tbuckley/cabot-search huggingface dataset:
Abstract 550: Predictive value of co-expression network consisting ofFOXM1and its neighbor genes in cancers
Authors: Bic-Na Song, In-Sun Chu
Journal: Cancer Research (2017)

Abstract Purpose: Forkhead box protein M1 (FOXM1) is a key regulator of tumorigenesis. Previous studies demonstrated that FOXM1 expression was strongly correlated with poor prognosis of various cancers. The aim of this study is to define a signature consisting of FOXM1 and its associated genes and assess its prognostic potential in cancers including hepatocellular carcinoma (HCC) and others. Experimental procedures: We analyzed a gene expression profile of 100 patients with HCC to identify FOXM1-correlated genes (the FOXM1 signature) associated with the prognosis of HCC patients. The validity of the FOXM1 signature was verified in an independent HCC cohort (n = 242). Using the signature, we also analyzed different cancer types including pancreatic adenocarcinoma, lung adenocarcinoma, breast carcinoma, and bladder urothelial carcinoma to verify the association between the FOXM1 signature and prognosis. Various statistical methods were applied to signature finding and validation. Upstream regulator and gene-to-gene network analyses were performed to identify potential key mediators of the FOXM1 signature. Results: Through a gene expression profiling in 100 patients with HCC, we identified a gene set consisting of FOXM1 and its co-expressed genes for predicting poor prognosis. A predictive value of the signature was validated in an independent cohort containing 242 HCC patients. In multivariate analysis, the FOXM1 signature showed the most significant prognostic value (HR = 1.706, 95% CI = 1.176-2.475, P = 0.005). By directly applying the signature to four data sets in different cancer types, our signature showed a consistent prognostic significance, regardless of tumor types. Finally, upstream regulator and gene-to-gene network analyses found an interconnection of network hubs composed by FOXM1, MYC, and E2F1 that might be common key mediators of patient survival in cancer. Conclusions: The FOXM1 signature represents a promising common diagnostic tool to identify high-risk cancer patients and may extend treatment options in various cancers. Note: This abstract was not presented at the meeting. Citation Format: Bic-Na Song, In-Sun Chu. Predictive value of co-expression network consisting of FOXM1 and its neighbor genes in cancers [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 550. doi:10.1158/1538-7445.AM2017-550
Abstract 5271: Prostate cancer chemoprevention by dietary isothiocyanates is associated with suppression of lipogenesis
Authors: Krishna B. Singh, Shivendra V. Singh
Journal: Cancer Research (2017)

Abstract Isothiocyanates (ITCs), including sulforaphane (SFN) and phenethyl isothiocyanate (PEITC), have been studied extensively for chemoprevention of prostate cancer using both in vitro and in vivo models, but the underlying mechanism is not fully understood. Dependence on fatty acid metabolism is progressively recognized as a unique trait of prostate cancer. Using in vitro and in vivo prostate cancer models, we demonstrate for the first time, that prostate cancer chemoprevention by ITCs is associated with suppression of fatty acid metabolism. Exposure of human prostate cancer cells to plasma achievable concentrations of SFN resulted in a marked decrease in levels of key fatty acid metabolism proteins, including acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and carnitine palmitoyl transferase 1A (CPT1A), that was accompanied by suppression of their transcription. Consistent with the in vitro results, oral administration of prostate cancer chemopreventive concentrations of SFN (6 µmol per mouse, three times per week) resulted in downregulation of ACC1, FASN, and CPT1A proteins in prostate adenocarcinoma of TRAMP transgenic mice when compared with control. Levels of fatty acid metabolites (free fatty acid, triglycerides and phospholipids), lactate, and acetyl-CoA were also lower in the plasma and/or prostate adenocarcinoma of SFN-treated TRAMP mice in comparison with controls. Because fatty acid oxidation is an important step to supply energy to the prostate cancer cells, we explored the possibility of whether SFN could affect the fatty acid oxidation in prostate cancer cells. Indeed, SFN exposure significantly decreased the level of proteins involved in fatty acid oxidation in prostate cancer cells. Many of these changes were also observed with PEITC. In conclusion, it is reasonable to propose that suppression of fatty acid metabolism is an important mechanism in prostate cancer chemoprevention by ITCs. This study was supported by the grants RO1 CA115498-10 and RO1 CA101753-12 awarded by the National Cancer Institute. Citation Format: Krishna B. Singh, Shivendra V. Singh. Prostate cancer chemoprevention by dietary isothiocyanates is associated with suppression of lipogenesis [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 5271. doi:10.1158/1538-7445.AM2017-5271
Abstract 16970: Relation of Coronary Artery Calcification to Outcomes Among Women Ages 50-59 in the Women’s Health Initiative Estrogen-alone Clinical Trial
Authors: Indu Poornima, Lewis H Kuller, Matthew Allison, JoAnn E Manson, Michael J LaMonte, J. Jeffrey Carr, Yuefang Chang, Rachel H Mackey
Journal: Circulation (2016)

Introduction: In the Women’s Health Initiative (WHI) Estrogen-Alone (E-alone) clinical trial (CT), women aged 50-59 at entry randomized to E-alone had lower risk of myocardial infarction (MI) and m...
Abstract 4448A: MicroRNA profiling of prostate cancer tissue identifies a prognostic 4-miRNA model and implicates one novel microRNA in prostate cancer cell viability
Authors: Linnea Schmidt, Jacob Fredsøe, Helle Kristensen, Anne Rasmussen, Peter Mouritzen, Søren Høyer, Michael Borre, Torben Ørntoft, Karina Dalsgaard Sørensen
Journal: Cancer Research (2017)

Abstract Purpose: New prognostic biomarkers for prostate cancer (PC) risk stratification are urgently needed. Here, we identify and validate a novel 4-microRNA prognostic ratio model for prostate cancer. We also identify a new microRNA with tumor suppressive characteristics in prostate cancer cell lines. Methods: PC tissue samples from 123 radical prostatectomy (RP) patients, 58 of whom experienced biochemical recurrence, were profiled for genome-wide miRNA expression using RT-qPCR (training cohort). Initially, we identified 11 top candidate prognostic microRNAs (P &amp;lt;0.05, univariate Cox regression). Based on these, all possible 2-4 microRNA ratio models were systematically tested for their potential to predict time to biochemical recurrence (BCR), as assessed by Kaplan-Meier, uni- and multivariate Cox regression analyses. The findings were validated in two independent RP cohorts. A novel microRNA, included in the final ratio model and with previously unknown function in prostate cancer, was over expressed using a microRNA mimic in PC3 and DU145 cells to evaluate its effect on prostate cancer cell viability and proliferation. Results: We identified a new prognostic 4-microRNA ratio model ((miR-23a-3p*miR-10b-5p)/(miR-133a*miR-374b-5p)) that significantly predicted time to BCR independently of established clinicopathological variables in a training RP cohort (n=123). The ratio model was successfully validated in two independent RP cohorts including 112 and 476 patients, respectively. Ectopic expression of one of these microRNAs (miR-374b-5p) significantly inhibited viability and proliferation in two prostate cancer cell lines, suggesting it has a tumor suppressor function in PC. Conclusions: Here, we describe the identification and independent validation of a 4-miRNA ratio model that allows risk stratifications of prostate cancer patients undergoing RP into different prognostic groups. Furthermore, we identify and functionally characterize a novel possible tumor suppressor miRNA in prostate cancer. Citation Format: Linnea Schmidt, Jacob Fredsøe, Helle Kristensen, Anne Rasmussen, Peter Mouritzen, Søren Høyer, Michael Borre, Torben Ørntoft, Karina Dalsgaard Sørensen. MicroRNA profiling of prostate cancer tissue identifies a prognostic 4-miRNA model and implicates one novel microRNA in prostate cancer cell viability [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 4448A. doi:10.1158/1538-7445.AM2017-4448A
Abstract 1543: Caspase-10 suppresses tumorigenesis by targeting ATP-citrate lyase
Authors: Rajni Kumari, Sanjeev Das
Journal: Cancer Research (2017)

Abstract p53 fosters metabolic reprogramming, which restricts metabolic adaptation of tumor cells under energy stress conditions. However, modulation and directionality of underlying cascades to induce or restrict metabolism are determined by the downstream target of p53. To explore the role of p53 in tumor metabolism upon metabolic stress, we performed a microarray screen in the presence or absence of p53 under glucose starvation. We observed caspase-10 to be upregulated by p53 upon metabolic stress. Caspase-10 belongs to the class of initiator caspases and is poorly understood in terms of substrate specificities. Emerging evidences also suggest intrinsic activation of caspase-10, distinct from its homologue caspase-8. Moreover, inactivating mutations as well as downregulation of caspase-10 in several carcinomas are suggestive of its role in tumorigenesis. Thus, we investigated the function of caspase-10 as a tumor suppressor. Our results indicated that caspase-10, upregulated in a p53-dependent manner in response to metabolic stress, was activated by homodimerization-induced intrinsic activation mechanism involving Adenylate Kinase 2 and FADD. We further performed a proteomic screen to identify novel caspase-10 substrates. We observed that several anabolic enzymes are caspase-10 interacting partners. However, in vitro and in vivo assays confirmed only ATP-Citrate Lyase (ACLY) as a novel substrate of caspase-10. Cleavage of ACLY by caspase-10 abrogates enzymatic conversion of cytosolic citrate to acetyl-CoA, leading to overall decrease in nucleocytosolic acetyl-CoA pool. Decrease in cytosolic acetyl-CoA levels suppress lipogenesis upon metabolic stress. Moreover, decreased levels of nuclear acetyl-CoA alter global histone acetylation. Further studies using RNAi established that alteration in histone acetylation is GCN5-dependent. Caspase-10-dependent abrogation of histone acetylation reprograms the epigenetic profile of metastatic and proliferative genes, leading to their diminished expression under metabolic stress. Concomitant suppression of both cytosolic lipogenesis and nuclear histone acetylation by caspase-10-mediated ACLY cleavage decreases proliferation capacity, migration potential and invasiveness of tumor cells. Further, studies in mouse tumor models confirmed that caspase-10 restricts tumorigenesis and metastases under metabolic stress via ACLY and GCN5. Taken together, our findings establish caspase-10 as a novel integrator of metabolism and epigenetics, by regulating acetyl-CoA levels. Hence, it functions as a tumor suppressor by disrupting lipogenesis-mediated metabolic reprogramming and GCN5-mediated epigenetic reprogramming. Citation Format: Rajni Kumari, Sanjeev Das. Caspase-10 suppresses tumorigenesis by targeting ATP-citrate lyase [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 1543. doi:10.1158/1538-7445.AM2017-1543
Abstract 5795: Loss of CDCP1 in patient prostate cancer metastasis leads to uncoupling of beta-1 integrin from its cytoplasmic signaling through FAK
Authors: Sara G. Pollan, Fangjin Huang, Joshua M. Lang, Jamie M. Sperger, Kavita Shah, Beatrice S. Knudsen
Journal: Cancer Research (2017)

Abstract The Cub-Domain Containing Protein - 1, CDCP1, is a transmembrane glycoprotein, which is able to sequester Src and PKCδ into unique microdomains within the plasma membrane. CDCP1 can either promote or suppress tumor metastasis, dependent on the cancer type and experimental system. How the loss of CDCP1 leads to tumor metastasis is not well understood. We demonstrated for the first time in patients with prostate cancer (PCA), a significant reduction of CDCP1 expression in circulating cancer cells (CTC) and tumor metastasis relative to primary tumors and concordant analytical results. To investigate how the loss of CDCP1 facilitates PCA metastasis, we determined the consequences of CDCP1 loss in non-adherent cancer cells, which provide an experimental model system of CTCs. In this system, CDCP1 silenced cells exhibit 3-fold higher proliferation, 4-fold greater anchorage independent growth with colonies exceeding 5 microns in diameter, and a 2-fold reduction in migration ability. In 10% human plasma, these cells up-regulate p-FAK, p-SRC, p-AKT and p-MAPK expression, and at the same time loose expression of activated β1-integrin. The loss of inside-out activation of β1-integrin occurs through prevention of TALIN phosphorylation. Upon loss of CDCP1, Talin is no longer phosphorylated by CDK5 and this causes the disassembly of the β1 integrin - Talin complex. In addition, β1-integrin dissociates from CDK5 and from the CDK5-regulatory subunit, p35, but remains bound to p-FAK. We determined the pathway by which the loss of CDCP1 arrests CDK5 kinase activity. Upon loss of CDCP1, SRC phosphorylates p35. This generates a binding site for the C2 domain of PKCδ and phosphorylation of CDK5-T77 by PKCδ. The subsequent dissociation of the regulatory subunit abolishes the activity of CDK5. We show that both SRC inhibition and silencing of PKCδ reestablish the inside-out activation of β1-integrin. Altogether we discovered a new mechanism of regulation of CDK5 in prostate cancer cells, which leads to the uncoupling of β1-integrin and FAK. The potential biological and clinical consequences of this mechanism are (1) a switch from cell-matrix to cell-cell adhesion, (2) increased sensitivity of CTCs to FAK inhibitors and (3) improved adaptation and survival of cancer cells in the circulation and at the metastatic sites. Citation Format: Sara G. Pollan, Fangjin Huang, Joshua M. Lang, Jamie M. Sperger, Kavita Shah, Beatrice S. Knudsen. Loss of CDCP1 in patient prostate cancer metastasis leads to uncoupling of beta-1 integrin from its cytoplasmic signaling through FAK [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 5795. doi:10.1158/1538-7445.AM2017-5795
Abstract 968: Podoplanin's diverse potential as a chemotherapeutic target for oral squamous cell carcinom
Authors: Edward P. Retzbach, Harini Krishnan, Jhon A. Ochoa-Alvarez, Yongquan Shen, Evan Nevel, David J. Kephart, Evelyne Kalyoussef, Soly Baredes, Mahnaz Fatahzadeh, Kingsley Yin, Alan J. Shienbaum, Yukinari Kato, Lasse Jensen, Gary S. Goldberg
Journal: Cancer Research (2017)

Abstract Oral cancer is diagnosed in over 300 thousand people, and kills over 100 thousand people, around the world each year. Current treatments rely on radiation and surgery procedures that often decrease the quality of life for oral cancer survivors. There is a clear need to improve treatments for these patients. Over 90% of oral cancers are oral squamous cell carcinoma (OSCC). Most OSCC cells express the transmembrane receptor podoplanin (PDPN), which has emerged as a promising target for OSCC treatment. The PDPN receptor promotes tumor cell invasion and metastasis which leads to the vast majority of cancer deaths. Here, we describe efforts to target PDPN in order to prevent and treat oral cancer. PDPN can be targeted with Maackia amurensis seed lectin (MASL) to inhibit tumor cell migration and viability. Recent evidence also suggests that PDPN may undergo cancer specific changes, which indicates another potential route for targeting PDPN in oral cancer. Taken together, these data indicate that PDPN can serve as a functionally relevant target to prevent and combat oral cancer. Citation Format: Edward P. Retzbach, Harini Krishnan, Jhon A. Ochoa-Alvarez, Yongquan Shen, Evan Nevel, David J. Kephart, Evelyne Kalyoussef, Soly Baredes, Mahnaz Fatahzadeh, Kingsley Yin, Alan J. Shienbaum, Yukinari Kato, Lasse Jensen, Gary S. Goldberg. Podoplanin's diverse potential as a chemotherapeutic target for oral squamous cell carcinom [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 968. doi:10.1158/1538-7445.AM2017-968
Abstract 2738: A commutable circulating tumor DNA (ctDNA) reference material
Authors: Yves Konigshofer, Farol L. Tomson, Matthew Ryder, Russell Garlick, Bharathi Anekella
Journal: Cancer Research (2017)

Abstract We developed and assessed a novel ctDNA reference material that was designed with an emphasis on commutability. Possessing qualities that are well-matched with clinical specimens is critical for a reference material, however many existing methods of preparing ctDNA analogues result in material that is not commutable for certain assays. For example, sonication of genomic DNA yields fragments across a broad range of sizes that must be used at greater input amounts relative to native cell-free DNA (cfDNA) - even after enzymatic end-repair to reduce damage. This can affect the utility of the reference material for assays that depend on the ligation of adapters to double-stranded DNA, such as many hybrid/capture-based Next Generation Sequencing (NGS) assays. If higher input amounts are not used, then the LOD and precision of such an assay may appear substantially poorer than expected. At the same time, sonicated DNA has been shown to be acceptable for amplicon-based ctDNA assays. We created commutable ctDNA reference material by starting with genomic DNA from GM24385 cells and mixing with synthetic variant-containing DNA sequences at defined ratios. The use of GM24385 cells allows for the comparison of detected variants against the NIST RM 8391 high confidence variants. The use of synthetic DNA permits addition of large numbers of different cancer-associated variants at defined allele frequencies. Fragmentation was followed by size-selection in order to obtain ctDNA-like sizes. Additional steps were performed to increase the amount of output material from the size-selection step. The general method of preparing the reference material is also compatible with native cfDNA, such as that isolated from cancer patients. The reference material was submitted to several testing laboratories along with similar sonicated material. When tested using hybrid/capture-based assays, variant detection was superior in the novel reference material compared to sonicated DNA when similar amounts of material were used as the input. We therefore conclude that our new reference material has greatly improved commutability compared to existing materials composed only of sonicated DNA. Citation Format: Yves Konigshofer, Farol L. Tomson, Matthew Ryder, Russell Garlick, Bharathi Anekella. A commutable circulating tumor DNA (ctDNA) reference material [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 2738. doi:10.1158/1538-7445.AM2017-2738
Abstract 3657: Phosphatidylserine-targeting antibodies enhance anti-tumor activity of a tumor vaccine in a HPV-induced tumor model
Authors: Genevieve Weir, Tara Quinton, Jeff T. Hutchins, Bruce D. Freimark, Marianne Stanford
Journal: Cancer Research (2017)

Abstract Antibodies targeting phosphatidylserine (PS) have been shown to induce anti-tumor responses by induction of tumor-specific T cells. Based on this observation, we evaluated the responses of PS and PD-1 targeting antibody therapy to enhance anti-tumor responses of a HPV16 peptide vaccine formulated in DepoVax™ (DPX) in mice bearing HPV-transformed C3 mouse tumors. The addition of PS-targeting antibody (mch1N11) to DPX/metronomic cyclophosphamide (mCPA) immunotherapy prolonged survival in comparison to mice receiving an isotype control in combination with DPX/mCPA. When anti-PD-1 was added to mch1N11 + mCPA, there was no increase in survival. The addition of mch1N11 to DPX/mCPA immunotherapy had no effect on tumor growth or survival in the aggressive B16-F10 model. TIL analysis revealed an increase in CD8+ T cells, antigen specific CD8+ T cells and PD-1+ T cells in the tumor with mch1N11 treatment. The expression of surface markers for macrophages (CD68high, F4/80) and dendritic cells (CD11c) were also increased in the tumors of mice treated with mch1N11. RT-qPCR analysis of the tumor confirmed higher mRNA expression of T cells markers (CD8, Granzyme B, PD-1) and antigen presenting cell markers (F4/80, CD74). In the spleen, expression of cell surface markers for monocytes (CD11b) and PD-1+ T cells (CD8) were elevated in groups treated with mch1N11 in combination with anti-PD-1. Combined, these findings indicate that in this model, PS-targeting antibodies can enhance the activity of phagocytic cells involved in antigen presentation. We have found that PD-1 expression increases as anti-tumor activity increases, therefore these results also provide an indication that antibodies targeting PS enhance the anti-tumor immune response induced by DPX/mCPA therapy. The observations suggest that PS-targeting antibodies may enhance therapeutic vaccines for the treatment of cancer. Citation Format: Genevieve Weir, Tara Quinton, Jeff T. Hutchins, Bruce D. Freimark, Marianne Stanford. Phosphatidylserine-targeting antibodies enhance anti-tumor activity of a tumor vaccine in a HPV-induced tumor 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 3657. doi:10.1158/1538-7445.AM2017-3657