tbuckley/cabot-search huggingface dataset:
Abstract 2580: Ceramide-rubusoside nano-micelles restores p53-mediated tumor suppression in p53R248W mutant ovarian cancer cells
Authors: sachin K. khiste, Zhijun Liu, Yong-Yu Liu
Journal: Cancer Research (2017)

Abstract Ceramide (Cer), a sphingolipid metabolite, has crucial functions in anti-proliferation, cell differentiation and apoptosis. Cellular Cer levels highly correlates to therapeutic efficacy of anticancer drugs, however, the hydrophobicity Cer has limits to develop it as a therapeutic agent. Here, we report that Cer-rubusoside (Cer-RUB) nanomicelles enhanced Cer bioavailability and restored p53-mediated tumor suppression. These nanomicelles significantly increased the levels of NBD-C6-Cer by more than 50-fold in serum, 40-fold in tumor and 70-fold in lung of tumor-bearing mice (1 mg/kg, i.p., 24 hr), respectively. Cer-RUB (3 µM) significantly increased OVCAR-3 (p53 R248W) cell sensitivity to cisplatin, and the IC50 values decreased by 3-fold, even though these values were no significant changes in A2780 (wt p53) cells. Furthermore, Cer-RUB treatments (1 mg/kg, i.p. every 3 days for 24 days) significantly increased cisplatin efficacy in tumor growth-arrest in OVCAR-3 tumor-mice, and the tumor volumes reduced by 52% (1653 vs. 805 mm3) in combination with cisplatin, compared to cisplatin alone. We found that ovarian cancer stem cells (CD44+/CD133+) decreased by 10-fold (0.85 vs. 0.08% of total cells) in OVCAR-3 tumors treated with Cer-RUB combined with cisplatin, as compared to cisplatin alone, respectively. Western blotting showed that Cer-RUB treatments selectively increased the expression levels of phosphorylated p53 (Ser15), BAX and p21 in OVCAR-3 cancer cells and tumors, respectively. These studies indicates that the gain-of-function (GOF) of p53 R248W leads OVCAR-3 cell resistance to cisplatin and tumor growth. Cer-RUB can restore p53 and eliminates the GOF of p53 R248W in cancers. Citation Format: sachin K. khiste, Zhijun Liu, Yong-Yu Liu. Ceramide-rubusoside nano-micelles restores p53-mediated tumor suppression in p53R248W mutant ovarian cancer cells [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 2580. doi:10.1158/1538-7445.AM2017-2580
Abstract 557: SPOP mutant subclass prediction and its impact on prostate cancer prognosis
Authors: Deli Liu
Journal: Cancer Research (2017)

Abstract SPOP mutations define a distinct and key molecular class of prostate cancer, but there is no signature to identify SPOP mutant subclass based on transcriptional data, and its impact on prognosis and clinical outcomes of prostate cancer patients is unknown. We developed the SPOP mutant transcriptional signature with high sensitivity and specificity based on transcriptional data. After we predicted SPOP mutant subclass from a large cohort project with transcriptional signature, we studied its association with clinicopathologic variables and prognosis in prostate cancer patients. On univariate analysis, SPOP mutant subclass was associated with lower preoperative serum prostate-specific antigen, extraprostatic extension and older patients (p&amp;lt;0.05). On multivariate analysis, SPOP mutant subclass was associated with metastasis (p&amp;lt;0.05). Combined SPOP mutant status and CAPRA-S models have slightly better prediction for metastasis. On Kaplan-Meier analysis, we found the significant association of SPOP mutant subclass with better patient outcomes of metastasis, and patients without radiation therapy with even better metastatic outcomes. The SPOP mutant subclass could be predicted by using our SPOP mutant signature purely based on transcriptional data. Clinical and prognosis difference were found among SPOP mutant subclass. Citation Format: Deli Liu. SPOP mutant subclass prediction and its impact on prostate cancer prognosis [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 557. doi:10.1158/1538-7445.AM2017-557
Genes associated with metastasis and epithelial-mesenchymal transition (EMT) in human colon cancer cells
Authors: Puei Nam Tay, Tze Chin Tan, Mirtha Laban, Hongqing Liang, Carol Ho-Wing Leung, Shing Chuan Hooi
Journal: Cancer Research (2007)

4707   Metastasis is the leading cause of death among colorectal cancer patients. Although the physiological steps in the metastatic cascade are well defined, the underlying molecular mechanisms are poorly understood. One of the mechanisms of metastasis in colorectal tumors appear to involve primarily cells at the invasive front, where the cells exhibit alterations in epithelial structure/function, leading to enhanced motility and invasion: a process known as epithelial-mesenchymal transition (EMT). Therefore, a global transcriptome analysis of whole tumor samples may obscure important genetic changes that occur in the minority of cells within a tumor. We attempt to identify genes associated with colon cancer metastasis by comparing the gene expression profiles of cell lines with different metastatic abilities. To derive metastatic variants, poorly metastatic HCT116 colon cancer cell line was injected into the spleen of nude mice. Metastatic tumors that formed in the liver were harvested to obtain cell lines whose metastatic ability was confirmed by  in vivo  experiments in nude mice and  in vitro  invasion assays. Gene expression profiles of the derived lines were compared against parental HCT116 cell line by microarray analysis. Amongst the derived metastatic lines, the E1 clonal line, was highly metastatic and most invasive. This line also exhibited characteristics reminiscent of EMT i.e. a transition from epithelial to fibroblast-like morphology with actin cytoskeleton remodeling and decreased cell-cell adhesion. However, the E1 cells did not show any loss of E-cadherin expression nor gain in vimentin expression, molecular markers associated with the epithelial and mesenchymal phenotype, respectively. Novel candidate genes that have not been associated with metastasis before were selected from the above microarray analysis to characterize this EMT-like phenotype and its role in metastasis. One of these genes is palladin, an actin-associated phosphoprotein that binds to several actin-binding proteins such as α-actinin, VASP and ezrin. Palladin was most downregulated in the E1 cell line, both at mRNA and protein levels. Downregulation of palladin was also observed in immunohistochemical studies on liver metastases sections. The dysregulation of palladin expression will be studied with respect to actin remodeling, motility and metastatic ability of the colon cancer cells. Gene expression profile of the E1 cell line as compared to parental HCT116 cell line also showed an upregulation of genes that have been associated with metastasis such as S100A4, Jag1, Tiam1 and upregulation of several genes linked to the Wnt/β-catenin pathway such as Sox4, Sox9, BMP4. The involvement of these genes in the EMT-like phenotype and in colon cancer metastasis and their potential interactions with palladin will be explored.
Abstract 4776: Circulating clusters in breast cancer express cancer stem cell phenotypes
Authors: Ramdane Harouaka, Gabrielle Hodges, Allison David, Rishika Polasani, Spencer Freeman, Katherine Sanchez, Kaitlin Harvey, Max S. Wicha
Journal: Cancer Research (2017)

Abstract Breast cancer is a leading cause of death in women and its metastatic spread to distant organs is responsible for over 90% of these deaths. Circulating tumor cells (CTCs) implicated in the metastatic process occur when cancer cells undergo cytoskeletal and phenotypic transitions that enhance motility, then penetrate into the blood circulation. While CTC dissemination has typically been considered as the spread of single cells, recent evidence suggests that collective migration results in polyclonal circulating clusters that are the main drivers of metastasis. To study circulating clusters we have developed a dual microfiltration system employing two stages of antigen-independent mechanical cell isolation. As whole blood is passed through the system, circulating clusters are trapped by the first stage while single CTCs are retained by the second stage. Characterization experiments using cell lines demonstrated a capture efficiency of 87.1% for clusters and 85.7% for single cells on their respective microfilters. This system was used to investigate circulating cells in the metastatic MMTV-PyMT syngeneic mouse breast cancer model. Both clusters and single CTCs were detected in mice with histological evidence of lung metastases (14-16 weeks old), but not in mice that had not yet developed metastatic tumors (&amp;lt;12 weeks old). Immunofluorescence assays were established to determine expression of CD24, CD90, cytokeratins, CD45 and DAPI. Tumor cells were identified as nucleated cells that expressed epithelial cytokeratins, but not the leukocyte antigen CD45. While PyMT cells with a CD90+/CD24+ stem cell phenotype comprise only ~1.5% of tumors, they were observed in &amp;gt; 50% of circulating clusters. The presence of cancer stem cells was correlated to cluster size, with smaller clusters containing a greater percentage of CD90+/CD24+ cells. Isolated clusters will be further analyzed to quantify expression levels of cancer stem cell markers in each individual constituent cell. The analysis of circulating clusters may provide crucial insight into the mechanisms of metastatic disease and provide the means to discover novel targets for therapeutic intervention. Citation Format: Ramdane Harouaka, Gabrielle Hodges, Allison David, Rishika Polasani, Spencer Freeman, Katherine Sanchez, Kaitlin Harvey, Max S. Wicha. Circulating clusters in breast cancer express cancer stem cell 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 4776. doi:10.1158/1538-7445.AM2017-4776
Abstract 725: Feasibility and evaluation of exosomal RNAs as novel diagnostic biomarkers for high grade serous epithelial ovarian cancer
Authors: Emily N. Prendergast, Xianzhi Lin, Rosario I. Corona, Dennis J. Hazelett, Beth Y. Karlan, Kate Lawrenson
Journal: Cancer Research (2017)

Abstract Introduction: High-grade serous ovarian cancer (HGSOC) survival has been essentially unchanged over the last ten years despite new therapeutic strategies. In order to make a large-scale impact on overall survival, early detection strategies are imperative. Exosomes are cell-derived vesicles derived from multivesicular bodies or the plasma membrane that carry a variety of biomolecules, including protein, DNA, and RNA. Exosomal contents represent a novel and underexplored source of tumor biomarkers, in particular for HGSOC. This study aimed to first evaluate approaches to exosomal RNA purification and to then compare the exosomal RNA profiles from serum of patients with benign ovarian disease and HGSOC to determine if unique profiles exist, and to identify biomarkers useful for early detection. Methods: Cell free serum was obtained from patients in each of the following categories: HGSOC with early (n=24) or late stage (n=24) disease, benign ovarian masses (n=24) and healthy age-matched controls (n=24). We compared ultracentrifugation and a commercial precipitation solution to enrich and isolate exosomes. Exosomal enrichment was confirmed by both transmission electron microscopy (TEM) and western blot using anti-CD63 antibodies. RNA was extracted for each and deep sequencing analysis was performed for 12 candidates within each group. A second cohort of 48 samples will be used for validation of the best performing candidate biomarkers from the discovery cohort via RT-qPCR. Results: Enrichment of exosomes was confirmed via qualitative assessment using TEM and Western blot analysis. RNA quality was superior when RNA isolations were performed using the QIAgen RNeasy kit compared to the AllPrep kit. Mean RNA yield for each group ranged from 10.3-28.6ng/µl and RNA yield and quality was independent of sample age. RNAseq analyses are ongoing to identify biomarkers specific to HGSOC that can be detected at the earliest stages. The top differentially RNAs for the ovarian cancer groups will be validated in an independent cohort of specimens. A panel will then be generated in combination with CA125 to determine the clinical utility of an integrated -omics approach in early stage detection of HGSOC. Conclusions: Efficient isolation of exosomes and RNA can be achieved from archived specimens &amp;gt;10 years old. Evaluation of exosomal RNA in HGSOC provides a novel method for biomarker discovery. Citation Format: Emily N. Prendergast, Xianzhi Lin, Rosario I. Corona, Dennis J. Hazelett, Beth Y. Karlan, Kate Lawrenson. Feasibility and evaluation of exosomal RNAs as novel diagnostic biomarkers for high grade serous epithelial ovarian 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 725. doi:10.1158/1538-7445.AM2017-725
Abstract 5248: Pioglitazone prevents hepatocellular carcinoma development in a rat model of cirrhosis
Authors: Shen Li, Sarani Ghoshal, Gunisha Arora, Derek J. Erstad, Michael Lanuti, Kenneth K. Tanabe, Bryan C. Fuchs
Journal: Cancer Research (2017)

Abstract Introduction: Advanced hepatocellular carcinoma (HCC) is a leading cause of mortality worldwide with limited treatment options. There is a readily identifiable cohort of cirrhosis patients at risk and they are ideal candidates for chemoprevention. Anti-hyperglycemic agents have garnered interest for their potential anti-fibrotic as well as chemo-preventive effects. Pioglitazone, a selective PPAR-γ agonist, has been shown to reduce non-alcoholic steatohepatitis (NASH), but its role as an anti-fibrotic and chemopreventive agent has yet to be elucidated. The hypothesis of this study is that Pioglitazone reduces cirrhosis and subsequent HCC development in rats with diethylnitrosamine (DEN)-induced cirrhosis. Methods: Male Wistar received DEN 50mg/kg by intraperitoneal injection. DEN injury reliably recapitulates histological and molecular features of human HCC development with induction of hepatic fibrosis at 8 weeks, cirrhosis at 12 weeks, and HCC by 18 weeks. DEN-injured rats were randomized to receive oral gavage of pioglitazone at 3mg/kg/day (n=9) or vehicle control (n=9). Initiation of pioglitazone coincided with the development of liver fibrosis at 8 weeks. All animals were sacrificed at 18 weeks. Results: As expected, repeated injections of DEN in rats resulted in progressive fibrosis, cirrhosis, followed by HCC formation. Treatment with pioglitazone resulted in a 56% reduction of surface nodules relative to treatment with vehicle (7.4±4.9 vs. 17±7; p&amp;lt;0.005). Liver sections were stained by picrosirius red to assess fibrosis and pioglitazone significantly reduced collagen deposition in DEN-injured rats (collagen proportional area = 3.2±1.8% vs. 9.2±2%; p&amp;lt;0.035). This histologic observation was further confirmed by gene expression analysis with reductions in collagen-I, α-smooth muscle actin, and transforming growth factor beta in rats treated with pioglitazone. Finally, weekly injection of DEN also caused a significant decrease in overall body weight in comparison to untreated rats (398.1±60 vs. 598±46 grams; p&amp;lt;0.015), and pioglitazone treatment resulted in a trend for better protection of body weight relative to vehicle (398.1±60 vs. 427.5±56.3 grams). Conclusion: Overall our data supports the hypothesis that the anti-diabetic agent pioglitazone may be repurposed as a drug to reduce fibrosis and prevent HCC. This could be beneficiary in patient management given the low cost as well as minimal side effects. Citation Format: Shen Li, Sarani Ghoshal, Gunisha Arora, Derek J. Erstad, Michael Lanuti, Kenneth K. Tanabe, Bryan C. Fuchs. Pioglitazone prevents hepatocellular carcinoma development in a rat model of cirrhosis [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 5248. doi:10.1158/1538-7445.AM2017-5248
Abstract CT159: IFN-γ analysis in blood and tissue as a potential prognostic and/or predictive biomarker
Authors: Nikoletta Kallinteris, Leora Horn, Min Tang, Tobias Guennel, Shen Yin, Jennifer Lai, Joseph Shan, Rachel E. Sanborn
Journal: Cancer Research (2017)

Abstract Background SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer (NSCLC), demonstrated similar overall survival (OS) in both treatment arms. Immune correlate analyses including pre-treatment IFN-γ levels in blood and tumor tissue were used to potentially identify prognostic and/or predictive correlation with clinical outcome. Methods Serum was isolated from all randomized NSCLC patients at screening, periodically during treatment and at disease progression for evaluation of IFN-γ levels using the SimoaTM assay (Myriad RBM, Austin, TX, USA). Available archival tissue was also tested for 91- immune gene activation markers, including IFN-γ by the Fluidigm-based gene-expression platform (Sirona Dx, Lake Oswego, OR, USA). Kaplan-Meier statistical methods and Cox proportion hazards models were utilized to evaluate and contrast the correlation of peripheral and intratumoral IFN-γ levels with OS. Patients were classified paradoxically as IFN-γ "low" with a favorable disease prognosis versus "high" associated with more aggressive disease based on the median. Results Pretreatment serum results were available for 582 out of the 597 randomized patients. Each patient was classified to be pre-treatment IFN-γ high or low (&amp;lt; cut-off) using cut-off 0.093 pg/ml, which is the median IFN-γ value in the D+B group. Median overall survival (mOS) in all patients with IFN-γ low is 11.3 months (95% confidence interval [CI], 10.1-13.5) versus 10.4 months (95% CI, 8.4-11.3) in all IFN-γ high; p=0.047. mOS of D+B arm is 11.6 months (95% CI, 10.2-13.9) and 11.1 months (95% CI, 9.1-14.7) in the D group; p=0.982 for IFN-γ low. mOS of D+B arm is 9.0 months (95% CI, 6.7-11.2) and 10.6 months (95% CI, 8.9-13.0) in the D group; p=0.252 for IFN-γ high. With the limited intratumoral IFN-γ gene expression data (n=33), no statistically significant correlation with OS was observed. Conclusions Correlative approaches identified low peripheral low IFN-γ at pretreatment as a biomarker of interest correlating with more favorable clinical outcomes and is consistent with the hypothesis that bavituximab may demonstrate more immunomodulatory effects in patients with “immune cold” tumors. Citation Format: Nikoletta Kallinteris, Leora Horn, Min Tang, Tobias Guennel, Shen Yin, Jennifer Lai, Joseph Shan, Rachel E. Sanborn. IFN-γ analysis in blood and tissue as a potential prognostic and/or predictive biomarker [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 CT159. doi:10.1158/1538-7445.AM2017-CT159
Abstract 1706: Neoantigen frequency as an independent prognostic factor in patients with clear cell ovarian carcinoma (CCOC)
Authors: Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Akira Nishijima, Yuichi Imai, Kayo Asada, Yuji Ikeda, Takahiro Karasaki, Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhiro Kakimi
Journal: Cancer Research (2017)

Abstract Aim: Neoantigens derived from tumor-specific somatic mutations are thought to be targets for antitumor immune responses. It has been reported that mutation/neoantigen burdens correlate with prognosis of certain cancers under checkpoint blockade immunotherapy. In clear cell ovarian carcinoma (CCOC), checkpoint inhibitors provided durable responses in a subset of patients. To test whether the same may apply in CCOC patients, who are not on immunomodulatory therapy, we investigated the number of mutations or neoantigens, and immune signature of CCOC by integrated molecular analysis. Methods: We performed exome sequencing and expression array for 74 CCOC patients. Candidate neoantigens derived from mutations were identified by MHC class I binding prediction algorism (NetMHCpan v 2.8). Immune signature was assessed by gene ontology and gene set enrichment analyses for immune cell lineage or molecule genes. We also analyzed their relationships with clinical outcomes. Results: Neither number of missense mutations nor neoantigens correlated with clinical outcomes in CCOC. However, we found neoantigen frequency defined here as the number of neoantigens per missense mutation correlated with clinical outcomes. A cox multivariate regression analysis demonstrated that high neoantigen frequency correlated with decreased progression free survival (PFS) and was an independent prognostic factor (p=0.032). Immune-related genes including those related to effector memory CD8 T cell were dominantly expressed in tumors with low neoantigen frequency. This may suggest that CD8 T cell-mediated immunity is constantly eliminating immunogenic subclones expressing neoantigens (immunoediting). In contrast, we observed increased ratio of CTLA-4 and PD-1 to CD8A expression in tumors with high neoantigen frequency. This may imply that restricted antitumor immunity by immunoinhibitory mechanism result in the limited immunoediting and poor prognosis Conclusions: Neoantigen frequency underlying immunoediting in CCOC is an independent prognostic factor for clinical outcome and may become a potential candidate biomarker for an immunomodulatory-based treatment. Citation Format: Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Akira Nishijima, Yuichi Imai, Kayo Asada, Yuji Ikeda, Takahiro Karasaki, Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhiro Kakimi. Neoantigen frequency as an independent prognostic factor in patients with clear cell ovarian carcinoma (CCOC) [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 1706. doi:10.1158/1538-7445.AM2017-1706
Abstract 3258: Genomic analyses define molecular subtype of lung squamous cell carcinoma
Authors: Ji won lee, Ahreum kim, Jong-Yeon shin, Young Tae kim, Jeong-Sun Seo
Journal: Cancer Research (2017)

Abstract Lung squamous cell carcinoma, which account for 25 percent of all lung cancers, have not been well characterized owing to a lack of systematic understanding of molecular pathogenesis. We performed the whole-exome and transcriptome sequencing from 101 tumors and matched normal samples from Korean patients. Somatic mutations and gene expression defined two intrinsic subtypes: (1) classical subtype; (2) immunogenic subtype. Classical subtype displayed upregulation of cell cycle related genes and enriched for gene mutations (TP53, NAV3, NFE2L2, CDKN2A, PIK2CA, KEAP1 and RB1) involved in cell proliferation, squamous differentiation and oxidative stress. Immunogenic subtype had more tumor-infiltrating immune cells than classical type. More proportion of adaptive immune cells was also detected in immunogenic subtype. Immune genes, involved in adaptive immune response, were also upregulated in immunogenic subtype. Taken together, our finding revealed that each subtype has different immune mechanisms in lung squamous cell carcinoma and provides potential opportunities for therapeutic development. Citation Format: Ji won lee, Ahreum kim, Jong-Yeon shin, Young Tae kim, Jeong-Sun Seo. Genomic analyses define molecular subtype of lung squamous cell carcinoma [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 3258. doi:10.1158/1538-7445.AM2017-3258