tbuckley/cabot-search huggingface dataset:
Abstract 369: Therapeutic targeting of the Wnt antagonist DKK1 with a humanized monoclonal antibody in oncology indications
Authors: Michael H. Kagey, Yinyuan Wu, Xinjun Zhang, Cynthia A. Sirad, Shane E. Mulligan, Xi He, Christopher K. Mirabelli
Journal: Cancer Research (2017)

Abstract Wnt signaling is a fundamental pathway that is dysregulated in oncology. The Wnt antagonist DKK1 is expressed in a variety of tumor types which frequently correlates with a poor prognosis, including overall survival. DKK1 has known oncogenic activity by stimulating proliferation, metastasis, and angiogenesis, and recently been implicated in contributing to an immunosuppressive tumor microenvironment. The neutralization of DKK1 is hypothesized to have efficacy from both a direct antitumor effect and through an immune stimulated response. Here we describe the characterization of DKN-01, a humanized monoclonal therapeutic antibody to DKK1. DKN-01 binds DKK1 with high affinity and selectivity, disrupts the interaction of DKK1 with the LRP6 co-receptor, and neutralizes DKK1 activity in a cell based assay. In vivo, DKN-01 has efficacy both as a monotherapy and in combination with chemotherapies in a non-small cell lung (NSCLC) cancer A549 xenograft model. Results suggest that DKN-01 has an antiangiogenic effect and may stimulate a NK cell mediated antitumor response. Clinically, DKN-01 is being evaluated in relapsed/refractory esophageal cancer patients in combination with paclitaxel, and preliminary results demonstrate promising activity. Archival patient tumor samples are currently being analyzed genetically and by IHC for DKK1 and β-catenin staining for biomarker identification. Taken together, our results suggest that DKN-01, a novel therapeutic, has clinical efficacy by disrupting Wnt signaling, which results in a direct anti-tumor effect and stimulates a pro-inflammatory tumor response. Citation Format: Michael H. Kagey, Yinyuan Wu, Xinjun Zhang, Cynthia A. Sirad, Shane E. Mulligan, Xi He, Christopher K. Mirabelli. Therapeutic targeting of the Wnt antagonist DKK1 with a humanized monoclonal antibody in oncology indications [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 369. doi:10.1158/1538-7445.AM2017-369
Abstract 1256: Non-steroidal anti-inflammatory drugs induce ER stress and have an immunomodulatory role in the suppression of colorectal tumorigenesis
Authors: Rochelle E. Fletcher, Lin Zhang, Brian Leibowitz, Jian Yu
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in the United States. A number of epidemiological studies, clinical trials, and animal studies have demonstrated the chemopreventive effect of non-steroidal anti-inflammatory drugs (NSAIDs) on CRC. However, the exact mechanism by which NSAIDs suppress colorectal tumorigenesis has remained unclear. Our previous study showed that NSAID-induced death receptor signaling, along with loss of the gatekeeper APC tumor suppressor, triggers a synthetic lethal interaction and apoptotic death in an otherwise normal cell. In this study, we determined how NSAIDs induce death receptor signaling, and found a critical role of the endoplasmic reticulum (ER) stress response. Treating CRC cells with the NSAIDs sulindac or indomethacin upregulated C/EBP homologous transcription factor (CHOP), a key mediator of the ER stress response that is required for the induction of death receptor 5 (DR5) by NSAIDs. Blocking ER stress abolished the apoptotic effect of NSAIDs in CRC cells and in normal colonic epithelial cells with knockdown of APC, and also suppressed the chemopreventive activity of NSAIDs in APCMin/+ mice. Furthermore, we identified plasma membrane translocation of calreticulin in cells undergoing NSAID-induced apoptosis, suggesting the involvement of immunomodulation in this tumor suppression. Our results provide novel insight into the chemopreventive mechanism of NSAIDs, which may help design more effective chemopreventive strategies and agents. Citation Format: Rochelle E. Fletcher, Lin Zhang, Brian Leibowitz, Jian Yu. Non-steroidal anti-inflammatory drugs induce ER stress and have an immunomodulatory role in the suppression of colorectal 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 1256. doi:10.1158/1538-7445.AM2017-1256
Abstract 1042: CLIC4 is incorporated into extracellular vesicles of murine breast cancer cells and may influence metastatic burden
Authors: Alayna B. Craig-Lucas, Vanesa C. Sanchez, Abigail Read, Ji Lou, Anjali Shukla, Stuart H. Yuspa
Journal: Cancer Research (2017)

Abstract Chloride intracellular channel 4 (CLIC4) is an evolutionarily conserved, 29kD, dimorphic protein that contributes to TGF-β signaling by preventing the de-phosphorylation of phospho-SMAD2/3 upon nuclear translocation. In several cancer types, CLIC4 is excluded from the nucleus and downregulated in the cytoplasm of the tumor cells as the tumor progresses, suggesting that CLIC4 acts as tumor suppressor. In a parallel sequence, CLIC4 becomes upregulated in the stromal compartment, where it enhances tumor growth and invasion. Recent reports have suggested that CLIC4 is detectable in the serum of cancer patients and incorporated into extracellular vesicles, and has potential as a biomarker. We hope to gain a better understanding of the role that CLIC4 plays in the tumor stromal and epithelial compartments as well as their respective release of extracellular vesicles. Using in-vitro and in-vivo assays, we have conducted experiments using the FVB mouse MMTV-c-MYC 6DT1 breast cancer model. By CRISPR/ Cas9 system, CLIC4 was deleted from wild type 6DT1 cells. Following clonal selection, the loss of the CLIC4 protein at both the cellular and released vesicle level was validated. Both functional assays on CLIC4 deleted clones and evaluation of their extra-cellular vesicles were undertaken in order to further understand their tumorigenic and metastatic capabilities. In-vitro, CLIC4 was not necessary for vesicle biogenesis and its deletion did not have a significant effect on cellular proliferation. In vivo, selected clones were orthotopically injected into the 4th mammary fat pad of wild type FVB mice. Compared to wild type 6DT1 clones, CLIC4 deleted clones formed primary tumors that had greater mass but a fewer number of lung metastasis. Future studies are designed to isolate vesicles circulating in tumor bearing hosts to determine their stromal or epithelial origin and to provide a better understanding of the role that CLIC4 may play in tumor growth, creating a metastatic niche and as a potential serological biomarker. Citation Format: Alayna B. Craig-Lucas, Vanesa C. Sanchez, Abigail Read, Ji Lou, Anjali Shukla, Stuart H. Yuspa. CLIC4 is incorporated into extracellular vesicles of murine breast cancer cells and may influence metastatic burden [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 1042. doi:10.1158/1538-7445.AM2017-1042
Abstract 5535: Effect of LKB1 activity on the sensitivity to PI3K/mTOR inhibitor in non-small-cell lung cancer
Authors: Takehito Shukuya, Tadaaki Yamada, Michael J. Koenig, Mohammad A. Rahman, Joseph M. Amann, David P. Carbone
Journal: Cancer Research (2017)

Abstract The serine-threonine liver kinase B1 (LKB1, also called STK11) is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival and polarity. Germline mutation of LKB1 causes Peutz-Jeghers syndrome, which is an autosomal dominant disease characterized by mucocutaneous pigmentation and hamartomatous polyps. In non-small-cell lung cancer (NSCLC), LKB1 is frequently rendered non-functional, either through mutation or down regulation. As a tumor suppressor and a protein whose function is lost, identifying pathways that are activated with LKB1 loss may be the only way to target such tumors. Some previous studies have suggested that inhibition of mTOR, a growth promoting pathway negatively regulated by LKB1, as a potential target in LKB1 mutant NSCLC. In this study, we investigated the effect of LKB1 activity on the sensitivity to a PI3K/mTOR inhibitor using four LKB1 mutant NSCLC cell lines to which LKB1 gene was transduced and one LKB1 wild type NSCLC cell line in which LKB1 gene was knocked out by CRISPR technology. Transduction of LKB1 resulted in significant resistance to a PI3K/mTOR inhibitor in two of the four LKB1 add-back cell lines, while knocking out LKB1 in the LKB1 wild type cell line induced PI3K/mTOR inhibitor sensitivity. The mechanism behind these observed results appears to be through regulation of phosphorylation of AKT. The presence of LKB1 led to a persistent AKT phosphorylation even in the presence of the PI3K/mTOR inhibitor, both in add back cell and wild type cells. Our data suggest that the identification of LKB1 activity may be a promising biomarker for the sensitivity to PI3K/mTOR inhibition. Further investigation into the mechanism of LKB1 loss and increased sensitivity to inhibition of the PI3K and mTOR pathways is warranted. Citation Format: Takehito Shukuya, Tadaaki Yamada, Michael J. Koenig, Mohammad A. Rahman, Joseph M. Amann, David P. Carbone. Effect of LKB1 activity on the sensitivity to PI3K/mTOR inhibitor in non-small-cell lung 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 5535. doi:10.1158/1538-7445.AM2017-5535
Abstract LB-282: Two different strategies of delivery CRISPR/Cas9 system to gene edit rs4644 SNP inLGALS3gene
Authors: Alda Corrado, Irene Lepori, Simona Miglietta, Simone Batoni, Marianna Vitiello, Monica Evangelista, Elisa Chisci, Roberto Giovannoni, Laura Poliseno, Federica Gemignani, Stefano Landi
Journal: Cancer Research (2017)

Abstract Galectin-3 is a glycoprotein of 31KDa with a chimeric structure. It is encoded by a single gene, LGALS3, located on chromosome 14. Previous studies showed a relation between the single nucleotide polymorphism (SNP) (rs4644, c.191C&amp;gt;A, p.Pro64His) and the risk of cancer. In literature, some data show different results indicating that SNP could have different roles in base on the tissues. The aim of our study is to create isogenic cell lines that differ only for SNP permitting further studies about the function of SNP in different cancers. The “generation” of the cell lines is performed with a Clustered Regularly Interspaced Short Palindromic Repeats-associated Endonuclease 9 (CRISPR/Cas9) system. We have used two different strategies to deliver the system. In the first strategy, our aim was the reduction of the problem of efficiency of transfection that could depend on different cell lines. In fact, we have used the lentivirus method to deliver all components of the CRISPR/Cas9 on Nthy-Ori (normal thyroid tissue) and HCT 116 +/+ (colorectal cancer tissue) cells. Two different vectors (pCW-Cas9 and pLXgRNA) are used to build up the inducible CRISPR/Cas9 system and HR410PA-1 vector (transfected by Lipofectamine 3000) is used to knock-in. HR410PA-1 is a particular vector that facilities the homologous recombination (HR) to repair the double strand break. Moreover, to improve HR, we use also Scr7, which is an inhibitor of DNA IV ligase. In the second approach, we have used the double nickase system using two modified Cas9 vectors (SpCas9D10a) that produce only a single strand break. In this way, the problem of off-targets is notably reduced. In this approach, the knock-in is due to or single-stranded oligodeoxynucleotides (ssODNs) or HR410PA-1 vector. The first results show that some of the transfected cells are edited in a correct way. In the further steps, we will isolate the “positive clones” using the selection cassette in HR410PA-1 vector (GFP protein and/or puromycin) or the single cell dilution assay (1 cell/well) for the transfected cells with ssODNs. Citation Format: Alda Corrado, Irene Lepori, Simona Miglietta, Simone Batoni, Marianna Vitiello, Monica Evangelista, Elisa Chisci, Roberto Giovannoni, Laura Poliseno, Federica Gemignani, Stefano Landi. Two different strategies of delivery CRISPR/Cas9 system to gene edit rs4644 SNP in LGALS3 gene [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-282. doi:10.1158/1538-7445.AM2017-LB-282
Abstract LB-277: Four noval activating and resistance mutations of EGFR drug response targets were discovered in northern Chinese patients
Authors: Geng Tian
Journal: Cancer Research (2017)

Abstract Background and Objective: Lung cancer is the most rapidly developed cancer in terms ofmorbidity and fatality rate. The presence of EGFR mutations is a useful tool to determine NSCLC patients' prognosis. But there are differences in Eastern Asian and European and American. The aim of this study is to discoveryand validate the new EGFR drug targets in Northern Chinese patients with non-small cell lung cancer (NSCLC) via bioinformatics analysis, molecular biology experiments and clinical outcomes, and raise new possibilities for designing personalized treatments for patients carrying specific mutations. Methods: In this study, a new computational method and drug model was firstly established by referring to the HotSpot3D[1], which was applied to process mutagenesis data and identify new drug targets. We subsequently applied the computationaltool to more than 500 tumors of NSCLC patients in North China.The captured target DNAs were analyzed by next-generation sequencing using a nine gene lung cancer panel to find somatic variations. We then validated our predictions in cell-line-based experimental combining the results of the clinical follow-up. Results: We used a new computational tool to analyze more than 500 tumors data of NSCLC patients in North China, discovering several rarely reported druggable mutations, including EGFR mutations (p.Val742Ile, p.Ile789Met, p.Asn842His) with erlotinib, gefitinib, lapatinib and EGFR mutations (p.Ser811Cys) with afatinib. Furthermore, we performed an experiment examining the sensitivity of the EGFR proteins with these variants to the target drugs mentioned above. We found that EGFR with the p.Ile789Metvariant was sensitive to gefitinib, consistent with a previous report [1]. In parallel, of the 500NSCLC patients, 200 were treated with the above targetdrugs, and clinical outcomes of treated patients were collected. The results were consistent with the cell-line-based experiments. Verification of other EGFR variants is still in progress. Conclusion: In this study, severalnew EGFR druggable mutations were for the first time found and validated in NorthernChinese patients with non-small cell lung cancer (NSCLC). Our results will provide better treatment options for patients carryingthese specific mutations. [1] Niu B, Scott A D, Sengupta S, et al. Protein-structure-guided discovery of functional mutations across 19 cancer types[J]. Nature Genetics, 2016, 48(8). Citation Format: Geng Tian. Four noval activating and resistance mutations of EGFR drug response targets were discovered in northern Chinese patients [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-277. doi:10.1158/1538-7445.AM2017-LB-277
Factors influencing prostate cancer treatment decisions for African American (AA) and Caucasian (CA) men.
Authors: Brittaney-Belle Elizabeth Gordon, Ramsankar Basak, Deborah S Usinger, Paul Alphonso Godley, Ronald C. Chen
Journal: Journal of Clinical Oncology (2017)

6517 Background: Prostate cancer causes a disproportionate burden to AA men, and AA men are less likely than CA men to receive aggressive treatment. This is the first study to examine factors influencing treatment decision-making of AA vs. CA men in a population-based cohort. Methods: 1171 men were enrolled soon after diagnosis and before treatment through Rapid Case Ascertainment of the North Carolina state cancer registry. Researchers asked patients regarding their priorities in treatment decision-making and information sources. Differences in AA and CA men were compared using the chi-square test. Results: The most important factor for both AA and CA men was curing cancer, and preserving QOL was second most important. However, AA men were more concerned about additional factors including impact on daily activities (74% very important AA vs 58% CA for intermediate/high risk disease), recovery time (81% vs 50%), cost (66% vs 32%) and treatment time (76% vs 39%) (p &lt; .001 for each item). The most important source of information impacting treatment decisions for CA men were physician recommendations (61%), personal research (32%) and family/friend opinion (7%); for AA men, the corresponding numbers were 50%, 32% and 19%. Conclusions: AA and CA men with prostate cancer are both concerned about curing cancer, but AA men are more likely to consider multiple other social and personal factors as important in their decision-making process. Improved understanding of these differences may provide opportunities to address racial disparities in prostate cancer. [Table: see text]
Abstract 3882: Identification of targetable EMT markers in cancer stem-like cells derived from therapeutic resistant melanoma
Authors: William P. Crosson, Elyse Berlinberg, Ramin Nazarian
Journal: Cancer Research (2017)

Abstract Melanoma is the deadliest form of skin cancer, expected to claim approximately 10,000 lives in 2016. An activating mutation in BRAF(V600E) occurs in 50-60% of melanomas and 7% of all cancers. Despite an unprecedented initial response, patients treated with a highly effective BRAF inhibitor, vemurafenib (FDA approved 2011), acquire drug resistance within 6-9 months. Vemurafenib-resistant sub-lines, derived from BRAFV600E isogenic parental melanoma cells, have altered cell morphology and upregulated PDGFRβ expression. Epithelial-to-mesenchymal transition (EMT), a hallmark of cancer-stem-like cells (CSC), is a potential mechanism that melanomas employ to evade targeted therapy. Through immunocytochemical, immunoblot, and flow cytometric analysis, we investigated the expression profile of EMT biomarkers within parental and resistant melanoma cell lines. Our findings indicate CSCs within melanoma populations may serve as progenitor cells for therapy-resistant melanoma sublines through differential expression of key EMT-related biomarkers. Furthermore, resistant cell lines were significantly more invasive in migration assays. Our results implicate notable EMT biomarkers in CSCs that can be used as novel targets for diagnosis and treatment of tumor resistance in melanoma patients. Citation Format: William P. Crosson, Elyse Berlinberg, Ramin Nazarian. Identification of targetable EMT markers in cancer stem-like cells derived from therapeutic resistant melanoma [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 3882. doi:10.1158/1538-7445.AM2017-3882
Abstract 1643: Cytotoxic T lymphocyte CD3+, CD8+, and immunoscore as prognostic marker in patients after radical cystectomy
Authors: Jose J. Mansure, Alice Yu, Shraddha Solanki, Ana B. Dias, Miguel M. Burnier, Fadi Brimo, Wassim Kassouf
Journal: Cancer Research (2017)

Abstract Purpose: Prognosis after radical cystectomy for bladder cancer can be unpredictable. There is increasing evidence that the presence of cytotoxic T lymphocytes correlates with survival. The Immunoscore, a new approach to classification of cancer using the number, type and distribution of immune cells, is an independent predictor for survival in colon cancer. Our objective was to evaluate the prognostic impact of lymphocyte distribution and the Immnoscore in bladder cancer. Methods: Cystectomy sections with core tumor (CT) involvement and identifiable invasive margin (IM) were selected and stained for CD3+ and CD8+ lymphocytes. Three non-contiguous areas of highest lymphocyte density were selected from both CT and IM. The number of lymphocytes in each area was used to calculate the Immunoscore based on previously defined criteria. Kaplan-Meier curves were used to determine differences between Disease-free Survival (DFS) and Overall Survival (OS). Multivariate Cox proportional hazards model was used to determine hazard ratios. Results: Total of 67 patients who had cystectomy for invasive bladder cancer were included in the study. High concentration of CD8+ lymphocytes in the tumour margin was associated with better DFS (P=0.005) and OS (P=0.03). Similar results were found for CD3+ lymphocytes with regards to DFS (P=0.05). A higher Immunoscore was also associated with better DFS (P=0.04). On multivariate analysis, CD8+ in the invasive margin was independently associated with better prognosis. Conclusions: The host’s own immune system plays a valuable role in clinical outcome. Our data suggests that a strong immune response in the tumor margin is independently associated with better prognosis. Citation Format: Jose J. Mansure, Alice Yu, Shraddha Solanki, Ana B. Dias, Miguel M. Burnier, Fadi Brimo, Wassim Kassouf. Cytotoxic T lymphocyte CD3+, CD8+, and immunoscore as prognostic marker in patients after radical cystectomy [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 1643. doi:10.1158/1538-7445.AM2017-1643