tbuckley/cabot-search huggingface dataset:
Abstract 4126: Validation of hypoglycosylated MUC1-CIN85 protein-protein interaction as a new therapeutic target for prevention of cancer invasion and metastasis
Authors: Sandra Cascio, Jacque Faylo, Raahul Sriram, Anda Vlad, Carlos Camacho, Olivera J. Finn
Journal: Cancer Research (2017)

Abstract Overexpression and abnormal glycosylation of the epithelial glycoprotein MUC1 in cancer cells promotes metastasis. We have identified CIN85 (Cbl-interacting protein 85 KDa), as a binding partner of MUC1 in tumors. MUC1/CIN85 complex is found in early as well as advanced clinical stages of breast, ovarian, colon and prostate cancers among others. Co-localization of MUC1 and CIN85 on invadopodia structures enhances invasion and migration of cancer cells. Our hypothesis is that preventing the formation or dissociating existing CIN85/MUC1 complexes may result in a less aggressive tumor by decreasing local invasion and preventing distant metastases. To test this hypothesis, we have already identified and tested two novel compounds that significantly reduce the association between hypoglycosylated form of MUC1 and CIN85, and at 10μM concentration drastically reduce the migratory activity of mouse and human epithelial cancer cells. Our preliminary data also suggest that dissociation of the MUC1 and CIN85 complex decreases expression of hypoglycosylated MUC1, restoring the expression of its normal, fully glycosylated form. We are currently investigating the MUC1/CIN85-dependent signaling pathway with a particular focus on the ability of CIN85 to modulate MUC1 glycosylation by controlling its plasma membrane-Golgi trafficking. Ongoing experiments in an in vivo mouse model will confirm the ability of these drug compounds to decrease tumor growth and metastasis and validate CIN85/MUC1 complex as a viable therapeutic target and support development and testing of more potent antagonists. Citation Format: Sandra Cascio, Jacque Faylo, Raahul Sriram, Anda Vlad, Carlos Camacho, Olivera J. Finn. Validation of hypoglycosylated MUC1-CIN85 protein-protein interaction as a new therapeutic target for prevention of cancer invasion and 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 4126. doi:10.1158/1538-7445.AM2017-4126
Abstract 1262: Aspirin inhibits the carcinogenesis of esophageal squamous cell carcinoma and enhances its responses to cisplatin
Authors: Zhigeng Zou, Hongjun Fan, Xiying Yu, Shuming Zhang, Liping Guo, Wei Jiang, Shih-Hsin Lu
Journal: Cancer Research (2017)

Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Over 70% of ESCC cases occur in China. Unfortunately, the treatment of ESCC has hardly been improved all these years. Several studies suggested that aspirin (ASA) might decrease the risk of ESCC and prolonged the survival of patients with ESCC. However, it is unclear if ASA could prevent ESCC and/or enhance ESCC treatment by chemotherapy. In this study, a N-nitroso-N-methylbenzylamine (NMBzA) - induced ESCC model was employed to prove that aspirin could prevent the growth of esophageal tumor. F344 rats were treated with NMBzA by subcutaneous injection with or without ASA in drinking water (2mg/ml). After 35 week ASA-NMBzA or NMBzA alone treatment, rats were killed and esophageal tumor development were examined. The results showed that F344 rats treated with NMBzA and receiving a daily intake of ASA developed much less tumors than F344 rats treated with NMBA alone both in amount and in size (Tumor count: 2.40 ± 1.57 vs 10.85 ± 3.86 , P &amp;lt; 0.001; Tumor volume: 11.10 ± 13.38 mm3 vs 70.79 ± 41.65 mm3, P &amp;lt; 0.001). Immunohistochemical analysis indicated that a higher rate of apoptosis was observed in the basal layer of esophageal epithelium in ASA-NMBzA treated rats than in NMBzA alone treated rats. These results indicated that ASA prevented development of esophageal tumors in rats induced by NMBzA. Moreover, using in vitro human ESCC cell culture and in vivo xenograft models, we showed that ASA has strong beneficial effects on inhibition of ESCC cell proliferation and colony formation, reduction of ESCC cancer stem cells and enhance of ESCC cell cytotoxicity induced by cisplatin treatment. Biochemical analysis revealed that these effects of ASA on human ESCC cells in vitro and in vivo were due to inhibiting the repairing of DNA damage, decreasing the efflux activity and ALDH1 activity of the tumor cells, and blockades of PI3K/Akt pathway. Thus, our results demonstrated a positive role of aspirin in the prevention and treatment of ESCC. Note: This abstract was not presented at the meeting. Citation Format: Zhigeng Zou, Hongjun Fan, Xiying Yu, Shuming Zhang, Liping Guo, Wei Jiang, Shih-Hsin Lu. Aspirin inhibits the carcinogenesis of esophageal squamous cell carcinoma and enhances its responses to cisplatin [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 1262. doi:10.1158/1538-7445.AM2017-1262
Abstract 3255: Circulating adipose stromal cells (CASCs) as a potential biomarker of response to weight loss interventions in obese women at high risk for breast cancer
Authors: Hailey Baker, Amy L. Kreutzjans, Jennifer L. Nydegger, Teresa L. Phillips, Richard C. Hasting, Dan A. Dixon, Bruce F. Kimler, Carol J. Fabian
Journal: Cancer Research (2017)

Abstract Background Obesity is a modifiable risk factor for breast cancer in the United States. White adipose tissue is increased in obese (BMI ≥ 30 kg/m2) women, releasing estrogens and pro-inflammatory cytokines. Adipose stromal cells play a key role in releasing estrogens, while circulating adipose stromal cells (CASCs, characterized as CD34+CD31-CD45-) home to tumor sites and promote angiogenesis and vascularization. CASCs have been correlated with BMI in both cancer and non-cancer patients. However, BMI alone as a marker of adiposity has its limitations. We examined whether CASCs correlate with additional measures of adiposity in women who are at high risk for development of breast cancer. Methods Women at high risk for development of breast cancer but without prior breast cancer were recruited for random periareolar fine needle aspiration (RPFNA), DEXA body composition, anthropomorphic assessment, and non-fasting venous blood collection. Mononuclear cells were isolated and the frequency of CD34brightCD31-CD45- cells was assessed by flow cytometry. Results CASC frequency ranged from 0 to 0.018% (median 0.001%) for 13 non-obese and 20 obese women. There was no association between CASC frequency and BMI (range 19 - 46 kg/m2), either as a linear correlation or when dichotomized at a BMI of 30 kg/m2. However, there were tendencies for greater CASC frequencies in pre-menopausal women, women with greater waist circumference (p&amp;lt;0.050), and women with visceral fat mass greater than 50%. With limited numbers, there was no apparent association of CASC frequency with cytology or proliferation (Ki-67) of benign breast epithelial cells acquired by RPFNA. Conclusions This is the first study to investigate CASC frequency in a cohort of women at high-risk for development of breast cancer. Our results to date do not show an association between CASC frequency and obesity (BMI). However, associations with other indices of visceral fat suggest that evaluation of circulating adipose stromal cells could have value as a biomarker of response in clinical trials of obese breast cancer survivors and high risk women undergoing weight loss (especially fat mass) interventions. Citation Format: Hailey Baker, Amy L. Kreutzjans, Jennifer L. Nydegger, Teresa L. Phillips, Richard C. Hasting, Dan A. Dixon, Bruce F. Kimler, Carol J. Fabian. Circulating adipose stromal cells (CASCs) as a potential biomarker of response to weight loss interventions in obese women at high risk for breast 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 3255. doi:10.1158/1538-7445.AM2017-3255
Abstract 3956: Intra-individual genomic heteroneity of ovarian cancer and clinical utility of ascitic cancer cells for mutation profiling
Authors: Youn Jin Choi, Min Sung Kim, Sug Hyung Lee
Journal: Cancer Research (2017)

Abstract Intra-individual tumoural heterogeneity (ITH) is a hallmark of solid tumours and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian high-grade serous carcinomas (OSCs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSC genomes using multiregional biopsy from 13 intra-ovarian lesions, 12 extra-ovarian tumour lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSCs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, 8 shared, and 24 private mutations were observed in known cancer-related genes. Common mutations had a higher mutant allele frequency and included TP53 mutations in all four OSCs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA, and RB1 were also identified. Of note, the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a poly-seeding origin of somatic mutations in ascitic cells. Our results demonstrate that despite ITH, somatic mutations, CNAs, and DNA methylations in both “common” category and cancer-related genes were highly conserved in ascitic cells of OSCs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumour cells may serve as a potential resource to discover somatic mutations of primary OSC with diagnostic and therapeutic relevance. Note: This abstract was not presented at the meeting. Citation Format: Youn Jin Choi, Min Sung Kim, Sug Hyung Lee. Intra-individual genomic heteroneity of ovarian cancer and clinical utility of ascitic cancer cells for mutation profiling [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 3956. doi:10.1158/1538-7445.AM2017-3956
Abstract 1133: Discovery of novel small molecule inhibitors of RNA-binding protein Musashi-1
Authors: Lan Lan, Amber Smith, Xiaoqing Wu, Anuradha Roy, Ragul Gowthaman, John Karanicolas, Amber D. Somoza, Clay C.C. Wang, Berl Oakley, Roberto De Guzman, Kristi Neufeld, Liang Xu
Journal: Cancer Research (2017)

Abstract 1) Background and Objective: Musashi-1(Msi1) is an RNA-binding protein that negatively regulates translation by binding to the 3′-UTRs of target mRNAs including Numb, APC and p21WAF-1, key regulators of Notch, Wnt signaling and cell cycle progression, respectively. We aim to identify small molecule inhibitors of Msi1’s mRNA-binding activity thus blocking the growth of a broad range of cancer cells. 2) Methods: Fluorescence polarization assay was used to screen for small molecules that disrupt the binding of Msi1 to its consensus RNA binding site. Hits were validated by surface plasmon resonance, amplified luminescent proximity homogeneous assay and nuclear magnetic resonance. 3) Results: Among ~2,000 small molecules we screened, we found several clusters of compounds that disrupt the Msi1-numb RNA binding potently, including natural products, herbal extracts and fungal metabolites. One of the clusters is the derivatives of the secondary metabolites from Aspergillus nidulans. The top hit, Aza-9, from this cluster was validated by amplified luminescent proximity homogeneous assay. Further validation by surface plasmon resonance and nuclear magnetic resonance indicate that Aza-9 binds to Msi1 directly, in the RNA binding pocket. 4) Discussion and Conclusions: Our study supports the hypothesis that Msi1 inhibition is a viable and effective anti-cancer strategy. More target validation assays will be carried out for the compounds from other clusters. Citation Format: Lan Lan, Amber Smith, Xiaoqing Wu, Anuradha Roy, Ragul Gowthaman, John Karanicolas, Amber D. Somoza, Clay C.C. Wang, Berl Oakley, Roberto De Guzman, Kristi Neufeld, Liang Xu. Discovery of novel small molecule inhibitors of RNA-binding protein Musashi-1 [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 1133. doi:10.1158/1538-7445.AM2017-1133
Abstract 1850: Development of a NOTCH1 loss of function and PIK3CA mutant transgenic model of HNSCC
Authors: Samantha N. Devenport, Nicole L. Michmerhuizen, Elizabeth Leonard, Brittany Jewell, Jacob Swanson, Sunny Wong, Thomas E. Carey, J Chad Brenner
Journal: Cancer Research (2017)

Abstract Head and neck squamous cell carcinoma (HSNCC) is a debilitating disease with a poor 5-year survival rate. The use of in vivo models to study tumorigenesis and to identify potential targeted therapies, especially those that work in combination with immune checkpoint inhibitors, is essential in improving overall patient care. However, the overall number of HNSCC transgenic models with recurrent genetic lesions identified by the HNSCC TCGA project has been limited. For example, TCGA data has shown both Notch1 loss of function mutations and PIK3CA activating mutations as some of the most common in HNSCC, but bi-genic models of these lesions do not yet exist. Here, we have designed a model which utilizes K14-CreERT to drive a bi-genic model with Notch1flox and PIK3CAH1047R mutations in epithelial compartments. Characterization of this line both in the context of spontaneous and carcinogen induced tumor formation is a tool which can be utilized to better understand common mutations in HNSCC. Immunohistochemistry confirms the overexpression of PIK3CA in tamoxifen induced mice. Furthermore, early characterization of this model with chronic treatment of the smoking analogue 4-Nitroquinoline N-oxide (4NQO) in drinking water shows tumor formation on the tongue and surrounding head and neck regions in as little as 12-16 weeks. Hematoxylin and Eosin staining confirmed the squamous tumor formation, while Ki67 staining showed enhanced proliferation of the transformed cells. In the future, this model can be used to study tumor formation over time and in response to targeted inhibitors and common therapies that are being advanced as companion diagnostic strategies for either NOTCH1 deficient or PIK3CA aberrant HNSCC tumors. Further detailed characterization of this model will allow for a deeper understanding of the mechanisms which drive HNSCC and will translate to improved patient care. Citation Format: Samantha N. Devenport, Nicole L. Michmerhuizen, Elizabeth Leonard, Brittany Jewell, Jacob Swanson, Sunny Wong, Thomas E. Carey, J Chad Brenner. Development of a NOTCH1 loss of function and PIK3CA mutant transgenic model of HNSCC [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 1850. doi:10.1158/1538-7445.AM2017-1850
Abstract 3410: Phenotypic characterization of allelic variation within the HEAT repeats of the mechanistic target of rapamycin
Authors: Patricia A. Wiley, Joy Gary, Zaw Phyo, Shuling Zhang, Amanda Sciorillo, Dorian Fraizer
Journal: Cancer Research (2017)

Abstract The mammalian target of rapamycin (mTOR), a protein in the phosphoinositide 3-kinase (PI3K) pathway important to cell cycle regulation, is frequently activated in cancer. This signaling pathway regulates cell growth and metabolism, and when dysregulated in cancer, it contributes to tumor angiogenesis and growth. mTOR contains two distinct complexes, MTORC1, and MTORC2. MTORC1 plays a role in biosynthesis, while MTORC2 helps with cellular metabolism. It has been shown that mTOR knockout models are embryonically lethal to mice. However, lower levels of functional mTOR have been shown to be beneficial and slow cancer progression. Allelic variation occurs within inbred strains of mice, including BALB/c mice. One allelic variant in mTOR, R628C, which contributes to tumor susceptibility has been identified in BALB/c mice. This single amino acid change occurs in the HEAT repeats of mTOR. HEAT repeats have been shown to facilitate binding partner interactions, dimerization, and localization. Studies on mutations found within the HEAT repeats in several proteins have altered protein function and emphasize the structural importance of HEAT repeats. The goal of this study is to further elucidate the functional significance of HEAT repeats in TOR function and how allelic variation in the HEAT repeats may contribute to tumor susceptibility. Characterization of this allelic variant has shown stress inputs, such as irradiation, lead to a more severe phenotype and reduced mTORC1/2 signaling. Subsequent in vitro studies using a tetracycline inducible expression system (T-RExTM) have shown differential binding to mTORC1/2 complex partners in cells expressing the Balb/c allele. Additional studies are being performed to assess other complex binding partners, dimerization state and localization of the allelic variant. Our findings will model mTOR signaling activation mechanisms in humans to aid in development of new cancer treatments. Note: This abstract was not presented at the meeting. Citation Format: Patricia A. Wiley, Joy Gary, Zaw Phyo, Shuling Zhang, Amanda Sciorillo, Dorian Fraizer. Phenotypic characterization of allelic variation within the HEAT repeats of the mechanistic target of rapamycin [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 3410. doi:10.1158/1538-7445.AM2017-3410
Extracellular Hyaluronic Acid Influences the Efficacy of EGFR Tyrosine Kinase Inhibitors in a Biomaterial Model of Glioblastoma
Authors: Sara Pedron, Jacob S. Hanselman, Mark A. Schroeder, Jann N. Sarkaria, Brendan A. C. Harley
Journal: Advanced Healthcare Materials (2017)

3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient-derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified in 50% of GBM patients. Here, hyaluronic acid (HA) decorated methacrylamide-functionalized gelatin (GelMA) hydrogels are used to examine the synergies between microenvironmental factors and a model EGFR tyrosine kinase inhibitor (TKI) using patient-derived xenograft cells. The in vitro behavior of 3 patient-derived xenografts that reflect a clinically relevant range of EGFR variants is characterized: GBM10 (EGFR, wild type), GBM12 (EGFR+), and GBM6 (EGFRvIII). GelMA hydrogels support xenograft culture; cells remain viable, active, respond to matrix-immobilized HA, and upregulate genes associated with matrix remodeling and tumor growth. Interestingly, matrix-immobilized HA alters the response of GBM cells to a model tyrosine kinase inhibitor, erlotinib. While constitutively activated EGFRvIII cells are sensitive to TKI in gelatin hydrogels, hyaluronic acid mediated adhesive signaling interacts with EGFRvIII signaling to increase cell metabolic activity, increase soluble hyaluronic acid synthesis, and modify response to erlotinib exposure.
Abstract 3083A: C6-ceramide nanoliposomes sensitize paclitaxel resistant ovarian cancer cells to chemotherapy treatment
Authors: Danielle C. Llaneza, Tye G. Deering, Samantha G. Sherwood, John R. Cornelison, Mark Kester, Charles N. Landen
Journal: Cancer Research (2017)

Abstract Ovarian cancer is the fifth leading cause of cancer deaths among women, and the majority of women are diagnosed at advanced stages resulting in poorer outcomes and survival rates. One of the driving forces behind these outcomes is the development of chemoresistance, and subsequent proliferation and invasion of tumor cells. In a patient-derived xenograft model of ovarian cancer, we identified the sphingosine pathway as significantly enriched in tumors after treatment with conventional chemotherapy. In order to target the sphingosine pathway, we investigated the potential effects of combining paclitaxel with C6-ceramide nanoliposomes in paclitaxel-resistant ovarian cancer cell lines, HeyA8-MDR and SKOV3-TR. Ceramide has been shown to be a key player in several processes important for tumor suppression including apoptosis, autophagy, and cell cycle arrest. We administered paclitaxel and C6-ceramide to HeyA8-MDR and SKOV3-TR cell lines in vitro and measured cell viability and expression of apoptotic and autophagic proteins. Results showed that in both cell lines, C6-ceramide significantly decreases the IC50 dose of paclitaxel, compared to control ghost nanoliposome treated cells. The IC50 of paclitaxel decreased in HeyA8-MDR cells from 400nM to 150nM, and in SKOV3-TR cells from 1000nM to 450nM. Western blot analyses indicate that combination treatment increases expression of apoptotic (cleaved caspase-3) factors in HeyA8-MDR cells, and autophagic (LC3) factors in SKOV3-TR cells, over single agent treatment or control. Paclitaxel is known to increase expression of apoptotic factors while decreasing expression of autophagic factors. Ceramide may increase both apoptotic and autophagic factors. In an orthotopic mouse model with the HeyA8-MDR line, combination treatment of paclitaxel and C6-ceramide resulted in significantly decreased tumor burden (1.38g +/- 0.74), compared to control ghost (p = 0.022, 2.81g +/- 1.57), C6-ceramide alone (p = 0.078, 2.50g +/- 1.58), and paclitaxel alone (p = 0.005, 2.48g +/- 0.75) groups. The combination of C6-ceramide and paclitaxel may prove useful in elucidating and targeting underlying chemoresistance mechanisms in ovarian cancer. Citation Format: Danielle C. Llaneza, Tye G. Deering, Samantha G. Sherwood, John R. Cornelison, Mark Kester, Charles N. Landen. C6-ceramide nanoliposomes sensitize paclitaxel resistant ovarian cancer cells to chemotherapy treatment [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 3083A. doi:10.1158/1538-7445.AM2017-3083A