tbuckley/cabot-search huggingface dataset:
Abstract 2137: Differential gene expression identifies a transcriptional regulatory network involving ESR1and PITX1 in invasive epithelial ovarian cancer
Authors: Yichao Li, Sushil Kumar Jaiswal, Rupleen Kaur, Dana Alsaadi, Xiaoyu Liang, Frank Drews, Julie A. DeLoia, Thomas Krivak, Hanna M. Petrykowska, Valer Gotea, Lonnie Welch, Elnitski Laura
Journal: Cancer Research (2021)

Abstract The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in invasive processes, but the molecular factors that drive aggressive behavior remain nebulous. In this study, we analyzed two types of EOC at opposite ends of the invasiveness spectrum, high-grade serous ovarian cancers (HGSOCs) and serous borderline tumors (SBTs). We identified differentially expressed genes to guide follow on studies of regulatory networks. Initially, in a discovery sample set, we generated transcriptome sequences to identify 11 differentially expressed genes in SBTs and HGSOCs, and a nonoverlapping set of 17 differentially expressed genes stage II and stage III HGSOCs. We validated the classification performance of these gene expression signatures on a validation set of SBT and HGSOC with classification rates of 94 and 98% using the 11-gene and 17-gene sets, respectively. Transcription factor binding sites enriched in the differentially expressed gene promoter regions were examined by Chip-seq analysis in ovarian cancer and other cell lines. We identified a suite of transcription factors implicated in the differential regulation associated with invasiveness, including ERα, RARA, PITX1, FOXA1/FOXF1, and BHLHE41/E40. These data implicate estrogen responsive gene regulatory networks in ovarian cancers and suggest that dynamic regulatory interactions determine malignant EOC outcomes. Citation Format: Yichao Li, Sushil Kumar Jaiswal, Rupleen Kaur, Dana Alsaadi, Xiaoyu Liang, Frank Drews, Julie A. DeLoia, Thomas Krivak, Hanna M. Petrykowska, Valer Gotea, Lonnie Welch, Elnitski Laura. Differential gene expression identifies a transcriptional regulatory network involving ESR1and PITX1 in invasive epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2137.
Abstract 1595: Small molecule inhibition of the ubiquitin ligase CBL-B results in potent T and NK cell mediated anti-tumor response
Authors: Ryan Rountree, Frederick Cohen, Austin Tenn-McClellan, Alexandra Borodovsky, Marilena Gallotta, Jennifer Stokes, Jose Gomez Romo, Chris Karim, Gwenn M. Hansen, Cristiana Guiducci, Arthur Sands, Jennifa Gosling
Journal: Cancer Research (2021)

Abstract The E3 ubiquitin ligase Casitas B-lineage lymphoma b (CBL-B) is expressed in T cells where it functions as an important negative regulator of immune activation. CBL-B d attenuates T-cell activation initiated by TCR engagement in part by mediating the requirement for CD28 co-stimulation, thus setting the threshold for T cell activation. CD4+ and CD8+ T cells from mice deficient in cbl-b have 5 to 10-fold enhanced secretion of IL-2 and IFN-γ when stimulated ex vivo with anti-CD3. Cbl-b deficient mice also demonstrate enhanced NK cell function. Here we describe NX-1607, an investigational, orally bioavailable, small molecule inhibitor of CBL-B. NX-1607 demonstrates potent biochemical inhibition of CBL-B leading to stimulatory effects on human immune cells at low nanomolar concentrations. NX-1607 induction of IL-2 and IFN-γ secretion occurs in primary human T cells stimulated with anti-CD3 antibodies, in both the presence and absence of CD28 co-stimulation, although to a lesser degree in the absence of co-stimulation. In vivo, oral administration of NX-1607 in mice demonstrated significant tumor growth inhibition in two colon carcinoma tumor models, CT26 and MC38, as well as a triple negative breast tumor model, 4T1. The change in tumor microenvironment caused by NX-1607 treatment leads to rapid NK cell infiltration followed by infiltration of activated CD8+ T cells. Depletion of CD8+ T cells or NK cells completely abrogated NX-1607 antitumor activity. Importantly, the combination of NX-1607 and anti-PD-1 can substantially increase the median overall survival and the frequency of complete tumor rejections in all three tumor models. These studies provide significant insights into the antitumor activity of this novel, small molecule E3 ligase inhibitor and deliver experimental support for clinical development of NX-1607 given as monotherapy or in combination with PD-1 blockade. Citation Format: Ryan Rountree, Frederick Cohen, Austin Tenn-McClellan, Alexandra Borodovsky, Marilena Gallotta, Jennifer Stokes, Jose Gomez Romo, Chris Karim, Gwenn M. Hansen, Cristiana Guiducci, Arthur Sands, Jennifa Gosling. Small molecule inhibition of the ubiquitin ligase CBL-B results in potent T and NK cell mediated anti-tumor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1595.
Abstract 1582: T-SIGn cancer gene therapy and anti-EGFR CAR-T cells synergize in combination therapy to clear A549 lung tumor xenografts and lung metastases in NSG mice
Authors: Olmo Sonzogni, Daniel Zak, Katy West, Rochelle Lear, Alice Muntzer, Brian R. Champion, James B. Rottman
Journal: Cancer Research (2021)

Abstract Chimeric antigen receptor (CAR) T cell therapy is an effective treatment for hematologic malignancies but has demonstrated limited efficacy in solid tumors. This is largely attributed to the immunosuppressive tumor microenvironment (TME) that impairs the ability of CAR-T cells to infiltrate, become activated, and kill tumor cells. Virotherapy is another emerging cancer treatment that has so far shown only limited clinical efficacy as a monotherapy for solid tumors. Importantly, in addition to their ability to directly kill tumor cells, viral vectors can also be leveraged to deliver transgenes to “reprogram” the TME from an immunosuppressive to a pro-inflammatory environment. We hypothesized that IV-deliverable T-SIGn cancer gene therapy vectors based on the oncolytic adenovirus enadenotucirev, which carry a transgene cassette encoding human immunomodulatory molecules to aid recruitment and activation of T-cells, could enhance the anti-tumor activity of human anti-EGFR CAR T cells in vivo. To test this hypothesis, NSG mice implanted subcutaneously with human lung cancer A549 xenografts, were treated intravenously with the T-SIGn virus followed by treatment with human anti-EGFR CAR-T cells. This treatment regimen demonstrated clearance of the xenograft and pulmonary metastases, whereas either therapy alone showed either no efficacy or delayed disease progression. When xenograft transcript analysis was performed, robust expression of the virus-encoded transgenes, as well as an upregulation of transcripts involved in type I IFN responses (e.g. IRF1, SOCS1), antigen presentation (e.g. HLA.DRA, TAP1), T cell activation (IFNγ, GrB), and inflammation (e.g. CXCL9, TNFSF10) was measured in the xenografts of animals treated with combination therapy, indicating a reprogramming of the TME to more effectively recruit and/or enhance T-cell responses. In addition, the combination treatment also dramatically reduced the number of A549 tumor cell micrometastases detectable in the lungs. Since both agents were delivered systemically, this observation may reflect direct therapeutic activity at the metastatic sites. Taken together, these results indicate that combination therapy with a T-SIGn vector and CAR T cells holds great potential to be efficacious in humans with solid tumors. Citation Format: Olmo Sonzogni, Daniel Zak, Katy West, Rochelle Lear, Alice Muntzer, Brian R. Champion, James B. Rottman. T-SIGn cancer gene therapy and anti-EGFR CAR-T cells synergize in combination therapy to clear A549 lung tumor xenografts and lung metastases in NSG mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1582.
Intramuscular Metastasis of Carcinoid Tumor
Authors: Ekaterina Tiktinsky, Tifha Horne, Svetlana Agranovich, Sophie Lantsberg
Journal: Clinical Nuclear Medicine (2008)

Scintigraphy with In-111 Octreoscan (octreotide) is useful for imaging various neuroendocrine tumors, especially in patients with midgut carcinoids. This radiopharmaceutical imaging technique is currently used for detecting primary and metastatic carcinoid lesions. Such a relatively rare group of tumors can present a difficult diagnostic dilemma, and octreotide imaging may be essential for diagnosis, staging, and choice of treatment. We report on a 43-year-old man with a history of left upper lobectomy due to an atypical bronchial carcinoid tumor. Octreotide was performed for suspected local tumor recurrence, revealing metastasis in skeletal muscle.
Abstract 2359: MicroRNA 494-5p acts as tumor suppressor in colorectal cancer by targeting JAK1
Authors: Heike Allgayer, Nitin Patil, Omar Abdelrahim, Joerg H. Leupold
Journal: Cancer Research (2021)

Abstract Recently, we have characterized the metastatically relevant microRNA landscape by comparing microRNA (miR) expression between human colorectal metastasis and matched primary tumors and normal tissues (Mudduluru et. al. Cancer Res. 2015; PMID: 26069251). One of these, miR-494-5p, was deregulated already in primary tumors. In vitro invasion and migration (Boyden chamber and Matrigel) assays of cultured colorectal cancer cells were significantly reduced after miR-494-5p overexpression (mimic). Conversely, this was abolished by anti-miR-494-5p as an inhibitor. Overexpression of miR-494-5p in cell lines showed a significant reduction in cellular proliferation, which was reversed upon inhibitor co-transfection in a time dependent manner. In silico analysis suggested an interaction of miR-494-5p with the 3´UTR of JAK1. Accordingly, an overexpression of miR-494-5p in cultured colon cancer significantly reduced luciferase activity of a reporter plasmid containing the wild type JAK1-3'UTR, which was abolished when the miR-494-5p seed sequence was mutated to prevent miR-494-5p binding, suggesting a physical interaction and translational repression of JAK1 by miR-494-5p. Furthermore, overexpression of miR-494-5p led to a significant reduction of JAK1 expression in colorectal cancer cell lines in a time dependent manner, which was abolished by co-transfecting a specific anti-miR-494-5p as an inhibitor. Taken together, our preliminary data suggests that miR-494-5p inhibits the expression of JAK1 as a direct molecular target via specific interaction at the JAK1-3'UTR. Additionally, miR-494-5p is capable of reducing proliferation, migration, and invasion, suggesting miR-494-5p as an early tumor suppressor molecule in colorectal cancer. Citation Format: Heike Allgayer, Nitin Patil, Omar Abdelrahim, Joerg H. Leupold. MicroRNA 494-5p acts as tumor suppressor in colorectal cancer by targeting JAK1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2359.
Safety evaluation of combined PD-1+CTLA4 inhibition concurrently to Chemoradiotherapy (CRT) in localized Muscle Invasive Bladder Carcinoma (MIBC)
Authors: B. De Ruiter, J.W. Van Hattum, T.M. De Reijke, J.R. Oddens, M.C.C.M. Hulshof, A.D. Bins
Journal: European Urology (2021)
Impact of peri-operative testosterone levels on oncological and functional outcomes in radical prostatectomy (ENFORCE trial)
Authors: D.J.H. Baas, J.J.H. Beck, J-P.A. Van Basten, J.P.M. Sedelaar, H.J.E.J. Vrijhof, H.H.E. Van Melick, H.M. Bruins, P.J. Van Leeuwen, R.P.W.F. Wijn, P. Busch Østergren, D.M. Somford
Journal: European Urology (2021)
Abstract 14417: M2 Macrophage Polarization is a Cause of Vascular Fibrosis and Stiffening in Hypertension
Authors: Jeffrey P Moore, Samy Sakkal, Sharon L Ricardo, Tracey Gaspari, Barbara Kemp-Harper, Christopher G Sobey, Grant R Drummond
Journal: Circulation (2013)

Arterial stiffening is a hallmark of hypertension and contributes to elevated systolic blood pressure (SBP), increased cardiac afterload, poor coronary perfusion and end organ damage. Hypertension ...
The rescue of F508del-CFTR by elexacaftor/tezacaftor/ivacaftor (Trikafta) in human airway epithelial cells is underestimated due to the presence of ivacaftor
Authors: Frédéric Becq, Sandra Mirval, Thomas Carrez, Manuella Lévêque, Arnaud Billet, Christelle Coraux, Edouard Sage, Anne Cantereau
Journal: European Respiratory Journal (2021)

Trikafta, currently the leading therapeutic in cystic fibrosis (CF), has demonstrated a real clinical benefit. This treatment is the triple combination therapy of two folding correctors elexacaftor/tezacaftor (VX445/VX661) plus the gating potentiator ivacaftor (VX770). In this study, our aim was to compare the properties of F508del-CFTR in cells treated with either lumacaftor (VX809), tezacaftor, elexacaftor, elexacaftor/tezacaftor with or without ivacaftor. We studied F508del-CFTR function, maturation and membrane localisation by Ussing chamber and whole-cell patch-clamp recordings, Western blot and immunolocalisation experiments. With human primary airway epithelial cells and the cell lines CFBE and BHK expressing F508del, we found that, whereas the combination elexacaftor/tezacaftor/ivacaftor was efficient in rescuing F508del-CFTR abnormal maturation, apical membrane location and function, the presence of ivacaftor limits these effects. The basal F508del-CFTR short-circuit current was significantly increased by elexacaftor/tezacaftor/ivacaftor and elexacaftor/tezacaftor compared to other correctors and nontreated cells, an effect dependent on ivacaftor and cAMP. These results suggest that the level of the basal F508del-CFTR current might be a marker for correction efficacy in CF cells. When cells were treated with ivacaftor combined to any correctors, the F508del-CFTR current was unresponsive to the subsequently acute addition of ivacaftor, unlike the CFTR (cystic fibrosis transmembrane conductance regulator) potentiators genistein and Cact-A1 which increased elexacaftor/tezacaftor/ivacaftor and elexacaftor/tezacaftor-corrected F508del-CFTR currents. These findings show that ivacaftor reduces the correction efficacy of Trikafta. Thus, combining elexacaftor/tezacaftor with a different potentiator might improve the therapeutic efficacy for treating CF patients.
Astaxanthine attenuates cisplatin ototoxicity in vitro and protects against cisplatin-induced hearing loss in vivo
Authors: Benyu Nan, Zirui Zhao, Kanglun Jiang, Xi Gu, Huawei Li, Xinsheng Huang
Journal: Acta Pharmaceutica Sinica B (2021)

Astaxanthine (AST) has important biological activities including antioxidant and anti-inflammatory effects that could alleviate neurological and heart diseases, but its role in the prevention of cisplatin-induced hearing loss (CIHL) is not yet well understood. In our study, a steady interaction between AST and the E3 ligase adapter Kelch-like ECH-associated protein 1, a predominant repressor of nuclear factor erythroid 2-related factor 2 (NRF2), was performed and tested via computer molecular docking and dynamics. AST protected against cisplatin-induced ototoxicity via NRF2 mediated pathway using quantitative PCR and Western blotting. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential revealed that AST reduced ROS overexpression and mitochondrial dysfunction. Moreover, AST exerted anti-apoptosis effects in mouse cochlear explants using immunofluorescence staining and HEI-OC1 cell lines using quantitative PCR and Western blotting. Finally, AST combined with poloxamer was injected into the middle ear through the tympanum, and the protection against CIHL was evaluated using the acoustic brain stem test and immunofluorescent staining in adult mice. Our results suggest that AST reduced ROS overexpression, mitochondrial dysfunction, and apoptosis via NRF2-mediated pathway in cisplatin-exposed HEI-OC1 cell lines and mouse cochlear explants, finally promoting cell survival. Our study demonstrates that AST is a candidate therapeutic agent for CIHL.
Abstract 43: Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer
Authors: Lawrence B. Snyder, Taavi K. Neklesa, Xin Chen, Hanqing Dong, Caterina Ferraro, Deborah A. Gordon, Jennifer Macaluso, Jennifer Pizzano, Jing Wang, Ryan R. Willard, Nicholas Vitale, Ron Peck, Marcia Dougan Moore, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor
Journal: Cancer Research (2021)

Abstract Prostate cancer is the second leading cause of cancer death in men in the United States. The androgen receptor (AR) plays critical roles in both early disease and advanced prostate cancer. Current therapeutic approaches targeting the androgen/AR axis are initially effective, but castration resistant prostate cancer (CRPC) inevitably develops. CRPC is tightly linked with increased AR activity via gene overexpression, amplification, and gain-of-function mutations. To address these mechanisms of AR-dependent prostate tumor growth, we have developed a novel therapeutic agent, ARV-110, a proteolysis targeting chimera (PROTAC®) that induces a protein-protein interaction between the AR and E3 ubiquitin ligase complexes, leading to the ubiquitination of AR and its subsequent degradation via the proteasome. In vitro, ARV-110 robustly degrades AR in various prostate cancer cell lines with a half-maximal degradation concentration (DC50) of ~1 nM. Whole cell lysate proteomics and ubiquitin proteomics demonstrated high selectivity for AR in VCaP cells. ARV-110 potently downregulates androgen responsive genes, inhibits proliferation and induces apoptosis in AR dependent prostate cancer cells. In vivo, ARV-110 is orally bioavailable and robustly degrades AR with a &amp;gt;90% observed maximum degradation (Dmax) at efficacious doses. ARV-110 significantly and dose-dependently inhibits tumor growth in murine LNCaP and VCaP xenograft models, including enzalutamide-resistant VCaP and enzalutamide-insensitive patient-derived xenograft models. These preclinical data supported the clinical development of ARV-110 for the treatment of men with metastatic CRPC. The discovery, chemical structure and initial clinical data of ARV-110 will be presented Citation Format: Lawrence B. Snyder, Taavi K. Neklesa, Xin Chen, Hanqing Dong, Caterina Ferraro, Deborah A. Gordon, Jennifer Macaluso, Jennifer Pizzano, Jing Wang, Ryan R. Willard, Nicholas Vitale, Ron Peck, Marcia Dougan Moore, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor. Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 43.
Human volatilome analysis of patients with prostate cancer: prospective, two-arm non-randomized monocentric study
Authors: A. Filianoti, M. Costantini, U. Anceschi, A.M. Bove, A. Brassetti, M.C. Ferriero, R. Mastroianni, L. Misuraca, G. Tuderti, G. Ciliberto, G. Simone
Journal: European Urology (2021)
CDC Recommends Self-injected Contraceptive Option
Authors: Bridget M. Kuehn
Journal: JAMA (2021)

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Cytotoxic T lymphocytes regenerated from iPS cells have therapeutic efficacy in a patient-derived xenograft model of renal cell carcinoma
Authors: S. Kashima, T. Maeda, K. Masuda, S. Nagano, T. Inoue, T. Kobayashi, K. Terada, Y. Agata, K. Numakura, M. Saito, S. Narita, M. Yasukawa, O. Ogawa, H. Kawamoto, T. Habuchi
Journal: European Urology (2021)
Abstract 2901: Pdcd4 inhibits slug translation to suppress E-cadherin expression and invasion in colon tumor cells
Authors: Qing Wang, Jiang Zhu, Hsin-Sheng Yang
Journal: Cancer Research (2021)

Abstract Programmed cell death 4 (Pdcd4) has been demonstrated to function as a tumor suppressor and protein translation inhibitor. We previously reported that knockdown of Pdcd4 down-regulated E-cadherin expression. E-cadherin is a key regulator for tumor cell invasion and metastasis, whose expression is controlled by transcription repressors Snail, Slug, ZEB1/2, and Twist. Both Slug and Snail have been shown to repress E-cadherin expression and contribute to tumor progression in various cancers including colon cancer. Here, we reported that knockdown of Pdcd4 increased Slug protein level but not SLUG mRNA level in colon tumor cells. Conversely, over-expression of Pdcd4 decreased Slug expression. Using sucrose gradient fractionation assays, Pdcd4 knockdown was found to increase the population of SLUG mRNA in the polysomal fractions. These results indicate that Pdcd4 translationally regulates Slug expression. To understand the mechanism by which Pdcd4 regulates Slug translation, the SLUG 5' untranslated region (5'UTR) was cloned and fused with luciferase reporter and named as 5'UTR-Slug-Luc. Knockdown of Pdcd4 significantly enhanced the translation of 5'UTR-Slug-Luc while ectopic expression of Pdcd4 repressed the translation of 5'UTR-Slug-Luc, suggesting that SLUG 5'UTR is an essential element for Pdcd4 to inhibit Slug translation. Moreover, cells treated with silvestrol, an inhibitor for translation initiation factor 4A (eIF4A), significantly suppressed Slug translation. In addition, ectopic expression of Pdcd4 inhibited Slug translation and thereby decreased E-cadherin expression. By contrast, Pdcd4(D418A), a mutant that does not bind with eIF4A, failed to suppress the expression of Slug and E-cadherin. These findings suggest that Pdcd4-inhibited Slug translation is through suppressing eIF4A. Furthermore, knockdown of Slug in Pdcd4 knockdown cells restored the E-cadherin expression and reversed the invasive capacity induced by Pdcd4 knockdown, indicating that up-regulation of Slug contributes to Pdcd4-knockdown enhanced invasion. Taken together, this study demonstrates that Pdcd4 inhibits translation of Slug to regulate E-cadherin expression and invasion in colon tumor cells. Citation Format: Qing Wang, Jiang Zhu, Hsin-Sheng Yang. Pdcd4 inhibits slug translation to suppress E-cadherin expression and invasion in colon tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2901.