tbuckley/cabot-search huggingface dataset:
Abstract 5083: A novel and highly efficacious small-molecule degrader of BET-BRD proteins for the treatment of acute leukemia
Authors: Ester Fernandez-Salas, Zhuo Chen, Mei Lin, Bing Zhou, Donna McEachern, Sally Przybranowski, Karson Kump, Luke F. Peterson, Malathi Kandarpa, Jiantao Hu, Fuming Xu, Liu Liu, Longchuan Bai, Bo Wen, Duxin Sun, Moshe Talpaz, Shaomeng Wang
Journal: Cancer Research (2017)

Abstract The bromodomain and extra-terminal domain (BET-BRD) family of lysine acetylation readers comprises BRD2, BRD3, BRD4, and BRDT that contain two conserved N-terminal bromodomains (BD1 and BD2) and a long C-terminal region containing the extraterminal (ET) protein-protein interaction domain. These proteins have key roles in the assembly of transcriptional regulatory complexes containing RNA polymerase II. BET-BRDs are new therapeutic targets for cancer treatment and several small-molecule BET-BRD inhibitors are currently in clinical development for a diverse set of cancers including leukemia. Based on the proteolysis targeting chimera (PROTAC) concept, we have developed novel and highly potent BET degraders, ZBC246 and ZBC260, with exceptional selectivity based upon a new class of BET inhibitor, ZBC11. ZBC260 effectively degrades all BET-BRD proteins at concentrations as low as 30 pM within a few hours of treatment in the RS4;11 leukemia cell line and achieves IC50 values of 50 pM in inhibition of RS4;11 cell growth. ZBC260 was tested in a panel of 10 acute leukemia cell lines generating IC50s ranging from 20 pM to 1 nM in 4-days cell growth inhibition assays. In contrast to the cytostatic effect observed with BET-BRD inhibition, degradation of BET-BRDs by ZBC246 and ZBC260 induced robust apoptosis demonstrating a differential biology between BET-BRD inhibitors and BET-BRD degraders. Significantly, ZBC260 induces rapid regression of RS4;11 xenograft tumors without overt signs of toxicity in mice. More importantly, treatment of leukemia cells obtained from 10 patients with ZBC260 demonstrated efficient degradation of BET-BRDs within 5 h at 0.3 nM, while treatment with the inhibitor (300 nM) induced up-regulation of BET-BRDs. Treatment of patients’ peripheral blasts with ZBC260 at 1 to 10 nM induced remarkable levels of apoptosis within 24 h, even in relapsed and refractory patient samples. In conclusion, ZBC260 represents a highly potent and efficacious BET-BRD degrader undergoing extensive preclinical evaluation for the treatment of acute leukemias. Citation Format: Ester Fernandez-Salas, Zhuo Chen, Mei Lin, Bing Zhou, Donna McEachern, Sally Przybranowski, Karson Kump, Luke F. Peterson, Malathi Kandarpa, Jiantao Hu, Fuming Xu, Liu Liu, Longchuan Bai, Bo Wen, Duxin Sun, Moshe Talpaz, Shaomeng Wang. A novel and highly efficacious small-molecule degrader of BET-BRD proteins for the treatment of acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5083. doi:10.1158/1538-7445.AM2017-5083
Abstract 1430: The spliceosome U2 snRNP factors promote genome stability through distinct mechanisms; transcription of repair factors and R-loop processing
Authors: Michihiro Tanikawa
Journal: Cancer Research (2017)

Abstract (Objective)Recent whole-exome sequencing studies of malignancies have detected recurrent somatic mutations in U2 snRNP components of the spliceosome. These factors have also been listed as novel players of DNA damage response in several genome wide screens and proteome analysis for DDR genes. Although accumulating evidences have implied that the spliceosome plays an important role in genome stability and is an emerging hallmark of carcinogenic pathways, its precise role in genome stability still remains ambiguous. The aim of this study is to clarify the functions of U2 snRNP splicing factors, especially SNRPA1 (Small Nuclear Ribonucleoprotein Polypeptide A1) in DDR pathway. (Methods)SNAPA1 and other U2 snRNP splicing factors were identified as HR repair genes by genome-wide screens based on homologous recombination and RAD51 immunofoci formation. Each splicing factor was depleted by siRNA knockdown in USOS cells. The functions of SNRPA1 in DNA repair were analyzed by HR assay (DR-GFP assay), immunofluorescence, real-time laser micro-irradiation and comet assay (single cell gel electrophoresis). (Results)HR assay showed strong HR deficiencies in splicing factor's depleted cells. In these cells, accumulation of BRCA1 and Rad51, major HR factors, to DNA damage sites were severely impaired. Especially, live cell imaging showed recruitment of SNRPA1 to laser induced DNA damage sites and unveiled its direct involvement to DNA damage repair. Comet assay also showed that depletion of SNRPA1 markedly caused DNA damage with the tail of broken DNA fragments. This DNA damage was R-loop (DNA-RNA hybrid) mediated DNA damage and rescued by overexpression of RNAseH1. (Conclusion) Here we unveiled two distinct pathways how spliceosome U2 snRNP factors contribute to genome stability. The main function is indirect, through transcription, to maintain the protein levels of essential repair factors and contribute to homologous recombination repair. Our data suggest that depletion of splicing factors can be one mechanism for HR deficiency (i.e. BRCAness). In addition real-time laser microirradiation analysis identified the rapid recruitment of SNRPA1 to DNA damage sites. Intensive functional analysis of SNRPA1 unveiled the other, more immediate and direct effect to process R-loop structure, deleterious transcriptional by-products for the genome, at sites of on-going transcription. Citation Format: Michihiro Tanikawa. The spliceosome U2 snRNP factors promote genome stability through distinct mechanisms; transcription of repair factors and R-loop processing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1430. doi:10.1158/1538-7445.AM2017-1430
Abstract 3234: Development of potent and selective antibody-drug conjugates with pyrrole-based KSP inhibitors as novel payload class
Authors: Hans-Georg Lerchen, Sven Wittrock, Nils Griebenow, Mario Lobell, Anne-Sophie Rebstock, Yolanda Cancho-Grande, Beatrix Stelte-Ludwig, Christoph Mahlert, Simone Greven, Anette Sommer, Sandra Berndt, Carsten Terjung, Heiner Apeler, Bertolt Kreft, Rolf Jautelat
Journal: Cancer Research (2017)

Abstract The number of cytotoxic payload classes with different modes-of-action which have been successfully employed in antibody-drug conjugates (ADC) is still rather limited. So far, only ADCs with microtubule inhibitors, DNA binding payloads or topoisomerase I inhibitors have been advanced into clinical testing. To this end, the identification of ADC payload classes with a novel mode of action will increase therapeutic options and potentially help to overcome resistance. Inhibitors of kinesin spindle protein (KSP/Eg5) have generated interest due to their high antitumor potency. However, transferring the preclinical potency of small molecule KSP inhibitors (KSPis) into highly efficient clinical regimens with a sufficient therapeutic window has remained challenging. We have investigated a new pyrrole subclass of KSPis which showed subnanomolar potency against a large panel of tumor cell lines for their utility as a novel payload class in ADCs. Towards this goal different attachment sites for linkers have been explored in the KSPi molecule which were found compatible with cleavable and/or non-cleavable linkers. Subnanomolar potency and selectivity of ADCs with antibodies targeting either HER2, EGFR or TWEAKR could be demonstrated in vitro. For selected ADCs, the intracellular trafficking and metabolite formation was investigated and KSP inhibition was confirmed as the ADC mode of action. Depending on the linker composition differential profiles of the ADC metabolites with regard to efflux, cellular permeation, and bystander effect have been achieved. Moreover, specific accumulation in the tumor versus other tissues was demonstrated in biodistribution studies in vivo. In conclusion, KSP inhibitors have been established as a versatile new payload class for the generation of highly potent and selective ADCs. Citation Format: Hans-Georg Lerchen, Sven Wittrock, Nils Griebenow, Mario Lobell, Anne-Sophie Rebstock, Yolanda Cancho-Grande, Beatrix Stelte-Ludwig, Christoph Mahlert, Simone Greven, Anette Sommer, Sandra Berndt, Carsten Terjung, Heiner Apeler, Bertolt Kreft, Rolf Jautelat. Development of potent and selective antibody-drug conjugates with pyrrole-based KSP inhibitors as novel payload class [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3234. doi:10.1158/1538-7445.AM2017-3234
Abstract 1157: Screening and identification of new generation glucose transporter inhibitors as anticancer therapeutics
Authors: Yanrong Qian, Pratik Shriwas, Xuan Wang, Dennis Roberts, Emma Kessler, Stephen Bergmeier, Xiaozhuo Chen
Journal: Cancer Research (2017)

Abstract Cancer is a top killer second only to cardiovascular diseases. Cellular metabolic reprogramming and altered energetics are key features of cancer. Opportunistic uptake of extracellular nutrients has recently been named as an emerging hallmark of cancer metabolism. Glucose is a key nutrient taken in by cancer cells for satisfying their high energy and biosynthesis needs. Drastic upregulation of glucose uptake and glycolytic activity, a phenomenon called the Warburg effect, is prevalent in cancers. Cancer cells overexpress specific glucose transporters (Gluts), particularly Glut1, on cell membranes for taking in glucose via facilitated diffusion. Considering the addiction of cancer cells for glucose and their sensitivity and vulnerability to changes in glucose supply, Gluts, especially Glut1, have been recognized as an attractive anticancer target. We previously reported the identification of first generation lead Glut1 inhibitor WZB117 (1). WZB117 treatment of human nonsmall cell lung cancer (NSCLC) A549 cells resulted in inhibition of glucose uptake, glycolysis and induction of apoptosis and necrosis. In addition, WZB-117 reduced tumor growth by ~70% in an A549 tumor mouse model. WZB117 inhibit cell growth of 7 cancer cell lines in 4 cancer types with IC50 values lower than 10 μM. Through a structure activity relationship (SAR) study of WZB117, a second generation lead, DRB18, has been identified. DRB-18 is much more stable and 5 to 10 times more potent than WZB117 in inhibiting growth and proliferation in about 90% of the 60 different cancer cell lines in 9 major cancer types as revealed in NCI-60 screenings. And its IC50s in many cancer cell lines are in the high nM range. In this study, we also report new compounds screening results for the objective of identifying novel compounds with higher glucose transport-inhibitory and cancer cell growth-inhibitory activities using nonsmall cell lung cancer cell lines as models. References: 1. Liu, Y., Cao, Y., Zhang, W., Bergmeier, S., Qian, Y., Akbar, H., Colvin, R., Ding, J., Tong, L., Wu, S. and Hines, J., 2012. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Molecular cancer therapeutics, 11(8):1672-1682. Citation Format: Yanrong Qian, Pratik Shriwas, Xuan Wang, Dennis Roberts, Emma Kessler, Stephen Bergmeier, Xiaozhuo Chen. Screening and identification of new generation glucose transporter inhibitors as anticancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1157. doi:10.1158/1538-7445.AM2017-1157
Abstract 2634: EVT801: Standalone cancer immunotherapy in VEGFR3+ tumors and combination with immune checkpoint therapies in VEGFR3- tumors
Authors: Michael Esquerré, Pierre Fons, Gaëlle Badet, Pauline Barron, Jérémy Kagan, Antoine Alam, Jérôme Meneyrol, Isabelle Blanc, Roselyne Broussy, Florence Gaujarengues, Joanna Lisztwan, Michael Paillasse, Mark Whittaker, Françoise Bono
Journal: Cancer Research (2017)

Abstract In collaboration with Sanofi, we previously showed that inhibition of the VEGFR3 pathway by SAR131675 leads to reduction of tumor growth by acting on the tumor microenvironment. We have identified a new drug candidate, EVT801, and evaluated its activity on tumor models expressing VEGFR3. For proof-of-concept, we transfected the mouse BNL hepatoma cell line with VEGFR3. EVT801 displayed a strong therapeutic activity by acting on both VEGFR3+ tumor cells and on the Tumor Microenvironment (TME). By deciphering the mechanism of action of the compounds we showed that EVT801 strongly decreased tumor-associated immunosuppression by decreasing MDSCs (Myeloid Derived Suppressor cells) and CD4+ regulatory T cells and by increasing macrophages with a M1 phenotype inside the tumor. As a consequence the T-cell:MDSC ratios were increased in the TME and also in peripheral blood. In addition to its immunomodulatory properties, EVT801 decreased angiogenesis without increasing hypoxia. We have evaluated EVT801 therapeutic activity in syngeneic tumor mouse models which are not expressing VEGFR3 such as 4T1 mammary carcinoma and CT26 colon carcinoma models. As expected, we observed an intermediate therapeutic activity of the compound on both tumor models. Positive modulation of the TME was equivalent to what we observed with the VEGFR3+ tumor model. With this unique mechanism of action of EVT801 on the TME, we evaluated its ability to increase therapeutic activity of standard Immune Checkpoint Therapies (ICT) such as anti-CTLA-4 and anti-PD-1 mAbs. Strong additive therapeutic activities were observed with EVT801 in combination with these ICT as illustrated by the development of long-term tumor-specific memory CD8+ T cell responses. Toxicological data show that EVT801 has a favorable pharmacological profile consistent with its entry into pre-clinical development. Taken together, these results indicate that EVT801 represents an innovative drug for cancer Immunotherapy which provide a favorable microenvironment to promote tumor regression. In addition, EVT801 may improve the frequency of response to ICT. Citation Format: Michael Esquerré, Pierre Fons, Gaëlle Badet, Pauline Barron, Jérémy Kagan, Antoine Alam, Jérôme Meneyrol, Isabelle Blanc, Roselyne Broussy, Florence Gaujarengues, Joanna Lisztwan, Michael Paillasse, Mark Whittaker, Françoise Bono. EVT801: Standalone cancer immunotherapy in VEGFR3+ tumors and combination with immune checkpoint therapies in VEGFR3- tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2634. doi:10.1158/1538-7445.AM2017-2634
siRNA silencing of mitochondrial thioredoxin-2 or peroxiredoxin-3 increases expression of glutaredoxin-2 and select members of the mitochondrial thioredoxin antioxidant pathway
Authors: Kara E. Rogers, Garth Powis
Journal: Cancer Research (2005)

1942  Urokinase-type plasminogen activator (uPA) is a serine protease and initiates the activation of matrix metalloproteinases (MMPs) as well as the conversion of plasminogen to plasmin. Furthermore, uPA is correlated with migration and invasiveness of normal and cancer cells. To gain insight on relationship between invasion of SW480 E- and R-type cells and uPA gene expression, mechanism of transcriptional regulation of uPA gene and signal transduction pathway by TPA in SW480 E- and R-type cells have been investigated. uPA mRNA were increased with maximal stimulation reached in 2 and 24 hours by TPA in SW480 E- and R-type cells, respectively. The inductions of uPA mRNA were dependent on the concentration of TPA. TPA-dependent induction of uPA mRNA was reduced by pretreatment of actinomycin-D but it was increased by cycloheximide. CAT activity of transfected p-uPA-CAT (-2345) was increased by TPA in SW480 E-type cells, but p-uPA-CAT (-72) was no effect. In DNase I footprinting analysis, the nuclear factors interacting with important three cis-elements were identified in the TPA-reated SW480 E- type cells; PEA3/AP-1 (-1965), AP-1 (-1881) and putative AP-1 (-1685), but NF-kB (-1579) was not detected. The trans-acting factors were bound to each cis element-specific and in proportion to the concentration of nuclear extract. In DNA mobility shift assay, the binding activities of PEA3/AP-1, AP-1 and NF-kB (-1859) were increased by TPA in SW480 E-type cells. TPA-dependent increase of uPA mRNA was inhibited by total protein kinase C inhibitor, Ro 31-8220 and partial inhibited by Rottlerin (protein kinase Cδ inhibitor). Go 6976 (protein kinase Cα, β and μ inhibitor) was no effect. SB 203580 (p38 MAP kinase inhibitor) partially inhibited TPA-dependent increase of uPA mRNA in SW480 E-type cells but PD 98059 (Erk1/2 inhibitor) was no effect. In DNase I footprinting and DNA mobility shift assay, TPA-dependent inductions of PEA3/AP-1, AP-1 and putative AP-1 were vanished by pretreatment of Ro 31-8220, but were not changed by PD 98059 and SB 203580. In zymography, TPA-dependent induction of uPA activity was inhibited by Ro 31-8220 and partially inhibited by SB 203580. TPA-dependent increase of uPA mRNA was inhibited by sulfasalazin and PDTC, and the binding activity of NF-kB (-1579) was also inhibited. TPA-dependent increase of invasiveness of SW480 E-type cells was inhibited by staurosporin as dose-dependent manner. These result suggest that TPA-dependent induction of uPA mRNA is differentially regulated SW480 E- and R type cells, and PEA3/AP-1, AP-1 and NF-kB (-1579) are important to transcriptional regulation of uPA gene. Moreover, protein kinase Cδ and p38 MAP kinase signaling pathway are related to TPA-dependent induction of uPA mRNA.
Gene therapy of cancer using an interleukin-2 transmembrane construct
Authors: Wolfram E. Samlowski, Nathan B. Adams, John R. McGregor
Journal: Cancer Research (2004)

658   Selective expression of cytokines on the surface of tumors is likely to stimulate tumor-infiltrating lymphocytes that are primed and already recognize tumor antigens. This may result in enhanced tumor recognition and killing. This gene therapy approach may avoid toxicity associated with systemic therapy with high doses of the cytokines needed to achieve the same effects. In order to test this concept, we have evaluated an IL-2 gene construct that is designed to induce tumor cells to express a membrane bound form of IL-2 (IL-2tm). A mammalian plasmid expression vector was designed to express a fusion gene consisting of human interleukin 2 with a Fc receptor epsilon transmembrane anchor derived from the gamma subunit of the Fc receptor epsilon. We demonstrated that mRNA and protein for the IL-2tm fusion protein was expressed in transfected RD995 tumor cells. Expression of the IL-2tm protein on the tumor cell surface membrane was confirmed by laser confocal microscopy. In order to assess biological function, RD995 transfected with IL-2tm or the empty expression vector (pCMV2b) were implanted subcutaneously into C3H/HEN mice. Non-transfected RD995 was also implanted subcutaneously for tumor growth comparison (control group). Groups of mice implanted with 10 6  or 10 5  RD995 transfected with IL-2tm grew considerably more slowly than RD995 transfected with pCMV2b or non-transfected control RD995 implanted tumors. Further preclinical evaluation of the IL-2tm gene therapy as a possible cancer treatment is underway.
Abstract 3878: Musashi-2 (MSI2) regulation of ERBB family proteins in non-small cell lung cancer (NSCLC)
Authors: Alexander Kudinov, Alexander Deneka, Anna N. Nikonova, Emmanuelle Nicolas, Vladislav A. Korobeynikov, Ilya G. Serebriiskii, John Karanicolas, Erica A. Golemis, Yanis Boumber
Journal: Cancer Research (2017)

Abstract The purpose of this study is to establish whether a new signaling axis we recently described can be targeted to improve patient survival in lung cancer, one of the leading causes of death worldwide, with over 1.6 million deaths annually. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. A small number of targeted therapies have been shown to be useful in lung cancer, including inhibitors of EGFR, but these are typically only active in a subset of tumors that maintain epithelial characteristics. Musashi-2 (MSI2), an RNA-binding protein that regulates mRNA translation, has been linked to maintenance of a stem cell state in multiple hematologic and solid tumor malignancies. We recently established (Kudinov et al, PNAS 2016, PMID:27274057) that MSI2 is elevated in a subset of NSCLC tumor upon progression and drives NSCLC metastasis, in part based on activity supporting a TGF-beta/SMAD3/claudin signaling cascade that enhances epithelial-mesenchymal transition (EMT). Using reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+;P53R172HΔG/+ murine NSCLC cell line models identified a significant 2.7-fold upregulation of HER3 upon MSI2 depletion. Negative MSI2-dependent regulation of ERBB3 protein expression was confirmed in multiple additional murine and human KRAS-dependent NSCLC models, based on analysis of MSI2 depletion or overexpression. In contrast, MSI2 positively regulated expression of the EGFR/ERBB1 protein in the same models. In detailed analysis, we have addressed the mechanism by which MSI2 regulates expression of the ERBB group of receptor tyrosine kinases. In addition, these data suggested the hypothesis that MSI2 expression might predict response to EGFR-targeted inhibitors, and that dual targeting of MSI2 and EGFR might be therapeutically valuable. We will present data on the activity of EGFR inhibitors in the context of depleted or elevated MSI2 expression, and the effect of combining inhibition of EGFR with recently developed MSI2 inhibitors. In summary, these results for the first time indicate a role of MSI2 in supporting EGFR expression in NSCLC and suggest that MSI2 may drive NSCLC development and progression in part via EGFR, and may modulate response to EGFR-targeted agents. Citation Format: Alexander Kudinov, Alexander Deneka, Anna N. Nikonova, Emmanuelle Nicolas, Vladislav A. Korobeynikov, Ilya G. Serebriiskii, John Karanicolas, Erica A. Golemis, Yanis Boumber. Musashi-2 (MSI2) regulation of ERBB family proteins in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3878. doi:10.1158/1538-7445.AM2017-3878