tbuckley/cabot-search huggingface dataset:
Abstract 4568: A novel TGF-beta receptor I kinase inhibitor demonstrated to be an effective immuno-therapy for cancer
Authors: Zusheng Xu, Yangtong Lou, Li Chen, Kun Zeng, Qingrui Sun, Yingying Qu, Wei Wang, Xiaodong Wu, Xiaomei Ge, Ying Gu, Yingjia Zhang, He Zhou
Journal: Cancer Research (2017)

Abstract TGF-beta (TGF-β) pathways, despite serving as tumor suppressor in early stage of carcinogenesis, have shown be one of the key tumor-promoting factors in later-stage tumor progression. TGF-β receptor I kinase (TGF-βR1) inhibitors have shown great potentials in their anti-tumor and anti-metastasis efficacy in preclinical studies and some of them are being tested in the clinical settings. A specific TGF-βR1 inhibitor YL-13027 was developed at Yingli Pharmaceutical. YL-13027 possesses good ADME and PK properties and shows potent inhibition of the TGF-β and receptor interaction both in cell-free and cell-based assays. Functionally, in vitro Treg differentiation assay demonstrated the significant inhibition of the induction of FoxP3 expressing cells as well as inhibiting the secretion of IL-10 by YL-13027. In murine colon cancer CT26 model, YL-13027 was well tolerated and significantly inhibited tumor progression with dose dependency. More mechanistic studies are on-going. These data suggest that YL-13027, a novel TGF-βR1 inhibitor, represents a promising and safe immune modulator and shows great potential as a cancer immuno-therapeutics. Citation Format: Zusheng Xu, Yangtong Lou, Li Chen, Kun Zeng, Qingrui Sun, Yingying Qu, Wei Wang, Xiaodong Wu, Xiaomei Ge, Ying Gu, Yingjia Zhang, He Zhou. A novel TGF-beta receptor I kinase inhibitor demonstrated to be an effective immuno-therapy for cancer [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 4568. doi:10.1158/1538-7445.AM2017-4568
Abstract 193: Inhibitors of MPS1: Discovery of CCT289346, a highly potent, selective and orally available preclinical candidate
Authors: Hannah L. Woodward, Paolo Innocenti, Kwai-Ming J. Cheung, Sébastien Naud, Angela Hayes, Alan T. Henley, Amir Faisal, Grace Mak, Gary Box, Isaac M. Westwood, Michael Carter, Melanie Valenti, Alexis De Haven Brandon, Lisa O’Fee, Harry Saville, Rosemary Burke, Rob van Montfort, Florence Raynaud, Suzanne A. Eccles, Spiros Linardopoulos, Julian Blagg, Swen Hoelder
Journal: Cancer Research (2017)

Abstract MPS1 (also known as TTK), is a dual-specificity protein kinase and one of the main components of the spindle assembly checkpoint. Cancer cells heavily rely on MPS1 to cope with aneuploidy resulting from aberrant numbers of chromosomes and MPS1 has been found to be upregulated in a large number of tumor types. Extensive work by us and other groups has shown that MPS1 inhibitors are effective against a variety of cancers, particularly when used in combination with other drugs, for example, tubulin-targeting agents. We recently reported the structure-based design and discovery of a series of pyrido[3,4-d]pyrimidines inhibitors of MPS1 (1). Advanced compounds showed very potent inhibition of MPS1 in biochemical and cellular assays. However, these compounds suffered from high lipophilicity and pronounced metabolism in human liver microsomes preventing progression into preclinical development. Here we report the optimisation of this series ultimately yielding CCT289346, our preclinical candidate. CCT289346 shows excellent potency, kinase selectivity, and ADME properties including stability in human liver microsomes. The compound has been produced on a kilogram scale and is currently undergoing preclinical development. We will discuss our design approach and hypotheses leading to the discovery of CCT289346 and disclose in vivo efficacy data. References 1. Innocenti P et al. Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. Journal of Medicinal Chemistry. 2016; 59(8):3671-88. Citation Format: Hannah L. Woodward, Paolo Innocenti, Kwai-Ming J. Cheung, Sébastien Naud, Angela Hayes, Alan T. Henley, Amir Faisal, Grace Mak, Gary Box, Isaac M. Westwood, Michael Carter, Melanie Valenti, Alexis De Haven Brandon, Lisa O’Fee, Harry Saville, Rosemary Burke, Rob van Montfort, Florence Raynaud, Suzanne A. Eccles, Spiros Linardopoulos, Julian Blagg, Swen Hoelder. Inhibitors of MPS1: Discovery of CCT289346, a highly potent, selective and orally available preclinical candidate [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 193. doi:10.1158/1538-7445.AM2017-193
Abstract 2534: miRNA expression as potential biomarker for synovial sarcoma
Authors: Laura Pazzaglia, Serena Pollino, Mattia Vitale, Amalia Conti, Piero Picci, Maria Serena Benassi
Journal: Cancer Research (2017)

Abstract Synovial sarcoma (SS) is a rare tumor, with dismal survival when metastatic. SS contains a characteristic translocation (X;18)(p11;q11), representing the fusion of SYT on chromosome 18 with either SSX1, SSX2, or rarely SSX4 on chromosome X The resulting fusion genes appear to be mutually exclusive and concordant in primary and metastatic tumours. New prognostic and predictive factors are needed. Chemokine receptor 4 (CXCR4) is a seven-transmembrane G protein-coupled chemokine receptor and it is the chemokine receptor most commonly expressed in tumour cells, involved in cell migration and invasion, as well as angiogenesis. microRNAs (miRNAs) are involved in post-transcriptional gene expression regulation and control important physiological processes like development, cell differentiation and cell signaling. Altered expression of miRNAs is strongly correlated with the malignant phenotype and there is data reporting a strong association between microRNA expression, patient age and STS prognosis. By three different databases (miRBase, TargetScan , miRanda) and by literature data we identified two miRNA regulators of CXCR4, miR-133b and miR-494. The expression of these miRNAs was evaluated by RT-PCR in 42 SS primary samples stored at Rizzoli biobank. 20 tissues from non oncologic patients were used as control. Our results showed a significant lower expression of miR-133b and miR-494 (respectively p=0.0005 and p=0.001) when compared to non tumor tissue. In vitro study on SW982 cell line with miR-133b precursor show a CXCR4 downregulation and a decrease of cell proliferation. Our preliminary data confirmed a miR-133b and miR-494 downregulation in SS. Correlation with clinical data, with CXCR4 expression and in vitro studies also with miR-494 in several SS cell lines are on-going to better investigate their role as potential prognostic and therapeutic markers. Citation Format: Laura Pazzaglia, Serena Pollino, Mattia Vitale, Amalia Conti, Piero Picci, Maria Serena Benassi. miRNA expression as potential biomarker for synovial sarcoma [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 2534. doi:10.1158/1538-7445.AM2017-2534
Abstract 2148: Phenyl butyrate inhibits pyruvate dehydrogenase kinase 1 and contributes to its anti-cancer effects
Authors: Wen Zhang, Kin Yip Tam
Journal: Cancer Research (2017)

Abstract In cancer cells, the metabolic features are significantly different from those of normal ones, which are hallmarks of several malignancies. Recent studies brought atypical cellular metabolism, such as aerobic glycolysis or the Warburg effect, into the scientific limelight. Pyruvate dehydrogenase kinase 1 (PDK1), a key enzyme in the pathway of glucose metabolism, could inactivate the pyruvate dehydrogenase (PDH) by phosphorylating it and preserving the substrates pyruvate, lactate and alanine for gluconeogenesis. Overexpression of PDK1 could block the oxidative decarboxylation of pyruvate to satisfy high oxygen demand in cancer cells, while inhibition of PDK1 could upregulate the activity of PDH and rectify the balance between the demand and supply of oxygen, which could lead to cancer cell death. Thus, inhibitors targeting PDK1 might be a promising strategy for cancer treatment by acting on glycolytic tumors while showing minimal side effects on the oxidative healthy organs. Phenyl butyrate (PB) has been proved to decrease PDH phosphorylation level and increase PDH activity by inhibiting PDK1 in fibroblast cells, PDH deficiency zebrafish and wild type mice. PB has also shown efficacy in many cancers and so far, all of its anti-tumor activity has been attributed to the histone deacetylase (HDAC) inhibitor mode of action. As PDK1/PDH controls the critical switch between oxidative phosphorylation and glycolysis in cancer cells, PDK1 is a key target in tumor metabolism for anti-cancer treatment. We hypothesize that the therapeutic effects of PB in cancers might depend on suppressing PDKs and promoting PDH activity, in addition to its proposed role as HDAC inhibitor. We showed that PB directly inhibited the kinase activity of PDK1 in a purified system. In several different cancer cell lines, PB reduced the phosphorylation level of PDH, increased the mitochondrial respiration, decreased glycolysis in cytoplasm, reversed mitochondrial hyperpolarization, activated some proteins in apoptotic signalling pathway and then induced the apoptosis of cells. In summary, this is the first study indicated that PB could exert its anti-cancer effects through inhibiting PDK1, altering the mitochondrial bioenergetics and inducing apoptosis. Note: This abstract was not presented at the meeting. Citation Format: Wen Zhang, Kin Yip Tam. Phenyl butyrate inhibits pyruvate dehydrogenase kinase 1 and contributes to its anti-cancer effects [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 2148. doi:10.1158/1538-7445.AM2017-2148
Abstract 1670: Identification and characterization of novel mediators of tumor-induced T-cell dysfunction
Authors: Geoffrey J. Markowitz, Mary Philip, Andrea Schietinger, Vivek Mittal
Journal: Cancer Research (2017)

Abstract Immunotherapies targeting T-cell functionality have been shown to have efficacy in numerous cancers, including non-small cell lung cancer (NSCLC). However, treatment with currently available therapeutics, such as anti-PD-1 and anti-CTLA-4, induce responses only in a subset of patients. This raises the possibility that numerous other effectors of T-cell dysfunction remain to be elucidated. To evaluate possible novel mediators of T-cell dysfunction, we isolated CD8+ T-cells from orthotopic KrasG12D/p53-/- murine lung adenocarcinomas (HKP-1) that exhibited either stable or progressive disease as a function of tumor growth. RNAseq analysis revealed increased expression of several genes including Tim3, PD-1, Lag3, 2B4, and CISH, and decreased expression of GzmB and Eomes in CD8+ T-cells isolated from progressive tumors indicative of a dysfunctional state, as well as multiple novel genes not previously associated with T-cell dysfunction. To explore the functional role of the novel candidate genes, we have developed in vitro and in vivo assays leveraging Ova and GFP overexpression in our HKP-1 cell line (KP1-Ova-GFP). We have begun to target these unique set of candidate genes in tumor-specific T-cells associated with dysfunction through innovative RNAi/shRNA and adoptive transfer approaches to facilitate therapeutic reprogramming and enhanced T-cell-mediated immunity in lung cancer. We expect to provide novel strategies for designing rational immunotherapies targeting dysfunctional tumor-specific CD8+ T-cells to generate durable anti-tumor immune responses for the treatment of lung adenocarcinoma. Citation Format: Geoffrey J. Markowitz, Mary Philip, Andrea Schietinger, Vivek Mittal. Identification and characterization of novel mediators of tumor-induced T-cell dysfunction [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 1670. doi:10.1158/1538-7445.AM2017-1670
Abstract 3449: Genistein inhibits renal cancer progression through long non-coding RNA HOTAIR suppression
Authors: Mitsuho Imai-Sumida, Shahana Majid, Pritha Dasgupta, Priyanka Kulkarni, Sharanjot Saini, Divya Bhagirath, Taku Kato, Shigekatsu Maekawa, Yutaka Hashimoto, Marisa Shiina, Guoren Deng, Varahram Shahryari, Yuichiro Tanaka, Rajvir Dahiya, Soichiro Yamamura
Journal: Cancer Research (2017)

Abstract Genistein, a soy isoflavone, has been shown to have anticancer effects on various cancers in vitro and in vivo including renal cancer. Long non-coding RNAs (lncRNAs) are differentially expressed in various tissues and have important functions in cellular processes such as cell proliferation, motility and apoptosis in various malignancies. HOX transcript antisense RNA (HOTAIR) is a lncRNA localized in the Homeobox C gene cluster on chromosome 12. HOTAIR interacts with the polycomb repressive complex 2 (PRC2), which enhances H3K27 trimethylation and represses the expression of tumor suppressors. In various cancers, HOTAIR is highly expressed and involved in their progression and metastasis. In this study, we investigated the molecular mechanisms of genistein action through a novel pathway that represses HOTAIR. We found that HOTAIR expression is higher in renal cancer cell lines compared to normal controls. Genistein treatment was found to significantly decrease HOTAIR expression in renal cancer cells (786-O and ACHN cells). Genistein treatment also reduced expression of epithelial-to-mesenchyme transition (EMT)-related proteins (ZEB1, Vimentin and Snail), causing reduced cell migration, invasion, and increased apoptosis. We performed RNA immunoprecipitation assays, and found that genistein inhibits HOTAIR binding to PRC2. One of the other EMT markers, a tight junction protein ZO-1, is upregulated by genistein. We are currently investigating if genistein represses PRC2 recruitment to the ZO-1 promoter by inhibiting binding of HOTAIR to PRC2. Our results indicate that genistein is a potent therapeutic agent for renal cancer. Citation Format: Mitsuho Imai-Sumida, Shahana Majid, Pritha Dasgupta, Priyanka Kulkarni, Sharanjot Saini, Divya Bhagirath, Taku Kato, Shigekatsu Maekawa, Yutaka Hashimoto, Marisa Shiina, Guoren Deng, Varahram Shahryari, Yuichiro Tanaka, Rajvir Dahiya, Soichiro Yamamura. Genistein inhibits renal cancer progression through long non-coding RNA HOTAIR suppression [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 3449. doi:10.1158/1538-7445.AM2017-3449
Abstract 5419: The relationship between glutamatergic signaling and altered glutamine metabolism in melanoma
Authors: Raj Shah, Andrew Boreland, Suzie Chen
Journal: Cancer Research (2017)

Abstract Aberrant glutamatergic signaling has been implicated in many cancer types, and is associated with dysregulated growth leading to cellular transformation and tumorigenesis. Our laboratory has previously illustrated the oncogenic properties of a neuronal receptor, metabotropic glutamate receptor 1 (GRM1) in melanocytes. Glutamate is the natural ligand of GRM1 and the major excitatory neurotransmitter in the central nervous system. Our group has demonstrated that glutamate production/release is upregulated in GRM1 expressing melanoma cells, resulting in constitutive activation of GRM1 and GRM1-associated downstream signaling pathways. We hypothesize that this activation of GRM1 in melanoma cells is associated with higher expression of c-Myc and increased enzymatic activity of glutaminase (GLS) converting glutamine to glutamate. We showed that reducing the extracellular glutamate levels by an inhibitor of glutamate release, Riluzole, led to significantly reduce melanoma cell proliferation in vitro and tumor progression in vivo. We also demonstrated that inclusion of CB-839, a potent, selective, and orally bioavailable GLS inhibitor, resulted in a significant inhibition of GRM1-expressing melanoma cell proliferation compared to GRM1 negative melanoma cell lines. Interestingly, we found that simultaneous targeting of glutamate production (CB-839) and release (Riluzole) in GRM1 expressing melanoma cells led to enhanced suppression of cell proliferation in vitro. Additionally, we found that wild type BRAF melanoma cells are more sensitive to CB-839 than mutated BRAF cells while responses to Riluzole were independent of BRAF genotypes. Furthermore, our data indicate that CB-839 acts by reducing the function, not the expression, of GLS. Currently, we are investigating the relationship between GRM1, c-Myc and GLS by genetic and pharmacological approaches, and if this cascade of events is linked with altered glutamine metabolisms described for many human cancers including melanoma. Citation Format: Raj Shah, Andrew Boreland, Suzie Chen. The relationship between glutamatergic signaling and altered glutamine metabolism in melanoma [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 5419. doi:10.1158/1538-7445.AM2017-5419
Abstract 4853: NRP2b, a unique isoform of NRP2, promotes aggressive lung cancer phenotypes
Authors: Anastasios Dimou, Patrick Nasarre, Joyce Nair-Menon, Federico Cappuzzo, Lorenza Landi, Armida D'Incecco, Hidetaka Uramato, Takeshi Yoshida, Eric Haura, Monica Gooz, Kent Armeson, Robert Gemmill, Harry Drabkin
Journal: Cancer Research (2017)

Abstract Neuropilins (NRPs) 1 and 2 are highly-related receptors for class 3 semaphorins, and interact with heparin-binding growth factors and their receptors (e.g. HGF-MET, VEGF-VEGFR2 etc.). We previously reported that NRP2 is upregulated by TGFβ and is required for its pro-tumorigenic activity. Here, we show that this upregulation preferentially involves NRP2b, a largely uninvestigated isoform encoding a divergent, yet highly-conserved C-terminus. Importantly, using a panel of lung cancer cell lines and orthotopic metastasis model, NRP2b promoted migration, invasion, metastasis and tumorsphere formation, whereas the prototype receptor, NRP2a had opposite effects. TGFβ-mediated resistance to gefitinib in EGFR mutated tumors also was dependent on NRP2b expression. In addition, NRP2b, but not NRP2a, linked MET activation by HGF to AKT phosphorylation. Mechanistically, in co-immunoprecipitation assays, we found that NRP2a robustly interacted with PTEN, while the interaction with NRP2b was weak. At the clinical level, NRP2b expression was commonly upregulated in patient lung cancer samples and this upregulation was a significant poor-prognostic factor. Collectively, these data indicate that NRP2b plays an important role in lung cancer invasion, metastasis and EGFR inhibitor resistance. Furthermore, isoform-specific interactions between NRP2 and PTEN may be responsible for the observed differences in MET signaling in response to HGF. Citation Format: Anastasios Dimou, Patrick Nasarre, Joyce Nair-Menon, Federico Cappuzzo, Lorenza Landi, Armida D'Incecco, Hidetaka Uramato, Takeshi Yoshida, Eric Haura, Monica Gooz, Kent Armeson, Robert Gemmill, Harry Drabkin. NRP2b, a unique isoform of NRP2, promotes aggressive lung cancer phenotypes [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 4853. doi:10.1158/1538-7445.AM2017-4853
Abstract 2059: Co-treatment of XL019, a selective Jak2 inhibitor, highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition
Authors: Ji Hyun Cheon, Yu Jin Park, Ji Yeon Son, Sung Pil Yoon, Hyung Sik Kim
Journal: Cancer Research (2017)

Abstract 1 Co-treatment of XL019, a selective Jak2 inhibitor, highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition Ji Hyun Cheon1, Yu Jin Park, Ji Yeon Son, Sung Pil Yoon, and Hyung Sik Kim Lab of molecular of toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, South Korea A high expression of P-glycoprotein (P-gp) is consistently observed in multidrug resistance (MDR) cancer cells. The purpose of our study was to identify conditions that would increase the sensitivity of P-gp-overexpressing drug-resistant KBV20C cancer cell line. We used commercially available epigenetic library, which includes 128 compounds. Using cellular viability test, we identified that XL019 highly sensitized KBV20C-resistant cells to vincristine treatment. However, XL019-induced sensitization was not observed in vincristine-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. Using FACS analysis, western-blot, and annexin V staining, we identified that XL109 sensitized vincristine-treated KBV20C cells via apoptosis and G2 arrest. Furthermore, sensitization potency of XL109 in combination with vincristine was measured in KBV20C cells when comparing with P-gp inhibitor verapamil or another Jak2 inhibitor CEP-33779. We further investigated the mechanisms of XL109 against sensitization of vincristine-treated KBV20C cells. The sensitization mechanism of XL109 was mainly depends on the inhibition of P-gp. In addition, ATPase activity was also conducted to identify as potential role of XL019 in P-gp inhibition. In the docking modeling, XL019 and CEP-33779 showed high binding affinity docking score against ABCB1 receptor protein by -10.590 and -9.104, respectively. Collectively, inhibition of P-gp by XL109 can increase the vincristine-sensitivity in MDR cancer cells through increased apoptosis and G2 arrest. Our findings indicate that Jak2 inhibitor may be a promising target in the treatment of patients resistant to anti-mitotic drug. Note: This abstract was not presented at the meeting. Citation Format: Ji Hyun Cheon, Yu Jin Park, Ji Yeon Son, Sung Pil Yoon, Hyung Sik Kim. Co-treatment of XL019, a selective Jak2 inhibitor, highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition [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 2059. doi:10.1158/1538-7445.AM2017-2059