tbuckley/cabot-search huggingface dataset:
Abstract 4357: ESRP1 overexpression and its role in ovarian cancer
Authors: Mi Jeong Kwon
Journal: Cancer Research (2017)

Abstract Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2) are RNA binding proteins which are recently known to be involved in tumor progression via regulation of alternative splicing of cancer-associated genes. However, their expression and clinical significance in ovarian cancer remain unclear. Here, we found that ESRP1 and ESRP2 gene expression is upregulated in ovarian cancer cells compared with immortalized ovarian surface epithelial (IOSE) cells and their overexpression at protein level was also confirmed in ovarian cancer tissues. Consistent with TCGA data of ESRP1 gene amplification, higher ESRP1 gene copy number was observed in ovarian cancer cells compared with IOSE cells, whereas there was little correlation between gene copy number and gene expression in ovarian cancer cells. Importantly, their gene expression was inversely correlated with DNA methylation in ovarian cancer cells and ESRP2 overexpression in ovarian cancer was significantly associated with DNA hypomethylation (P= 0.036). Of note, TCGA data analysis showed that high ESRP1 gene expression is significantly associated with shorter 5-year survival of patients with ovarian cancer. Ectopic expression of ESRP1 in ESRP1 low-expressing mesenchymal type ovarian cancer cells increased cell proliferation, whereas it suppresses cell migration. Furthermore, our results revealed that the effect of ESRP1 overexpression on cell proliferation and migration is related to activation of the Akt/CyclinD pathway and increased of E-cadherin expression. In conclusion, our findings suggest that ESRP1 overexpression is associated with poor outcome of patients and ESRP1 may play a cancer-promoting role in ovarian cancer. Citation Format: Mi Jeong Kwon. ESRP1 overexpression and its role in 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 4357. doi:10.1158/1538-7445.AM2017-4357
Abstract 1658: Establishment of CD137 humanized mouse model for efficacy assessment of agonistic anti-CD137 therapeutic antibodies
Authors: Davy Xuesong Ouyang, Gang Chen, Zhensheng Wang, Lei Zheng, Annie Xiaoyu An, Jean-Pierre Wery, Jay Liu, Xin Dong, Henry Q. X. Li
Journal: Cancer Research (2017)

Abstract CD137 belongs to the TNF receptor super family, and its activation is essential to the function of T cells and NK cells. Multiple agonistic CD137 antibodies are currently being tested in humans with advanced cancer, which expected to become an important new immuno-oncology therapeutics in clinic. It is important to establish preclinical models for efficacy assessment of investigational CD137 antibodies before entering clinic. Currently available animal models cannot meet this need. Syngeneic mouse tumor models provide a useful platform for testing surrogate immuno-oncology therapies, but cannot be used for testing human therapeutic antibodies due to the species specificity; human immunity reconstituted models, by human PBMC or hematopoietic stem cell inoculation into immune deficient mice, suffering from highly variable responses, are not robust enough to provide a reliable system for efficacy studies. Establishing target humanized models by replacing mouse therapeutic target with human counterpart while maintaining normal mouse immunity is a practical approach to evaluate human therapeutic antibodies in vivo. Using CRISPR-Cas9 gene editing, we have engineered human CD137 knock-in model expressing chimeric human/mouse CD137 composed of human extracellular and transmembrane domains (Exon 4-7), with intact mouse signal peptide and intracellular domain. FACS analysis of splenocytes derived from homozygous knock-in mice showed that CD3/CD28 stimulated T cells only express chimeric CD137 reactive to human CD137 antibodies, but not mouse CD137; Yet the expression levels of the chimeric CD137 in the knock-in mice are generally lower than endogenous mouse protein in wild-type C57BL/6 mice. At present, we are testing the efficacy of reference human CD137 agonistic antibodies by treating these homozygous knock-in mice grafted with syngeneic MC38 tumor cells. Data will be presented at the conference. Citation Format: Davy Xuesong Ouyang, Gang Chen, Zhensheng Wang, Lei Zheng, Annie Xiaoyu An, Jean-Pierre Wery, Jay Liu, Xin Dong, Henry Q. X. Li. Establishment of CD137 humanized mouse model for efficacy assessment of agonistic anti-CD137 therapeutic antibodies [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 1658. doi:10.1158/1538-7445.AM2017-1658
Mouse pancreatic cancer cells from KrasG12D/p53-/- transgenic mice overexpress Heat shock protein 70 (HSP70), and its inhibition by triptolide decreases cell viability.
Authors: Yumi Yokoyama, Vikas Dudeja, Rajinder Dawra, Daniel Borja-Cacho, Paul Zwolak, Rupjyoti Talukdar, Rohit Chugh, Christopher Klug, Selwyn Vickers, Ashok Saluja
Journal: Cancer Research (2008)

LB-190  Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States; its 5-year survival rate is less than 5%. To study pancreatic cancer biology and efficacy of drugs against it, mouse spontaneous tumor models are necessary.  Genetic analysis of PDAC patients showed that specific disease-associated mutations correlate with cancer progression. Kras gene activation as well as the loss of tumor suppressor gene p53 are reportedly associated with pancreatic intraepithelial neoplasias (PanIN). We have previously developed KrasG12D/p53-/- transgenic mice (Cancer Research 67 (17) 2007). We have also shown that HSP70 inhibitors triptolide (a diterpenoidtriepoxide) and quercetin (a flavonoid compound) decrease the viability of human pancreatic cancer cells in vitro and inhibit tumor growth in vivo (Cancer Research 67(2) and 67 (19) 2007).  AIM: In this study, we isolated tumor cells (PR53.63) from transgenic mice, and evaluated the efficacy of triptolide on mouse pancreatic cancer cells.  METHODS: Expression levels of heat shock protein 70 (HSP70) in PR53.63 in vitro and in vivo were examined by western blot, real-time PCR, and histochemical analysis using a confocal microscopy. 2) The efficacies of HSP70 inhibitors, such as triptolide and quercetin, on PR53.63 cell viability in vitro were examined and compared to human pancreatic cell lines. 3) PR53.63 cells were treated with triptolide or quercetin, and their effect on HSP70 levels was examined.  RESULTS: PR53.63 cells expressed HSP70 significantly more than normal pancreatic duct cells. PR53.63 cells administered subcutaneously in the flank and orthotopically in the pancreas in vivo expressed HSP70 at levels which were significantly higher than other normal organs such as lung, kidney, and liver. Inhibiting HSP70 expression by triptolide and quercetin decreased the viability of PR53.63. The cytotoxicity of triptolide and quercetin to PR53.63 cells is similar to that observed in human pancreatic cancer cell, Panc-1. Treatment with triptolide in vitro significantly decreased HSP70 levels in a dose-dependent manner.  CONCLUSION: This study suggested that the HSP70 inhibitor, triptolide, decreases viability and HSP70 expression not only in human cancer cell lines but also in mouse pancreatic cancer cells isolated from the KrasG12D/p53-/- transgenic mice. This spontaneous mouse pancreatic cancer model is very useful for studying cancer biology and developing new pancreatic cancer therapies.
Abstract 5498: Autoregulation of protein kinase D1 (PRKD1) expression in prostate cancer
Authors: Bita Nickkholgh, Sittadjody Sivanandane
Journal: Cancer Research (2017)

Abstract Protein kinase D1 (PRKD1) is down regulated in gastric, breast and prostate cancer. Several regulatory mechanisms modulate PRKD1 activity in cancers. In colon cancer, it has been shown that PRKD1 is down regulated by nuclear beta-catenin. We explored whether beta-catenin is involved in regulation of PRKD1 expression in prostate cancer as well. A CHIP assay performed using prostate cancer LNCaP cell lysate and pull down with beta -catenin antibody, which demonstrated recruitment of beta -catenin to promoter of PRKD1 gene as well as at downstream regions in the gene suggesting that beta -catenin could be involved in PRKD1 regulation. To identify the exact binding site of beta-catenin to PRKD1 gene, we carried out CHIP sequencing. The beta -catenin protein complex was bound to a 166 bp sequence near exon 2 (chr14:29899631-29899796). Because beta -catenin is a coactivator and not a known transcription factor, we performed a transcription factor promoter array, which showed that the MYC/MAX transcription factor complex may be the mediator of the regulatory effect of beta -catenin on PRKD1 expression. We validated the results by performing CHIP assay using MYC and MAX antibodies which showed recruitment of both MYC and MAX to the same beta -catenin binding site to PRKD1. In order to assess the functional impact of beta -catenin regulation of PRKD1 in prostate cancer, beta-catenin mutated at threonine 120 residue (we have previously shown that PRKD1 is the only known kinase to phosphorylate the site) demonstrated increased nuclear translocation of beta-catenin and increase down regulation of PRKD1 and increased androgen receptor (AR) activity (increased AR activity is well established to be associated with PC progression). Our data has identified a novel auto-regulatory mechanism of PRKD1 expression through beta-catenin phosphorylation. Citation Format: Bita Nickkholgh, Sittadjody Sivanandane. Autoregulation of protein kinase D1 (PRKD1) expression 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 5498. doi:10.1158/1538-7445.AM2017-5498
Abstract 3823: High intrinsic DPD activity matters too
Authors: Emmanuel Chamorey, Eric Francois, Marie-Christine Etienne-Grimaldi, Julien Viotti, Frederic Peyrade, Alexandre Bozec, Jean-Marc Ferrero, Renaud Schiappa, Gerard Milano
Journal: Cancer Research (2017)

Abstract Introduction: Fluoropyrimidines (FP) are of major use in treating cancer. Dihydropyrimidine dehydrogenase (DPD) is the main enzyme responsible for FP catabolism. Low DPD activity screening has proven its predictive clinical value in identifying patients at risk for toxicity. However, high DPD activity may translate to decreased FP activation and efficacy. Patients and methods: One hundred and forty-three patients (monocentric retrospective study) underwent a pretreatment assessment of DPD activity in lymphocytes between 01/01/2004 and 20/04/2016. Included patients were male or female, &amp;gt;18 years, FP-treatment-based. Cut-off for DPD activity was assessed using smoothing spline curves. Results: Median patient follow-up was 30 months [CI95%: 27.3-36.2], mean age 63+/-3 years, females accounted for 53%, 90% of patients had a good performance status (0 or 1). Fifty-eight percent of FP indications (65% 5-FU and 35% capecitabine) were adjuvant or neoadjuvant and 42% were prescribed for local or metastatic recurrences. Tolerance was poor for 43% of patients and 49% needed dose reduction. Objective response (complete and partial) was observed in 50% of patients, stable disease in 38% and progression in 12%. No significant correlation was observed between DPD activity and response to treatment. Mean DPD activity (pmol min−1 mg−1 protein) was 0.21+/-0.1 (quartile: [0.001-0.14-0.20-0.28-0.48]). DPD activity analyzed as a continuous variable was significantly linked to overall survival (OS) (p=0.042) but not with progression-free survival (PFS). The higher the DPD activity, the lower the OS. DPD activity analyzed as a binary variable (cut-off at 0.30) was significantly linked to overall survival (p=0.012) but also with PFS (p=0.016). A Cox regression model for OS and PFS adjusted for age, sex, type of cancer, type of administered FP, and associated surgical or radiotherapy treatment was performed. After adjustment, DPD activity remained significantly linked to OS (p=0.03) and PFS (p=0.021). Conclusions: DPD activity screening could lead to a two-pronged approach: FP dose reduction in the event of low DPD and dose increase for high DPD. Such a strategy needs to be prospectively validated under personalized DPD-based treatment. Note: This abstract was not presented at the meeting. Citation Format: Emmanuel Chamorey, Eric Francois, Marie-Christine Etienne-Grimaldi, Julien Viotti, Frederic Peyrade, Alexandre Bozec, Jean-Marc Ferrero, Renaud Schiappa, Gerard Milano. High intrinsic DPD activity matters too [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 3823. doi:10.1158/1538-7445.AM2017-3823
Abstract 3022: Novel hydrocarbon stapled peptide inhibitors suppresses β-catenin dependent cancer growth and immunomodulates colorectal tumors
Authors: David Zhu, Joy Jin
Journal: Cancer Research (2017)

Abstract Mutations in several components of the canonical Wnt pathway function as drivers in a range of common solid tumor cancers, including about 90% of sporadic colorectal cancers (CRCs), the third most common cancer in the US. In particular, activation of β-catenin (β-cat), a key Wnt signaling component, can initiate tumorigenesis in the intestine and promote cancer stem cell metastasis6,7. As such, targeting the Wnt pathway is an attractive approach to the development of cancer therapeutics. However, Wnt inhibitors tested to date, including those that disrupt β-cat activity, have either had limited efficacy or unacceptable side effect profiles1. Here, we developed a potent and robust, selective lead compound targeting oncogenic Wnt activity by disrupting the highly specific interaction of β-cat with its co-activators BCL9/B9L, which has been shown to abrogate transactivation. By using hydrocarbon stapled peptide technology and an acutely sensitive high throughput biochemical screening assay, we have identified several promising peptides that possess a strong pharmacokinetic profile. These peptides (i) exhibit robust activity in mouse models; (ii) inhibit cancer cell proliferation, metastasis, and stem cell progression; and (iii) modulate the immune microenvironment, demonstrating the feasibility of such peptide development and selection. Synergy is demonstrated between the stapled peptides and anti-PD1 antibodies, which has significant implications for combination therapy with commercial immune checkpoint blockers that have become standard of care for second-line melanoma treatment. These peptides represent a promising new potential therapeutic class for patients with CRC, for which traditional chemotherapy and targeted inhibitors have had limited therapeutic success. Citation Format: David Zhu, Joy Jin. Novel hydrocarbon stapled peptide inhibitors suppresses β-catenin dependent cancer growth and immunomodulates colorectal tumors [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 3022. doi:10.1158/1538-7445.AM2017-3022
Abstract 3540: Targeting obesity-related cancer progression with novel leptin receptor antagonists
Authors: Crystal C. Lipsey, Adriana Harbuzariu, Ruben R. Gonzalez-Perez
Journal: Cancer Research (2017)

Abstract Obesity is a global health issue that has been identified as a risk factor for several types of cancer. High levels of body fat and circulating leptin are typical identifiers of obesity in humans and animals. Leptin is a 16kD protein hormone which is secreted by adipocytes, and maybe secreted from cancer cells, that functions to control satiation via leptin receptor binding. However, obese individuals often develop “leptin resistance”, which is a mechanism that leads to the accumulation of excess leptin. Increased binding of leptin to its receptor (OB-R) due to leptin resistance has been associated with disease progression and poor prognosis in human cancers. Our group has previously shown that leptin-mediated cancer cell proliferation is inhibited by the LPrA2 (leptin peptide receptor antagonist 2). We have prepared novel leptin antagonists and tested their ability to block leptin-induced survival and chemoresistance to Paclitaxel (TAX) and Gemcitabine (GEM) in cancer cells and derived tumorspheres (pancreatic: PANC-1, MiaPaca2 and triple negative breast cancer: MDA-MB231 and MDA-MB468). Western blot protein analyses showed the ability of the antagonists to specifically inhibit leptin-induced phosphorylation of STAT3, and expression of cyclin D, and Notch1 in cancer cells. Additionally, potential toxicity of antagonists was tested using MTT assay with concentrations up to 100X higher than the effective dose in non-malignant breast cells (MCF-10A). Data generated show no toxicity of the novel antagonists in vitro. Leptin-induced proliferation of breast cancer and pancreatic cancer cells (120-160%) was significantly inhibited by the novel antagonists. In addition, leptin-mediated progression of S-phase was also reduced by the antagonists. Leptin increased TAX and GEM chemoresistance in cells and tumorspheres that were efficiently inhibited by the antagonists. These data suggest that the new antagonists could be equally or more effective than LPrA2 for adjuvant treatment of cancer. Acknowledgements: This work has been supported by Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP, and facilities and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR 03034 and 1C06 RR18386). Citation Format: Crystal C. Lipsey, Adriana Harbuzariu, Ruben R. Gonzalez-Perez. Targeting obesity-related cancer progression with novel leptin receptor antagonists [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 3540. doi:10.1158/1538-7445.AM2017-3540
Abstract P179: Human Peripheral Blood B Cells Improve Cardiac Function in Aged Rats After Myocardial Infarction
Authors: Traci T Goodchild, Michael B Sweet, Jai Pal Singh, Mark C Poznansky, Nicolas A Chronos
Journal: Circulation Research (2011)

Background: Aging is associated with increased mortality following acute myocardial infarction (AMI). Early cell therapy clinical trials for AMI have shown a modest improvement in cardiac function. Previous evidence suggest that B cells may be protective in tissue injury. Our initial studies showed that intramyocardial delivery of bone marrow derived B cells improves cardiac function in young rats. Aim: In this study, we determined the effect of B cell therapy in aged animals subjected to AMI using a clinically relevant protocol. Methods: Human PB B cells were isolated from buffy coats using CD19+ selection. Young (8-10wks) and aged (10-12mos) athymic rats had baseline echocardiography then coronary artery ligation (d1). At d7, rats had repeat echocardiography and received 1×10 7 B cells or vehicle intravenously. At d9 and d21, rats underwent follow-up echocardiography. Explanted hearts were measured for infarct size and B cell localization was determined in infarcted aged rat hearts after d8 in a subset of animals by IHC. Results: Fractional ventricular diameter shortening (FS) decreased at d7 compared to baseline in young (27.9 ±0.9 vs. 55.6±0.6%, P &lt;0.001) and aged (31.6±0.9 vs. 53.4±0.5%, P &lt;0.001) rats. At d9, FS was higher in B cell compared to control treated aged rats (44.9±2.6 vs. 29.3±3.0%, P &lt;0.001). FS was minimally changed in B cell compared to control treated young rats (37.3±3.3 vs. 31.2±3.5%, P =NS). At d21, FS was higher in aged rats receiving B cells compared to controls (38.6±2.2 vs. 30.0±2.6%, P &lt;0.001) and trended higher in B cell treated young rats compared to control (34.1±1.8 vs. 28.0±2.6%, P =0.058). FS was higher in aged rats receiving B cells stored for 1.5hrs at room temperature compared to freshly prepared B cells (35.1±3.2% vs. 27.1±2.4%, P =0.035). Infarct size was smaller in B cell treated aged rats compared to controls (12.9±2.3 vs. 22.4±2.4% LV, P =0.010); no difference in infarct size was detected in young rats. B cells were detected in the infarct of aged rats at d8. Conclusion: These data support that intravenous delivery of peripheral blood B cells is efficacious in improving cardiac function and limiting infarct size in aged rats, an experimental model more relevant to clinical population.
Peripheral T-Cell Lymphomas Not Otherwise Specified: Potential Novel Molecular Entities Based on Both Tumor and Microenvironment Cellular Components
Authors: Francesco Maura, Luca Agnelli, Anna Dodero, Javeed Iqbal, Niccolo Bolli, Cristiana Carniti, Tayla Heavican, Jiayu Yu, Elisabetta Mereu, Elisa Pellegrino, Alessio Pellegrinelli, Antonello Cabras, Annalisa Chiappella, Alice Di Rocco, Michela Ansuinelli, Francesco Zaja, Umberto Vitolo, Wing C. Chang, Roberto Piva, Antonino Neri, Paolo Corradini
Journal: Blood (2016)
Abstract 3105: Targeting microRNAs in brain tumors with oligonucleotide nanoparticle conjugates
Authors: Nilmary Grafals, Blanca I. Quiñones, Pablo E. Vivas, Gabriel Barletta
Journal: Cancer Research (2017)

Abstract Glioblastoma Multiforme (GBM) is the deadliest type of primary brain tumor being responsible for more than 14,000 deaths annually. The survival rate of GBM patients from time of diagnosis is 5 months if left untreated and 15 months with standard care of treatment. Despite great research efforts in the last 30 years, GBM survival rate has only increased by 2%. This is mostly due to high recurrence, treatment resistance, and the existence of the blood brain barrier (BBB) which restricts drug delivery to the tumor tissue. Therefore, the development of novel therapeutic modalities able to cross the BBB is urgently needed. MicroRNAs (miRNAs) are small (18-22 nt.) non-coding RNAs that regulate gene expression at the post-transcriptional level by binding to the 3’UTR of target mRNAs. Several dysregulated miRNAs have been reported in all tumor types, including GBM. Targeting oncogenic miRNAs with oligonucleotide miRNA inhibitors (OMIs) in vitro has shown therapeutic potential. However, in vivo administration requires the development of nanocariers capable of increasing the stability of OMIs in circulation and improving their delivery to target tissues. In addition, nanocarriers that can overcome the BBB are needed. The most studied and promising nanocarriers are gold nanoparticles (AuNP) and liposomes. While AuNPs have bioimaging and microscopy advantages, liposomes are clinically preferred. Therefore, we propose encapsulating OMIs-AuNPs to BBB targeted liposomes. In this study we present the characterization of miRNA inhibitors conjugated to AuNP. Briefly, 15 nm AuNP were functionalized to OMIs by two different techniques: Salt aging functionalization method and PEG and surfactant assisted conjugation method. Afterwards, both nanoconjugates were analyzed for particle size, zeta potential and loading capacity. The PEG and surfactant assisted functionalization proved to be superior in all of the analysis, resulting in 30 nm OMIs-AuNPs with a zeta potential of -8 mV and a loading capacity ratio of 64 oligonucleotides per AuNP. Further characterization studies such as cell internalization and cytotoxicity are under evaluation. Citation Format: Nilmary Grafals, Blanca I. Quiñones, Pablo E. Vivas, Gabriel Barletta. Targeting microRNAs in brain tumors with oligonucleotide nanoparticle conjugates [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 3105. doi:10.1158/1538-7445.AM2017-3105