tbuckley/cabot-search huggingface dataset:
Abstract 4938: A vicious cycle between osteoblasts-derived WISP-1 and mesenchymal-like cancer cells is essential to prostate cancer metastasis
Authors: An-Chen Chang, Show-Mei Chuang, Chih-Hsin Tang
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is the most commonly diagnosed malignancy in the United States and other Western countries. It is well established that tumor microenvironment plays an important role in cancer progression and metastasis. Wnt-induced secreted protein-1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV) that plays a key role in osteogenesis and tumor growth. We found that osteoblast-conditioned media (OBCM) stimulated migration and invasion in human PCa cells. Furthermore, the medium was collected 2 days after treatment of osteoblasts with PCa conditioned media which were designed as PCa-OBCM. The results showed that treatment of PCa cells with PCa-OBCM further increased the migration and invasion activity, as well as epithelial-mesenchymal transition (EMT), including the epithelial marker (E-cadherin) down-regulation and mesenchymal marker (N-cadherin and twist) up-regulation. Moreover, human cytokine array was used to measure the secretion of 32 Cytokines into PCa-OBCM. The data showed that WISP-1 is highly up-regulated with PCa-OBCM treatment compared to OBCM. Stimulation of osteoblasts with PCa conditioned media induced WISP-1 expression. In contrast, knockdown WISP-1 in osteoblasts impacted PCa-OBCM-mediated cancer migration, invasion, and EMT. In addition, conditioned media from PCa cells was incubated with another cytokine array membranes. The data showed that ADAM-9 and cathepsinL were overexpressed in PCa conditioned media but only ADAM-9 could regulate WISP-1 expression in osteoblasts. Taken together, these results demonstrated that primary PCa-secreted ADAM-9 promotes osteoblasts-derived WISP-1 up-regulation, which in turn enhances primary PCa cells migration, invasion, and EMT, resulting in cancer metastasis. Our study suggests that inhibition of osteoblasts-derived WISP-1 is a new therapeutic target for treating metastasis in human PCa patients. Citation Format: An-Chen Chang, Show-Mei Chuang, Chih-Hsin Tang. A vicious cycle between osteoblasts-derived WISP-1 and mesenchymal-like cancer cells is essential to prostate cancer metastasis [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 4938. doi:10.1158/1538-7445.AM2017-4938
Abstract 5245: Peretinoin prevents the accumulation of somatic gene mutations and reverts neoplastic lesions to normal liver-like in platelet-derived growth factor-c transgenic mice
Authors: Taro Yamashita, Hikari Okada, Masao Honda, Shuichi Kaneko
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) develops with progressive accumulation of multiple genetic changes. An acyclic retinoid peretinoin is reported to suppress the development of HCC, but the molecular mechanism in detail remains to be obscure. Here we evaluated the effect of peretinoin on preneoplastic nodules and HCC developed in platelet derived growth factor-c (PDGF-C) transgenic mice liver by gadolinium ethoxybenzyl diethylenetriamide pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and whole exome sequence analysis. We confirmed the progressive accumulation of somatic mutations in hypervascular liver cancer tissues compared with hypovascular precancerous tissues and non-cancerous background liver tissues in PDGF-C transgenic mice. Surprisingly, peretinoin treatment in HCC as well as preneoplastic nodules resulted in the accumulation of less gene mutations compared with vehicle. Gd-EOB-DTPA uptake capacity and its transporter OATP1 was confirmed to be re-activated in peretinoin treated nodules in mice. Gene and protein expression analysis indicated the inactivation of cell cycle with low Ki-67 labeling indexes in peretinoin treated nodules. The reversion of Gd-EOB-DTPA uptake capacity was confirmed in preneoplastic nodules and a subset of classical hypervascular HCCs. Notably, peretinoin supplementation induced the expression of OATP1B3 in mature hepatocyte-like HCC cell lines in vitro, whereas supplementation of tretinoin (all-trans retinoic acid) had no such effects and rather suppressed OATP1B3. Taken together, our data suggested the utility of peretinoin to revert the malignant transformation processes of hepatocytes by preventing accumulation of gene mutations especially in early stages of hepatocarcinogenesis. Peretinoin but not tretinoin can induce the expression of a mature hepatocyte marker OATP1B3, suggesting that peretinoin may exert its anti-tumor effect with hepatocytic differentiation capacity independently of the activation of retinoic acid signaling. Note: This abstract was not presented at the meeting. Citation Format: Taro Yamashita, Hikari Okada, Masao Honda, Shuichi Kaneko. Peretinoin prevents the accumulation of somatic gene mutations and reverts neoplastic lesions to normal liver-like in platelet-derived growth factor-c transgenic 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 5245. doi:10.1158/1538-7445.AM2017-5245
Abstract 3855: Excavation of therapeutic targets based on the molecular signature of patient-derived tumor xenografts in gastric cancer
Authors: Zuhua Chen, Jing Gao, Lin Shen
Journal: Cancer Research (2017)

Abstract Objective: The optimal preclinical models in new targeted drug development are patient-derived tumor xenografts (PDXs) models with definite molecular signatures, which will be excavated and validated in this study. Methods: The genomic profiles of 50 PDXs from advanced gastric cancer (AGC) were analyzed by targeted next-generation sequencing. The Epstein-Barr virus (EBV) infection, microsatellite instability (MSI) status, and expressions of EGFR, HER3, c-Met, PTEN and c-Myc were determined by in situ hybridization and immunohistochemisty, respectively. Results: A total of 581 non-synonymous single nucleotide variations (SNV), 513 Indels, and 225 amplifications were identified in 50 PDXs. Pathway analysis revealed recurrent alterations in the MAPK signaling, ErbB signaling, VEGF signaling, mTOR signaling and cell cycle pathway. The ErbB family amplified in 8% (EGFR), 10% (ERBB2), 2% (ERBB3) and 2% (ERBB4) of the 50 PDXs respectively. Meanwhile, several activating mutations in EGFR (L858R and G719S), ERBB3 (P1212S) and ERBB4 (R1174Q) were also detected in our study. Moreover, we detected 7 PDXs harboring PIK3CA activating mutations (E545K, Q546K, H1047R) and 2 PDXs with PTEN loss. Whether PI3K/Akt/mTOR inhibitors could turn over the primary or acquired resistance of anti-HER2 therapies remains further researches. Genes in the cell cycle pathway altered in 70% of the 50 PDXs. The mutation rates of TP53, BRCA1 and BRCA2 were 28%, 8% and 14%. We also detected amplifications of CCNE1, CCND1 and MYC in 16%, 6% and 20% of the xenografts. In this study, 9 PDXs (18%) were EBV positive, with frequent alterations of ARID1A but rare mutations of TP53, and a robust expression of PD-L1. However, we didn’t observe any loss of MMR protein expressions. Conclusions: Several potential therapeutic targets were identified based on the molecular signature of PDXs in advanced gastric cancer, which will provide evidences for drug development. Citation Format: Zuhua Chen, Jing Gao, Lin Shen. Excavation of therapeutic targets based on the molecular signature of patient-derived tumor xenografts in gastric 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 3855. doi:10.1158/1538-7445.AM2017-3855
Abstract 134: A dual mTOR-PI3K inhibitor DCB-HDG2-57 with Hedgehog signaling pathway antagonist activity
Authors: Ying-Shuan Lee, Mann-Yan Kuo, Chia Wei Liu, Yu-Wen Tseng, Win Yin Wei, Shian-Yi Chiou, Her Sheng Lin, Y.-Y. Lu, Chu-Bin Liao, Shao-Zheng Pen
Journal: Cancer Research (2017)

Abstract The Hedgehog (Hh) signaling pathway is a critical regulator of embryonic patterning, and aberrant Hh pathway activation has been implicated in a diverse spectrum of cancers. Therefore, components of the Shh pathway (such as Shh, SMO, and GLI1/2) are viable therapeutic targets for anti-tumor strategy. Smo antagonists such as GDC-0449 and NVP-LDE225 have received FDA approval for treating basal cell carcinoma. However, acquired resistance has emerged as a challenge to targeted therapeutics and may limit their anti-cancer efficacy. Studies have linked the hyperactive phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway in a variety of human cancers and drug resistance condition. The synergistic role of PI3K/AKT/mTOR in Hh signaling in embryonic development and Hh-dependent tumors has been reported. Both the PI3K/Akt/mTOR and Hh pathway also play important role in maintaining the stem cell-like properties of cancer stem cell (CSCs). We report here the development of a potent dual mTOR-PI3K inhibitor designated DCB-HDG2-57 with Hh signaling pathway antagonist activity. In vitro biochemical assays showed that DCB-HDG2-57 inhibited recombinant pI3Kα and mTOR kinase with IC50 of 27.2 and 133 nM, respectively. DCB-HDG2-57 is also highly active in cellular assays, as evidenced by inhibition of phosphorylation of cellular downstream targets of PI3K-mTOR kinases ribosomal protein S6 kinase (S6K1, Ser240/24) in the colon (LS-180) and pancreatic cancer (MiaPaCa2 and PANC1) cell lines. Interestingly, DCB-HDG2-57 demonstrated Hh signaling pathway antagonist activity in a 293 cell-based Gli-luciferase inhibition assay upon agonist treatment, and retains inhibition activity against the Smo wild-type and D473H mutant co-transfection with IC50 of 261.8 and 327.7 nM, respectively. In addition, DCB-HDG2-57 can significantly decrease the cancer stem cell liked side population of PANC1 pancreatic cell, and inhibited the migration of E3LZ10.7 pancreatic cancer cell. DCB-HDG2-57 demonstrated in vivo tumor growth inhibition activity in LS-180 colon cancer xenograft model and reduced the Gli-1 RNA abundance in the tumor. Taken together, our data demonstrate that combined pharmacological blockade of mTOR-PI3K and Hh pathway of DCB-HDG2-57 can provide a therapeutic strategy for targeting ligand-dependent Hh cancer. Citation Format: Ying-Shuan Lee, Mann-Yan Kuo, Chia Wei Liu, Yu-Wen Tseng, Win Yin Wei, Shian-Yi Chiou, Her Sheng Lin, Y.-Y. Lu, Chu-Bin Liao, Shao-Zheng Pen. A dual mTOR-PI3K inhibitor DCB-HDG2-57 with Hedgehog signaling pathway antagonist activity [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 134. doi:10.1158/1538-7445.AM2017-134
Abstract 4753: Prognostic significance of galectin-1 expression in patients with glioblastoma multiforme following radiotherapy
Authors: Eng-Yen Huang, Shang-Yu Chou
Journal: Cancer Research (2017)

Abstract Purpose: Galectin-1 is a radioresistant marker and prognostic factor in our previous study for cervical cancer. The aim of current study is to determine the prognostic significance of galectin-1 expression level in patients with glioblastoma multiforme (GBM) undergoing adjuvant radiotherapy (RT). Materials and Methods: We included 45 patients with GBM who treated with maximal safe surgical resection or biopsy only, followed by adjuvant RT of EQD2 &amp;gt;= 60 Gy (equivalent doses as 2-Gy fractions) for homogeneous treatment. Paraffin-embedded tissues acquired from the Department of Pathology were analyzed using immunohistochemistry staining for galectin-1 expression. Overall survival (OS) and cancer-specific survival were compared between strong and weak expression of galectin-1. Results: According to univariate analysis for optimal cutoff of galectin-1 expression level, better median survival (27.9 months) in patients with weak level than that (10.7 months) in patients with strong level (p = 0.009) was revealed. We compared characteristics between weak and strong galectin-1 expression level, and only galectin-3 expression level was correlated. The weak galectin-1 expression group displayed a 3-year survival rate of 27.3% and 3-year cancer-specific survival (CSS) rate of 27.3%, but which are only 5.9% and 7.6% respectively in strong galectin-1 expression group (p = 0.009 and 0.020, respectively). Cox regression was used to confirm that the role of galectin-1 expression level (weak vs. strong) is a significant factor of OS (p = 0.020) and CSS (p = 0.022). Other parameters such as galectin-3 expression level, ECOG performance, gender, operation method, age &amp;gt; 50 years, or radiation field were not significant factors. Conclusion: Galectin-1 expression level affects OS and CSS in patient with GBM treated with adjuvant RT. Citation Format: Eng-Yen Huang, Shang-Yu Chou. Prognostic significance of galectin-1 expression in patients with glioblastoma multiforme following radiotherapy [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 4753. doi:10.1158/1538-7445.AM2017-4753
Abstract 440: The oncogenic activity of a pro-oxidant intracellular milieu is associated with redox dependent activation of NF-kB
Authors: Michelle Y. Yee, Stephen J. Chong, Shazib Pervaiz
Journal: Cancer Research (2017)

Abstract Evidence over the years has highlighted that intracellular redox status plays a critical role in determining cell fate. To date, we have shown that a pro-oxidant milieu, specifically a mild elevation of intracellular superoxide, promotes cancer cell survival and chemoresistance. To that end, we demonstrated in vitro that elevated superoxide, upon silencing of superoxide dismutase (SOD1), resulted in sustained phosphorylation of Bcl-2 at serine 70, thereby stabilizing its anti-apoptotic activity. These findings were corroborated by the abundance of Serine 70 Bcl2-phosphorylation and low SOD1 expression in lysates of patients with aggressive lymphomas and/or disease with poor prognosis. In addition to the anti-apoptotic protein Bcl-2, the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB)- mediated signaling was also shown to be modulated by intracellular redox milieu. As constitutive activation of NF-κB has been reported in various human tumors, which is often associated with malignant progression and chemotherapeutic resistance, here we set out to investigate whether a pro-oxidant environment, specifically the upregulation of intracellular superoxide, was associated with the induction of NF-κB transcriptional activity. Indeed, we demonstrate that elevated intracellular superoxide via the pharmacological inhibition and genetic silencing of SOD1 results in enhanced activation of canonical NF-κB signalling. This is accompanied by increased p65 nuclear localization and transcription of NF-κB regulated genes, which potentially confer survival advantages to tumour cells upon chemotherapeutic treatments. Considering the association between NF-kB activation, chronic inflammation and the process of carcinogenesis, these preliminary data provide a novel mechanism of activation of this master transcriptional factor with potential therapeutic implications. Citation Format: Michelle Y. Yee, Stephen J. Chong, Shazib Pervaiz. The oncogenic activity of a pro-oxidant intracellular milieu is associated with redox dependent activation of NF-kB [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 440. doi:10.1158/1538-7445.AM2017-440
Abstract 5879: Establishing doxorubicin resistant HCC1806 triple negative breast cancer cell lines result in the differential expression of let7a and miR34a
Authors: Checo J. Rorie, Malcolm M. Moses, Mohammed K. Musa, Sherette S. Godfrey
Journal: Cancer Research (2017)

Abstract Resistance to chemotherapy is one of the major difficulties in the treatment of triple negative breast cancer. Besides the typical known causes of drug resistance, tumor microenvironment can also promote resistance by preventing the drug from accumulating in tumor cells in order to elicit a cytotoxic response. TNBC is characterized by the loss or low expression of estrogen receptor, progesterone receptor, and HER2 proteins that have been targeted and established as somewhat effective therapy regiments in other breast cancer subtypes including liminal breast cancer. Since TNBC tumors are missing these well-known drug targets, there is little to no advancement in the establishment of drug therapies to accurately target this breast cancer subtype. TNBC is termed as aggressive due to the fact of its invasiveness and metastatic properties. One potential mediator of TNBC aggressive behavior may be due to the fact that this breast cancer subtype may have as high as an 80% p53 tumor suppressor gene mutation rate which may also play a role in the ability of TNBC to recur as a result of the inability to kill all remaining TNBC cells leading to chemotherapy resistance. In these studies, we hope to mimic TNBC recurrence by establishing doxorubicin resistant HCC1806 TNBC cell lines. Here we show that we were able to sustain TNBC cell growth after pulse treatments with increasing concentrations of doxorubicin, and we revealed that p53-related miRNAs, let7a and miR34a, were differentially expressed after pulse treating the HCC1806 cells. Understanding the molecular and mechanistic factors related to recurrence and doxorubicin-resistance in HCC1806 cells may help to develop a list of possible targets for molecular therapy to overwhelm tumor drug resistance in triple negative breast cancer and may develop or establish a list of potential targets for disabling, or combating resistance to doxorubicin treatment in TNBC patients. Note: This abstract was not presented at the meeting. Citation Format: Checo J. Rorie, Malcolm M. Moses, Mohammed K. Musa, Sherette S. Godfrey. Establishing doxorubicin resistant HCC1806 triple negative breast cancer cell lines result in the differential expression of let7a and miR34a [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 5879. doi:10.1158/1538-7445.AM2017-5879
Numerical intuitions in infancy: Give credit where credit is due
Authors: Sophie Savelkouls, Sara Cordes
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. overlook numerous human infant studies pointing to an early emerging number sense. These studies have carefully manipulated continuous magnitudes in the context of a numerical task revealing that infants can discriminate number when extent is controlled, that infants fail to track extent cues with precision, and that infants find changes in extent less salient than numerical changes.
Abstract 1645: CEACAM1-blockade for T-cell activation and antitumor T-cell response
Authors: So-Young Eun
Journal: Cancer Research (2017)

Abstract Immune checkpoint blockade became the most powerful way to control cancer without causing tremendous side effects, since anti-PD-1 blocking antibodies proved their superiority in clinical outcomes to those of traditional chemo- or targeted therapeutics. CEACAM1 (CCM1) is one of the several immune checkpoint receptors expressed on T cells that mediate suppression of inflammatory T cell response. CCM1 caught our attention for a cancer immune-therapeutic target, because of its inhibitory role in TCR proximal signaling complex. The anti-cancer therapeutic potential of CCM1-blockade has already been studied in mouse models, and one of the anti-human CCM1 antibody clones recently emerged in clinical Phase I studies. CCM1-targeting antibody candidates were screened out of our in-house synthetic libraries, among which a few of the clones stood out showing their significant blocking activities against CCM1-CCM1 homophilic interaction, enhancement of T cell activation, cytokine release, NFAT signaling, and tumor lysis. One of the clones (C25) showed its strongest efficacy equivalent to that of a reference Ab in CCM1-dependent T cell activation, proliferation, and IL-2 release, in parental Jurkat cells as well as in CCM1-overexpressing stable Jurkat cells. Moreover, C25 also enhanced tumor lysis by CCM1+ NK cells or CCM1+ cytotoxic T cells in a CCM1-dependent manner. In addition, C25 shows distinct characteristics in binding to CCM family from those of a reference Ab. Thus, C25 is thought to have a strong therapeutic potential on CCM1+ cancer. Citation Format: So-Young Eun. CEACAM1-blockade for T-cell activation and antitumor T-cell response [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 1645. doi:10.1158/1538-7445.AM2017-1645
Abstract LB-326: A novel oncomiR negatively regulates PTEN pathway in prostate cancer
Authors: Nadeem S. Bhat, Melissa Colden, Prerna Arora, Altaf A. Dar, Sharanjot Saini, Varahram Shahryari, Soichiro Yamamura, Yuichiro Tanaka, Taku Katu, Yutaka Hashimoto, Marisa Shiina, Priyanka Kulkarni, Pritha Dasgupta, Mitsuho Imai-sumida, Shigekatsu Maekawa, Guoren Deng, Rajvir Dahiya, Shahana Majid
Journal: Cancer Research (2017)

Abstract Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa. Here, we demonstrate that a novel microRNA, microRNA-4534 (miR-4534) is overexpressed in PCa and show that miR-4534 is hypermethylated in normal tissues and cell lines compared to PCa tissues/cells. miR-4534 exerts its oncogenic effects partly by downregulating the tumor suppressor PTEN gene. Knockdown of miR-4534 impaired cell proliferation, migration/invasion and induced G0/G1 cell cycle arrest and apoptosis in PCa. Suppression of miR-4534 and its effects on tumor growth was confirmed in a xenograft mouse model. We performed parallel experiments in non-cancer RWPE1 cells by overexpessing miR-4534 followed by functional assays. Overexpression of miR-4534 induced pro-cancerous characteristics in this non-cancer cell line. Kaplan-Meier and ROC analyses revealed that miR-4534 has potential to independently distinguish malignant from normal tissues and positively correlated with poor overall and PSA recurrence free survival. Taken together, our results show that depletion of miR-4534 in PCa induces a tumor suppressor phenotype partly through induction of PTEN. These results have important implications for identifying and defining the role of new PTEN regulators such as microRNAs in prostate tumorigenesis. Understanding aberrantly overexpressed miR-4534 and its downregulation of PTEN will provide mechanistic insight and therapeutic targets for PCa therapy. Note: This abstract was not presented at the meeting. Citation Format: Nadeem S. Bhat, Melissa Colden, Prerna Arora, Altaf A. Dar, Sharanjot Saini, Varahram Shahryari, Soichiro Yamamura, Yuichiro Tanaka, Taku Katu, Yutaka Hashimoto, Marisa Shiina, Priyanka Kulkarni, Pritha Dasgupta, Mitsuho Imai-sumida, Shigekatsu Maekawa, Guoren Deng, Rajvir Dahiya, Shahana Majid. A novel oncomiR negatively regulates PTEN pathway in prostate 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 LB-326. doi:10.1158/1538-7445.AM2017-LB-326