tbuckley/cabot-search huggingface dataset:
Abstract 3151: Loss of Axin1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions
Authors: Gabriele Picco, Consalvo Petti, Alessia Centonze, Erica Torchiaro, Alberto Bardelli, Enzo Medico
Journal: Cancer Research (2017)

Abstract In colorectal cancer (CRC), WNT pathway activation by genetic rearrangements of RSPO3 is emerging as a promising target. However, its low prevalence severely limits availability of preclinical models for in-depth characterization. Using a pipeline designed to suppress stroma-derived signal, we find that RSPO3 “outlier” expression in CRC samples highlights translocation and fusion transcript expression. Outlier search in 151 CRC cell lines identified VACO6 and SNU1411cells as carriers of, respectively, a canonical PTPRK(e1)-RSPO3(e2) fusion and a novel PTPRK(e13)-RSPO3(e2) fusion. Both lines displayed marked in vitro and in vivo sensitivity to WNT blockade by the porcupine inhibitor LGK974, associated with transcriptional and morphological evidences of WNT pathway suppression. Long-term treatment of VACO6 cells with LGK974 led to the emergence of a resistant population carrying two frameshift deletions of the WNT pathway inhibitor AXIN1, with consequent protein loss. Suppression of AXIN1 in parental VACO6 cells by RNA interference conferred marked resistance to LGK974. These results provide the first mechanism of secondary resistance to WNT pathway inhibition. Citation Format: Gabriele Picco, Consalvo Petti, Alessia Centonze, Erica Torchiaro, Alberto Bardelli, Enzo Medico. Loss of Axin1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions [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 3151. doi:10.1158/1538-7445.AM2017-3151
Metabolic Syndrome in Long-Term Survivors of Childhood Acute Leukemia Treated without Hematopoietic Stem Cell Transplantation: An L.E.Α. Study
Authors: Paul Saultier, Pascal Auquier, Yves Bertrand, Camille Vercasson, Claire Oudin, Audrey Contet, Dominique Plantaz, Marilyne Poirée, Stéphane Ducassou, Justyna Kanold, Marie-Dominique Tabone, Jean-Hugues Dalle, Patrick Lutz, Virginie Gandemer, Nicolas Sirvent, Sandrine Thouvenin, Julie Berbis, Hervé Chambost, André Baruchel, Guy Leverger, Gérard Michel
Journal: Blood (2016)
Abstract 4631: Enhanced glycolysis promotes function of tumor associated macrophages in mouse breast cancer model
Authors: Yan Liu, Wei Zhou, Wei Wang, Lipeng Bai, Huiwen He, Jian Guo, Yunping Luo
Journal: Cancer Research (2017)

Abstract Tumor associated macrophages(TAMs) represent a major part of immune cells in tumor microenvironment(TME) and play crucial roles in promoting tumor progression by secreting cytokines or enzymes that could remodel TME or enhance envision or migration capabilities of tumor cells. Given their indispensable effect on tumor, the mechanisms underlying TAMs’ tumor-promoting phenotype and function remain unclear. Glucose metabolism in tumor cells has been intensively studied; however, the status of glucose metabolism of TAMs is still unclear. In this study, we aim to identify glucose metabolism status in TAMs, and explore how glucose metabolism regulates phenotype and function of TAMs. In the begining, we isolated TAMs from 4T1 mouse breast tumor, spleen macrophages from normal mouse as a control, and performed RNA sequencing to analyze the expression pattern in glucose metabolism related genes. The results from transcriptomics showed that TAM shown up regulation of glycolysis genes pattern. Then we analyzed and found that HK’s activity was increased while IDH’s activity was decreased in mouse breast cancer moel. Furthermore, In vitro, we found that up regulation of impotent glycolysis genes including HK2, PFK-L and LDHA in mouse peritoneal macrophages (CMPM) and mouse bone marrow derived macrophages (CMBMDM) conditionally cultured with 4T1 supernatants. Glucose consumption or production of lactate and ATP were also increased in CMPM or CMBMDM. Then we monitored lactate producing rate with seahorse energy metabolism detector, and found that either CMPM or CMBMDM produced lactate faster than that of control. Moreover, inhibition of LDHA activity by oxamate ( inhibitor) also decreased glucose consumption and lactate production. Importantly, the expression of Arg1 and CD206, positively correlated with glycolysis and function of TAMs. Finally, we search the underneath mechanism and found PI3K/AKT pathway was activated in CMPM or CMBMDM. In detail it was found that p-p85 and p-AKT was upregulated at 8 hour after 4T1 supernatants stimulation. Inhibition of PI3K/AKT pathway by LY294002 (PI3K inhibitor), notably inhibited the expression of glycolysis genes and markers of TAMs, which indicated that PI3K/AKT pathway maybe involved in glycolysis of TAMs. Together, we identified that TAMs adopted glycolysis as a major way to consume glucose and glycolysis was directly contributed to the phenotype and function of TAMs, which was regulated by PI3K/AKT signaling pathway. Citation Format: Yan Liu, Wei Zhou, Wei Wang, Lipeng Bai, Huiwen He, Jian Guo, Yunping Luo. Enhanced glycolysis promotes function of tumor associated macrophages in mouse breast cancer model [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 4631. doi:10.1158/1538-7445.AM2017-4631
Abstract 1529:Scutellaria baicalensistargets the hypoxia-inducible factor-1α and attenuates ovarian cancer growth
Authors: Imran Hussain, Sana Waheed, Kashif A. Ahmad, John E. Pirog, Viqar Syed
Journal: Cancer Research (2017)

Abstract Hypoxia-inducible factor-1alpha (HIF-1α), a transcription factor important for maintaining cellular oxygen homeostasis, is aberrantly upregulated in many tumors and implicated in angiogenesis, metastasis and drug resistance. Therefore, developing treatments that target HIF-1α may be a viable therapeutic approach. For centuries, traditional Chinese medicine has used herbs, such as Scutellaria baicalensis (SB), as a natural remedy for tumors. However, the mechanisms by which SB inhibits tumor growth are not known. We have previously reported that SB inhibits cancer cell proliferation and targets NF-κB in endometrial and ovarian cancers and TGF-β in endometrial cancers. In this study, we examined the effects of SB on HIF-1α protein levels in three ovarian cancer cell lines, SKOV3, OVCA 429, and OVCA 420, grown under normoxic and hypoxic conditions. When treated daily with SB, cancer cells showed a decrease in HIF-1α expression after 48 hours. Investigation into the molecular mechanisms of SB-induced inhibition revealed a significant reduction of HIF-1α accumulation in cells treated with cycloheximide, a protein synthesis inhibitor. Further decrease of HIF-1α accumulation was seen when cycloheximide was combined with SB. Additionally, SB- induced HIF-1α proteasomal degradation was prevented by treatment of cells with proteasomal inhibitor MG132 and chloroquine, lysosome inhibitor, abrogated SB-induced inhibition of HIF-1α. Activation of PI3K/AKT and MAPK/ERK is shown in cancers. SB reduced levels of phospho-AKT and phospho-extracellular signal-related kinase (ERK) in ovarian cancer cells. Furthermore, pretreatment of cells with LY294002 (phosphoinositide 3-kinase inhibitor) and PD98059 (mitogen-activated protein kinase kinase inhibitor) reduced HIF-1α expression comparable to SB-treated cells. Hypoxia-induced cisplatin resistance is a major challenge in therapy of ovarian tumors. SB reduces the proliferation and reverses cisplatin resistance in ovarian cancer cells by attenuating the expression of HIF-1α. Taken together, the findings suggest that targeting HIF-1α with SB could be an effective treatment strategy for ovarian cancer and that SB can improve the sensitivity of cells to cisplatin. Note: This abstract was not presented at the meeting. Citation Format: Imran Hussain, Sana Waheed, Kashif A. Ahmad, John E. Pirog, Viqar Syed. Scutellaria baicalensis targets the hypoxia-inducible factor-1α and attenuates ovarian cancer growth [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 1529. doi:10.1158/1538-7445.AM2017-1529
Abstract 1251: Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice
Authors: Miki Miyazawa, Kotha Subbaramaiah, Priya Bhardwaj, Xi Kathy Zhou, Hanhan Wang, Domenick J. Falcone, Dilip D. Giri, Andrew J. Dannenberg
Journal: Cancer Research (2017)

Abstract Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and poor prognosis for PC patients. Recently, we showed that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by crown-like structures (CLS) consisting of dead or dying adipocytes surrounded by macrophages, was associated with high-grade PC in men. It’s possible, therefore, that agents that suppress periprostatic WAT inflammation will alter the natural history of PC. Pioglitazone, a ligand of PPARγ, is used to treat diabetes and possesses anti-inflammatory properties. Here our main objectives were to determine if pioglitazone inhibited obesity-related periprostatic WAT inflammation in mice and then to elucidate the underlying mechanism. Mice were fed either a high fat (HF) diet or low fat (LF) diet to determine if obesity caused periprostatic WAT inflammation as defined by the presence of CLS. To determine if pioglitazone inhibited obesity-associated periprostatic WAT inflammation, obese HF diet fed mice were either continued on HF diet alone or treated with HF diet containing two doses (0.005% or 0.05% w/w) of pioglitazone. Treatment with pioglitazone reduced the density of CLS in periprostatic WAT, and suppressed levels of TNF-α, TGF-β and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in MCP-1 knock out mice. Pioglitazone caused dose-dependent induction of both adiponectin, an anti-inflammatory adipokine, and its receptor AdipoR2 in cultured 3T3-L1 cells and in periprostatic WAT of obese mice. Pioglitazone blocked TNF-α-mediated induction of MCP-1 in 3T3-L1 cells, an effect that was attenuated when either adiponectin or AdipoR2 were silenced. Taken together, pioglitazone-mediated induction of adiponectin suppressed the elevation in MCP-1 levels thereby attenuating obesity-related periprostatic WAT inflammation. These findings strengthen the rationale for future efforts to determine whether targeting the PPARγ-adiponectin-MCP-1 axis will decrease periprostatic adipose inflammation and thereby reduce the risk of high-grade PC or improve outcomes for men with PC. Citation Format: Miki Miyazawa, Kotha Subbaramaiah, Priya Bhardwaj, Xi Kathy Zhou, Hanhan Wang, Domenick J. Falcone, Dilip D. Giri, Andrew J. Dannenberg. Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice [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 1251. doi:10.1158/1538-7445.AM2017-1251
Abstract 739: Orthogonal validation of oncomine cfDNA panel data with digital PCR using TaqMan Rare Mutation Assays
Authors: Vidya Venkatesh, Marion Laig, Kamini Varma, Yanchun Li, Kelli Bramlett, Dalia Dhingra, Richard Chien
Journal: Cancer Research (2017)

Abstract The discovery of circulating tumor DNA (ctDNA) in the blood, urine and other bodily fluids of cancer patients has led to a new type of non-invasive method of characterizing cancer-causing mutations, the liquid biopsy. With NGS technologies becoming increasingly sensitive, down to a 0.1% Limit of Detection (LOD), they are rapidly gaining traction as a valid assay for cancer genotyping and have potential to direct cancer treatment plans. The wide-angle view provided by NGS panels, combined with dPCR’s zoomed-in precision detection of DNA provide a comprehensive picture of a cancer’s genetic makeup. By applying these complementary techniques at the appropriate time based on the disease type and stage, cancer treatment will become quicker, more precise and more cost-effective in the future. NGS and digital PCR together provide a complete picture of the cancer genome. As part of our research, we wet-lab tested a subset of Rare Mutation Assays corresponding to the Oncomine cfDNA panel for next generation sequencing. Synthetic plasmid (GeneArt) carrying the mutation was spiked into wild-type genomic DNA to reflect a mutation rate of 0.1%. Wild-type genomic DNA was used as negative control. Thermal cycling was performed according to protocol for digital PCR using the QuantStudio 3D. In this study, we tested a pilot set of samples using AcroMetrix Oncology Hotspot Control and Horizon cfDNA Reference Standard with both NGS using Oncomine cfDNA panel and digital PCR with Rare Mutation Assays. Comparison of NGS and digital PCR results for the same sample showed excellent correlation in the low mutation range around 0.1%. This study confirms that digital PCR using QuantStudio 3D and Rare Mutation Assays is effective as a method for orthogonal validation of NGS data using the Oncomine cfDNA panel. Additionally, TaqMan Rare Mutation Assays offer a sensitive and precise solution for downstream mutation tracking over a time course. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Vidya Venkatesh, Marion Laig, Kamini Varma, Yanchun Li, Kelli Bramlett, Dalia Dhingra, Richard Chien. Orthogonal validation of oncomine cfDNA panel data with digital PCR using TaqMan Rare Mutation Assays [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 739. doi:10.1158/1538-7445.AM2017-739
Targeting malignant properties in glioblastoma multiforme
Authors: Michael Wong, Andrew Kaye, Christopher Hovens
Journal: Clinical Cancer Research (2007)

A30    Background:   Glioblastoma multiforme (GBM) is one of the most aggressive tumours. Intracellular signalling pathway PI3K/Akt and Ras/Erk have been shown to be important in tumour survival. SM018 is a novel compound developed in our laboratory which showed selective activities against the PI3K/Akt and Ras/Erk pathways in cancer cells. Our aim is to investigate the effects of SM018 on GBM in experimental models.   Methods:  Western blot analyses with anti-phospho Akt and anti-phospho Erk antibodies were performed on U87MG and U251MG cells after treatment with SM018. Subcutaneous and intracranial xenograft models were performed in nude mice to assess the in vivo effects of SM018.  Modified Boyden chamber assays were used to assess the effects of SM018 on cellular migration and invasion. The effects of SM018 were further investigated with Matrigel assays. In vivo effects of SM018 were studied with matrigel plug models in mice.   Results:  SM018 inhibits the level of phospho-Akt in U87MG cells but not in U251MG cells. Phospho-Erk level was also only affected in U87MG cells. However, both U87MG and U251MG tumours in mice were significantly reduced in size by SM018 indicating effective tumour control against GBM cells of different molecular makeup. This was shown in both subcutaneous and intracranial models. SM018 inhibits cellular proliferation, migration and invasion in vitro. Cellular invasion was significantly reduced by SM018 in matrigel plug model in mice.   Conclusion:  The present study showed novel effects of SM018 against GBM tumour growth. SM018 is affecting multiple different cellular mechanisms including proliferation, migration and invasion. Orally bioavailable SM018 is a potential new therapy for GBM.
Abstract 5062: Development of a first in class inhibitor of BET bromodomains and dopamine receptor 2
Authors: Makoto Yoshioka, Jay Chauhan, Steven Fletcher, Jeffrey W. Strovel
Journal: Cancer Research (2017)

Abstract ConverGene has developed a first-in-class dual-active small molecule inhibitor that i) inhibits BET family of bromodomain-containing proteins, and ii) antagonizes dopamine receptor D2 (DRD2). BET protein family includes BRD4, an epigenetic reader protein that mediates expression of MYC oncogene. Thus, BRD4 is considered as a cancer therapeutic target to indirectly suppress MYC expression. In addition to being a therapeutic target for psychiatric diseases, DRD2 is emerging as a potential therapeutic target in neuroendocrine tumors, subsets of pancreatic ductal adenocarcinoma and small cell lung cancer. Our lead compound showed high activity in a binding test against BRD4 (Ki = 34 nM); exhibited high bioavailability upon oral administration; profoundly suppressed MYC expression both in vitro and in vivo; inhibited growth of AML and solid tumor cells in xenograft models; potently inhibited both isoforms of DRD2 (IC50 0.1 µM); and interfered with DRD2/β-arrestin/Akt pathway in vitro. Therefore, our BRD4/DRD2 dual-active compounds may hold promise as a novel class of therapeutics that interferes with both cancer growth and maintenance by simultaneously interfering with MYC and DRD2 pathways. We currently are investigating these dual-active compounds in multiple in vitro and in vivo models and expect to report the outcomes at the AACR Annual Meeting in 2017. Citation Format: Makoto Yoshioka, Jay Chauhan, Steven Fletcher, Jeffrey W. Strovel. Development of a first in class inhibitor of BET bromodomains and dopamine receptor 2 [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 5062. doi:10.1158/1538-7445.AM2017-5062
Abstract 114: TG02 induces cell cycle arrest in glioblastoma
Authors: Yu-Ting Su, Robert Chen, Hallie Lappin, Herui Wang, Dragan Maric, Orieta Celiku, Aiguo Li, Mark R. Gilbert, Jing Wu
Journal: Cancer Research (2017)

Abstract Dysregulated cell cycle contributes to the limitless replicative potential of cancer cells. The cyclin-dependent kinases (CDKs) and cyclins, the CDK-regulatory proteins are the key cell cycle machinery and can be targets for cancer therapy. TG02, a pyrimidine-based multi-kinase inhibitor has an anti-glioma effect which was demonstrated by our previous studies. An in vitro kinase spectrum assay of TG02 demonstrated inhibitory effects in several CDKs at the nanomolar level. To further investigate the molecular mechanisms of TG02-induced cell cycle regulation in glioma, a cell cycle analysis was performed by flow cytometry using the Click-It Edu Flow Cytometric Assay Kit in GSC923 and U251 cell lines, a human stem-like cell and patient derived cell line, respectively. Protein expression of CDKs and cyclins was tested by Western blotting. RNAseq analysis using Next Generation Sequencing was performed (only GSC923) and followed by a supervised hierarchical clustering analysis of cell cycle pathways that were derived from Qiangen’s Ingenuity Pathway Analysis (IPA). Our results showed that TG02 treatment results in G2/M-phase arrest in glioma cell lines. The protein expression of CDK1, CDK2, cyclin A2 and cyclinB1 are downregulated in both TG02 treated cell lines. Additionally, RNAseq analysis revealed downregulation of cyclins A2, B1 and B2 and significant irregulation in mRNA expression of G2/M checkpoint and spindle formation proteins, indicating G2 checkpoint and mitosis progression are also affected by TG02. Taken together, we demonstrated that TG02 induced cell cycle G2/M arrest through downregulating CDK and cyclin expression signaling in the preclinical models of glioblastoma. These findings strongly support the further investigation of TG02 as a potential therapy for malignant gliomas. &amp;lt;!–EndFragment–&amp;gt; Citation Format: Yu-Ting Su, Robert Chen, Hallie Lappin, Herui Wang, Dragan Maric, Orieta Celiku, Aiguo Li, Mark R. Gilbert, Jing Wu. TG02 induces cell cycle arrest in glioblastoma [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 114. doi:10.1158/1538-7445.AM2017-114
Abstract 2158: Targeted intracellular disruption of oncogenic p53/HDM2 and p53/HDMX complexes underlies the therapeutic activity of a stapled peptide drug
Authors: Loren D. Walensky, Franziska Wachter, Ann Morgan, Marina Godes, Gregory Bird
Journal: Cancer Research (2017)

Abstract The first anti-cancer stapled peptide drug has now been advanced to clinical testing in relapsed human cancers that retain the expression of wild-type p53. A common mechanism for cancer cell suppression of wild-type p53 is overexpression of the negative regulators HDM2 and HDMX, which neutralize p53 through protein interaction. Selective HDM2 inhibitor molecules can effectively reactivate p53 in certain cancers, but the co-expression of HDMX can cause resistance, highlighting the need for dual HDM2/HDMX targeting. We previously developed stapled peptides modeled after the p53 transactivation domain to harness the natural propensity of this alpha-helical motif to engage both targets with high affinity and selectivity. Here, we demonstrate that ALRN-7041, a next-generation, clinical-grade stapled peptide, achieves time-dependent cellular uptake and nuclear localization without membrane perturbation, dose-dependently dissociates p53/HDM2 and p53/HDMX complexes as assessed by real-time protein interaction monitoring in live cells, and impairs the viability of cancer cells bearing wild-type p53 by inducing a surge in p53 protein level. Applying an unbiased statistical approach to determine which biophysical parameters dictate the cellular uptake of stapled peptides, we elucidated the design features of ALRN-7041 that confer intracellular access, providing a roadmap for generating cell-permeable stapled peptides with on mechanism cellular activity for clinical translation. We find that cancer cells exhibiting a signature of HDM2, HDMX, and wild-type p53 co-expression are strikingly susceptible to ALRN-7041, highlighting the therapeutic potential of dual HDM2/HDMX inhibition by a cell-penetrant stapled peptide in human cancer. Citation Format: Loren D. Walensky, Franziska Wachter, Ann Morgan, Marina Godes, Gregory Bird. Targeted intracellular disruption of oncogenic p53/HDM2 and p53/HDMX complexes underlies the therapeutic activity of a stapled peptide drug [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 2158. doi:10.1158/1538-7445.AM2017-2158