingly, no previous studies have assessed whether ICB also induces the internalization or endocytosis of PD-1 from the cell surface. Many, but not all receptors, undergo endocytosis upon antibody or ligand binding. In this study, PD-1 internalization was assessed on activated human T cells by flow cytometry and fluorescence microscopy. Immunoprecipitation and western blotting were performed to assess the destiny of PD-1 after internalization. Our results report that anti-PD-1 induces the rapid internalization of PD-1 from the surface of T-cells in a manner comparable to CD28. A substantial minority of receptors were also resistant to antibody-induced endocytosis. Further, Nivolumab was considerably more effective than Pembrolizumab in inducing the endocytosis of PD-1 in primary human T-cells. This difference was the result of several factors where Nivolumab bound to a greater number of PD-1 molecules on the surface of T-cells than Pembrolizumab, indicating that the co-receptor might exist with different conformations on activated cells. Moreover, Nivolumab induced more rapid endocytosis (5.5 versus 3.6% per minute) and a greater percentage of PD-1 molecules than Pembrolizumab (70% versus 50%). The relative effect of anti-PD-1 molecules on internalization was seen equally on activated CD4 helper and CD8+ effector/memory T-cells. The internalization and the degradation of PD-1 were partially blocked by the inhibition of clathrin-mediated endocytosis and proteasome activity. Our studies show for the first time that ICB involves a second level of modulation involving the internalization of PD-1 from the surface of T-cells, an event which will contribute to the efficacy of ICB. Citation Format: Elham Ben Saad, Andres Oroya, Christopher E. Rudd. Anti-PD-1 induces the endocytosis of the co-receptor from the surface of T-cells: Nivolumab is more effective than Pembrolizumab [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 6528.
Abstract 3039: Essential role of IRAK4/TPL2 signaling axis in MAPK activation by oncogenic RAS and genotoxic stress
Authors: Paarth B. Dodhiawala, Namrata Khurana, Daoxiang Zhang, Yi Cheng, Lin Li, Kuljeet Seehra, Hongmei Jiang, Patrick M. Grierson, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival of 9% and effective treatment options remain elusive. Oncogenic mutations of KRAS occur in &amp;gt;95% of PDACs and are well-established as the bona fide driver event. However, inhibition of KRAS oncoprotein or its downstream signaling cascades remains unsuccessful in PDAC patients. Furthermore, parallel survival pathways including constitutive activation of the NF-κB pathway poses an additional therapeutic barrier. Previous work from our lab showed that Interleukin-1 Receptor associated kinase 4 (IRAK4) is a major driver of NF-kB cascade in PDAC. Here, through an unbiased reverse phase protein array screen and RNA sequencing, we discovered IRAK4 controls MAPK activity downstream of KRAS. Ablation of IRAK4 completely abolishes RAS-induced transformation in human and murine cell lines. Mechanistically, we implicate a KRAS-driven IL-1β signaling loop that activates IRAK4 and uncover MAP3K8 (or TPL2/COT) as the kinase through which IRAK4 activates MEK and ERK. Suppression of TPL2 abrogates KRAS-driven MEK-ERK activity and transformed growth of PDAC cell lines. In addition, TPL2 inhibition suppresses p105/p50 NF-kB activation, a valuable phenomenon that distinguishes TPL2 inhibition from MEK inhibition. We find TPL2 inhibition synergizes with chemotherapy to suppress growth of PDAC cell lines in vitro and patient-derived xenograft tumor model in vivo. Analyses of PDAC tissue microarray showed TPL2 expression to be marginally associated with poor prognosis. Additionally, we are the first to characterize gain-of-function point mutations in TPL2 which hyperactivate MAPK and NF-kB, in part by preventing TPL2 protein degradation. Together, our study broadens the understanding of the oncogenic RAS signaling network and reveals IRAK4 and TPL2 as novel practical therapeutic targets in RAS-driven cancers. Citation Format: Paarth B. Dodhiawala, Namrata Khurana, Daoxiang Zhang, Yi Cheng, Lin Li, Kuljeet Seehra, Hongmei Jiang, Patrick M. Grierson, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Essential role of IRAK4/TPL2 signaling axis in MAPK activation by oncogenic RAS and genotoxic stress [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 3039.