tbuckley/cabot-search huggingface dataset:
Abstract 2799: Development of a mouse model of KRAS mutated colorectal cancer tumorigenesis
Authors: Radhashree Maitra, Madhu Kumar Venkatesh, Titto Alby Augustine, Carol Chandy, Qiang Liu, Sanjay Goel
Journal: Cancer Research (2017)

Abstract Introduction Development of a preclinical animal model that mimics KRAS mutated colorectal cancer disease etiology is essential for validation of new therapeutic interventions. Colorectal cancer patients with tumors harboring KRAS mutation are excluded from receiving anti EGFR monoclonal antibodies, and currently have no alternate FDA approved treatment options available. Ongoing research requires validations of different modalities on a robust preclinical study platform that will resemble the disease phenotype and genetic profile. In this context we have developed viable animal mouse model of colorectal cancer bearing KRAS mutation that authentically serves as a model for the disease. Methodology: The C57 BL/6 mice with truncated APC floxed allele was crossed with heterozygous KRAS floxed outbred mice to generate APC f/f KRAS +/f mouse colony. In another set of breeding APC floxed mice were crossed with CDX2-Cre-ERT2 mice and selected for APCf/f CDX2-Cre-ERT2 after second round of inbreeding. The final model of the disease was generated by the cross of the two aforementioned colonies when viable APC f/f KRAS +/f CDX2-Cre-ERT2 were genotyped and characterized. The model animals were tamoxifen induced to generate tumors. Micro-PET scan was used to detect and measure tumor volume. H &amp; E staining was done to establish neoplasm and immunohistochemistry was performed to determine histological similarities with human FFPE biopsies. The MSI/MSS status was also determined. Results Ø The newly developed animal model develops colonic tumors upon induction with Tamoxifen. Ø The tumors were malignant as confirmed by H and E staining. Ø The tumors showed a higher radioactive FDG uptake (SUV) in micro-PET scan Ø The tumors resembled human colorectal cancer tissue Ø Once tumor is generated the animals died of cachexia and rectal bleeding Conclusion: Heterozygous mutation of KRAS oncogene along with deletion mutation of Adenomatous polyposis coli (APC) gene is embryonically lethal in animal models. We have successfully developed a viable animal model of KRAS mutated colorectal cancer with tamoxifen inducible tumors harboring KRAS and APC mutations. The tumors mimic the human disease type both genetically and immunohistochemically. This model can serve as a robust preclinical platform for understanding the disease mechanism at the molecular level as well for evaluation of various therapeutic interventions. Citation Format: Radhashree Maitra, Madhu Kumar Venkatesh, Titto Alby Augustine, Carol Chandy, Qiang Liu, Sanjay Goel. Development of a mouse model of KRAS mutated colorectal cancer tumorigenesis [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 2799. doi:10.1158/1538-7445.AM2017-2799
Abstract 906: PATZ1 promotes migration and invasion of thyroid cancer cells through upregulation of the activity of plasminogen activator and matrix metalloproteinases
Authors: Asumi Iesato, Teruo Nakamura, Tsuyoshi Uehara, Hiroto Izumi, Ken-ichi Ito
Journal: Cancer Research (2017)

Abstract Background: PATZ1, a transcription regulator, has been reported to function as oncogene or tumor suppressor in several human malignant neoplasms. The aim of the study was to examine involvement of PATZ1 in carcinogenesis and progression of thyroid cancer. Materials and methods: PATZ1 expression in 165 clinical thyroid specimens obtained from 87 patients were evaluated by IHC. We examined the function of PATZ1 using an immortalized normal thyroid follicular epithelial cell line (Nthy-ori 3-1), and four thyroid cancer cell lines; TPC-1 (papillary cancer), FTC-133 (follicular cancer), FRO and ACT-1 (anaplastic cancer). Knockdown of PATZ1 in Nthy-ori 3-1 and thyroid cancer cell lines was performed with siRNA-PATZ1, and overexpression of PATZ1 in thyroid cancer cell lines was performed with pcDNA3-FLAG-PATZ1. Results: In the IHC analysis of clinical specimens, nuclear PATZ1 expression in anaplastic carcinoma was significantly less frequently than that in normal thyroid tissue or well-differentiated carcinoma (Table 1). Knockdown of PATZ1 in Nthy-ori 3-1 and differentiated thyroid cancer cell lines (TPC-1, FTC-133) induced morphological change of the cells and significant increase of cell proliferation and migration as well as moderate increase of invasion. Furthermore, the expression of u-PA, MMP2 and MMP11 was increased by inhibition of PATZ1 in TPC-1 and FTC-133. On the other hand, overexpression of PATZ1 in anaplastic cancer cell lines (FRO and ACT-1) decreased proliferation and migration of the cells along with the decreased expression of u-PA, MMP2, MMP9 and MMP11. Conclusion: Our study suggests that PATZ1 might play an important role as a tumor suppressor in thyroid follicular epithelial cells and might be involved in progression of thyroid cancer. Expression of nuclear PATZ1 in thyroid tumortypeNormal thyroid/ goiter (N=68)Follicular adenoma (N=5)Papillary cancer (N=39)Follicular cancer (N=8 )Poorly differentiated cancer (N=12)Anaplastic cancer (N=28)Medullary cancer (N=5)positive (%)68(100%)4(80.0%)35(89.7%)5(62.5%)7(58.3%)3(10.7%)4(80.0%)negative (%)0(0%)1(20.0%)4(10.3%)3(37.5%)5(41.7%)25(89.3%)1(20.0%) Citation Format: Asumi Iesato, Teruo Nakamura, Tsuyoshi Uehara, Hiroto Izumi, Ken-ichi Ito. PATZ1 promotes migration and invasion of thyroid cancer cells through upregulation of the activity of plasminogen activator and matrix metalloproteinases [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 906. doi:10.1158/1538-7445.AM2017-906
Abstract 5779: Building a novel 3D hyaluronan-based tri-culture model of the bone metastatic microenvironment for cancer studies
Authors: Lindsey K. Sablatura, Daniel A. Harrington, Mary C. Farach-Carson
Journal: Cancer Research (2017)

Abstract The high attrition rate of potential anti-cancer drugs entering clinical trials predicates a need for more predictive pre-clinical model systems. Three-dimensional (3D) culture systems provide cells a more physiological microenvironment than traditional cell culture methods—including relevant extracellular matrix (ECM) cues and cell-cell interactions—while allowing greater experimental control and higher-throughput studies than animal models. Prevalent cancers, including breast and prostate cancer, metastasize preferentially to bone, where they become incurable. The bone marrow microenvironment is a complex network of interacting bone homeostatic and hematopoietic niches that contribute to osteotropic cancer homing, proliferation, and treatment resistance. We created a 3D in vitro tri-culture model of the bone metastatic microenvironment to serve as a new platform to study the “trialogue” between bone metastatic cancer, bone marrow stroma, and bone marrow endothelial cells. This tool can be used to inform drug discovery and to combat treatment resistance. Within the present study, the utility of peptide-functionalized hyaluronan hydrogels for supporting the self-organization of 3D bone marrow microvascular networks was explored. Gel crosslinking density was varied to examine the effect of matrix porosity on cell migration and organization over time. Tubule length and diameter were quantified and the endothelial structures were assessed for indicators of mature vasculature, including lumen formation, basement membrane production, and the recruitment of supporting stromal cells. Breast/prostate cancer cell growth, survival, and physical association with bone marrow stromal and bone marrow microvascular endothelial cell networks was examined in tri-culture models. Ongoing studies seek to identify and disrupt key cell signaling pathways that mediate cell-cell interaction and promote cancer cell proliferation and survival, providing new tools to combat bone metastatic disease. Citation Format: Lindsey K. Sablatura, Daniel A. Harrington, Mary C. Farach-Carson. Building a novel 3D hyaluronan-based tri-culture model of the bone metastatic microenvironment for cancer studies [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 5779. doi:10.1158/1538-7445.AM2017-5779
Occupational Exposures and Subclinical Interstitial Lung Disease. The MESA (Multi-Ethnic Study of Atherosclerosis) Air and Lung Studies
Authors: Coralynn S. Sack, Brent C. Doney, Anna J. Podolanczuk, Laura G. Hooper, Noah S. Seixas, Eric A. Hoffman, Steven M. Kawut, Sverre Vedal, Ganesh Raghu, R. Graham Barr, David J. Lederer, Joel D. Kaufman
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

The impact of a broad range of occupational exposures on subclinical interstitial lung disease (ILD) has not been studied.To determine whether occupational exposures to vapors, gas, dust, and fumes (VGDF) are associated with high-attenuation areas (HAA) and interstitial lung abnormalities (ILA), which are quantitative and qualitative computed tomography (CT)-based measurements of subclinical ILD, respectively.We performed analyses of participants enrolled in MESA (Multi-Ethnic Study of Atherosclerosis), a population-based cohort aged 45-84 years at recruitment. HAA was measured at baseline and on serial cardiac CT scans in 5,702 participants. ILA was ascertained in a subset of 2,312 participants who underwent full-lung CT scanning at 10-year follow-up. Occupational exposures were assessed by self-reported VGDF exposure and by job-exposure matrix (JEM). Linear mixed models and logistic regression were used to determine whether occupational exposures were associated with log-transformed HAA and ILA. Models were adjusted for age, sex, race/ethnicity, education, employment status, tobacco use, and scanner technology.Each JEM score increment in VGDF exposure was associated with 2.64% greater HAA (95% confidence interval [CI], 1.23-4.19%). Self-reported vapors/gas exposure was associated with an increased odds of ILA among those currently employed (1.76-fold; 95% CI, 1.09-2.84) and those less than 65 years old (1.97-fold; 95% CI, 1.16-3.35). There was no consistent evidence that occupational exposures were associated with progression of HAA over the follow-up period.JEM-assigned and self-reported exposures to VGDF were associated with measurements of subclinical ILD in community-dwelling adults.
Abstract 1146: Biomarker-driven targeted oral treatment strategy for bladder cancer
Authors: Daley S. Morera, Andre Jordan, Vinata B. Lokeshwar
Journal: Cancer Research (2017)

Abstract INTRODUCTION AND OBJECTIVE: Hyaluronic acid (HA) family of molecules, HA-synthases (HAS-1,2,3), HA-receptors (CD44, RHAMM) and hyaluronidase (HYAL-1) are markers for bladder cancer (BCa) diagnosis and predicting prognosis. HA-family promotes tumor growth and metastasis by inducing epithelial mesenchymal transition (EMT). 4-Methylumbelliferone (4-MU) is an orally bioavailable dietary supplement that inhibits HA synthesis. We evaluated the expression of HA family and EMT markers in bladder tissues as well as the antitumor effects of 4-MU as a potential targeted therapeutic agent in preclinical models of BCa. METHODS: Quantitative PCR was used to measure mRNA expression of HA-family and EMT genes (β-catenin, Twist, and Snail) in 72 bladder tissue specimens (28 normal; 44 tumor); follow-up: 20.3±2.5 months; median 17 months. The effect of 4-MU (0-0.6 mM) on cell proliferation, apoptosis, intracellular signaling, and the expression of HA receptors, and EMT genes were examined in BCa cell lines by Q-PCR, immunoblotting, proximal ligation and PI-3K activity assays. Mechanism of action was analyzed by HA addition and mAkt overexpression. Effect of oral administration of 4-MU (100, 200-mg/kg) on tumor growth was analyzed in subcutaneous xenografts. RESULTS: HAS-1, -2 -3, HYAL-1 and Snail levels were 10-20-fold elevated in BCa tissues as compared to normal bladder (P&amp;lt;0.001). In univariate analysis, HAS-1, -2, HYAL-1 and Twist levels correlated with metastasis (P&amp;lt;0.001); HYAL-1 was an independent predictor of metastasis. 4-MU inhibited cell proliferation, chemotactic motility and invasion in a dose-dependent manner; 50-70% inhibition at IC50 (0.4 mM) for HA-synthesis inhibition. 4-MU induced apoptosis (&amp;gt;3-fold) via the death receptor pathway. 4-MU downregulated HA-signaling, specifically transcript and/or protein levels of CD44, RHAMM, p-Akt, β-catenin, pβ-catenin(S552). Snail and twist were downregulated by 2-5-fold, but pβcatenin((T41/S45), pGSK-3α/β and E-cadherin levels were increased. 4-MU also inhibited CD44/PI-3K complex formation and PI-3K activity. HA addition or myristoylated Akt expression attenuated 4-MU effects. In xenograft studies, 4-MU oral treatment abrogated tumor growth of established tumors (vehicle, day 50: 766±221 mm3; 4-MU: 128±61, day 50) by abrogating HA-synthesis. No weight loss or serum or organ toxicity was observed in treated mice. CONCULUSION: This study demonstrates that HA-family signaling is upregulated in BCa and can be specifically targeted for treatment by a non-toxic dietary supplement. Support: 7R01 CA072821-16; 7R01CA176691-03 Citation Format: Daley S. Morera, Andre Jordan, Vinata B. Lokeshwar. Biomarker-driven targeted oral treatment strategy for bladder 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 1146. doi:10.1158/1538-7445.AM2017-1146
Abstract 5755: In vitro reconstitution of high-grade serous ovarian carcinoma from primary fallopian tube secretory epithelial cells
Authors: Kohei Nakamura, Kentaro Nakayama, Tohru Kiyono, Noriyoshi Ishikawa, Toshiko Minamoto, Tomoka Ishibashi, Kaori Sanuki, Hitomi Yamashita, Ruriko Ono, Kouji Iida, Hiroki Sasamori, Razia Sultana, Mohammad Mahmud Hossain, Masako Ishikawa, Satoru Kyo
Journal: Cancer Research (2017)

Abstract Purpose: Recent studies suggest that fallopian tube secretory epithelial cells (FTSECs) are potential cells-of-origin for high-grade serous ovarian carcinoma (HGSOC). Several genetic alterations are involved in HGSOC carcinogenesis, but the minimal requirement for tumor initiation remains unclear. Therefore, we sought to identify oncogenic mutations indispensable for HGSOC carcinogenesis in a stepwise model using immortalized FTSECs. Experimental Design: We established an in vitro stepwise carcinogenesis model using immortalized FTSECs overexpressing cyclin D1, CDK4R24C, and hTERT, and mimicked select genetic abnormalities identified as gene alterations essential for carcinogenesis, including p53, c-Myc, or RAS/PI3K pathway mutations. Results: Our analyses revealed two distinct patterns of gene alterations essential for HGSOC carcinogenesis: p53/KRAS/AKT and p53/KRAS/c-Myc. Dominant-negative p53 expression alone or in combination with oncogenic KRAS (KRASV12), constitutively active AKT (CA-AKT), or c-Myc in immortalized cells failed to induce a tumorigenic phenotype; however, overexpression of either CA-AKT or c-Myc in combination with dominant-negative p53 and KRASV12 was sufficient to confer tumorigenic potential. Importantly, all transformed FTSECs formed tumors in xenograft mice, which were grossly, histologically, and immunohistochemically similar to human HGSOC. Interestingly, mice harboring tumors with c-Myc amplifications displayed extensive metastases, consistent with the increased dissemination observed in their human counterparts. C-Myc is associated with cell proliferation in vitro; therefore, this genetic abnormality may promote HGSOC progression. Conclusions: Collectively, our data showed that aberrant p53/KRASV12/c-Myc or p53/KRASV12/PI3K-AKT signaling is the minimal requirement for FTSEC carcinogenesis. Moreover, the model generated with this evidence will likely facilitate analysis of early events in HGSOC carcinogenesis. Citation Format: Kohei Nakamura, Kentaro Nakayama, Tohru Kiyono, Noriyoshi Ishikawa, Toshiko Minamoto, Tomoka Ishibashi, Kaori Sanuki, Hitomi Yamashita, Ruriko Ono, Kouji Iida, Hiroki Sasamori, Razia Sultana, Mohammad Mahmud Hossain, Masako Ishikawa, Satoru Kyo. In vitro reconstitution of high-grade serous ovarian carcinoma from primary fallopian tube secretory epithelial 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 5755. doi:10.1158/1538-7445.AM2017-5755
Abstract 74: Discovery of new therapeutic monoclonal antibodies to challenging GPCRs, ion channels and transporters
Authors: Lewis J. Stafford, Ross Chambers, Sharon H. Willis, Moniquetta Hall, Brad Screnci, Manu Mabila, David Tucker, Trevor Barnes, Rachel Fong, Andrew Ettenger, Jennifer Pfaff, Chidananda Sulli, Nicholas Molino, Andrew Hudacek, Benjamin J. Doranz, Joseph Rucker
Journal: Cancer Research (2017)

Abstract The objective of this work was to evaluate the ability to generate panels of monoclonal antibodies against a set of highly challenging targets including GPCRs (CB1, C5AR, CXCR5 and CGRPR), transporters (GLUT4), and ion channels (P2X3). Integral membrane proteins are important drug targets and monoclonal antibodies (MAbs) directed against them are highly sought for therapeutic purposes. However, the complex structure of multispan membrane protein targets makes the discovery of these MAbs especially challenging. To address this need, Integral Molecular has developed the MPS Discovery Engine® to enable the isolation, characterization, and engineering of monoclonal antibodies for GPCRs, ion channels, and transporters. MPS utilizes a collection of technologies to address each of the barriers to monoclonal antibody development against the native extracellular epitopes of multispan membrane proteins. These include, antigen engineering to attain high levels of surface expression, DNA and Lipoparticle immunization to present native epitopes to the immune system, diverse immunization host species to deal with highly conserved proteins, Lipoparticles (high concentration native membrane proteins) to enable phage display and microfludic B-cell isolation, and shotgun mutagenesis (comprehensive Alanine scanning) for epitope mapping. Using the MPS Discovery Engine® we were able to successfully generate large panels of antibodies to the targets that were able to bind to the native extracellular epitopes on cells by flow cytometry. A subset of the antibodies had antagonist activity. With this technology we have the ability to target intact, conformation specific, and functional antibodies to complex membrane proteins. Citation Format: Lewis J. Stafford, Ross Chambers, Sharon H. Willis, Moniquetta Hall, Brad Screnci, Manu Mabila, David Tucker, Trevor Barnes, Rachel Fong, Andrew Ettenger, Jennifer Pfaff, Chidananda Sulli, Nicholas Molino, Andrew Hudacek, Benjamin J. Doranz, Joseph Rucker. Discovery of new therapeutic monoclonal antibodies to challenging GPCRs, ion channels and transporters [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 74. doi:10.1158/1538-7445.AM2017-74
Abstract 2574: The PICT-1 is required for USP7 to effectively stabilize p53 protein, and codon 389 polymorphism is a risk factor for ovarian cancer
Authors: Masafumi Yoshimoto, Aoi Tokuda, Yuji Yaginuma
Journal: Cancer Research (2017)

Abstract The ovarian cancers causes the deaths of more than 100,000 women per year worldwide, and it is a complex disease, with multiple both histological subtypes and molecular characteristics recognized; therefore, overall survival rates have improved little in the last 30 years. We have to precisely identify genetic and molecular events which could serve as markers for early diagnosis or targets for new therapeutics for ovarian cancers. The PICT-1 (also named GLTSCR2), one of the nucleolar proteins, has several tumor suppressor functions, such as the stabilization of PTEN and p53. Some studies reported that the loss of or low PICT-1 expression is the common alteration in many cancers, such as brain, skin, lung, esophageal, prostate, kidney, breast, and cervix, but its association with ovarian carcinogenesis has been unknown. Therefore, we investigated its alteration, regulation mechanism, and the effect for p53 stabilization in ovarian cancer. We found that polymorphism on codon 389 (rs184994) was a statistically significant association with the risk of ovarian cancers. Furthermore, ectopic expression of PICT-1 was required for USP7 to effectively stabilize p53 protein. Because PICT-1 was reported to bind both p53 and MDM2 that enabled to form USP7-p53-MDM2 complex, we investigated whether PICT-1 was regulated by USP7-p53-MDM2 complex. Our results suggested that this complex was the important regulator for PICT-1. In the investigation of the role of PICT-1 that played in the ovarian carcinogenesis using immunohistochemical stainig, we found that PICT-1 protein levels decreased in ovarian cancer tissues compared to normal ovary, and there was a positive correlation between PICT-1 and USP7 protein expression. Our findings suggested that PICT-1 involved in exactly p53 regulation along with MDM2 and USP7, and PICT-1 should be considered as a potential target for therapeutic human cancers. Citation Format: Masafumi Yoshimoto, Aoi Tokuda, Yuji Yaginuma. The PICT-1 is required for USP7 to effectively stabilize p53 protein, and codon 389 polymorphism is a risk factor for 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 2574. doi:10.1158/1538-7445.AM2017-2574