tbuckley/cabot-search huggingface dataset:
Abstract 5625: Identification and validation of a PD-L1 specific peptide for determination of PD-L1 expression in tumors
Authors: Charles Caldwell, Cory Johnson, Richard Hammer, Raghuraman Kannan
Journal: Cancer Research (2017)

Abstract In recent years, immunotherapy has seen a resurgence as a promising method of treating cancers. The interaction between Programmed Death Ligand 1 (PD-L1) and its receptor, Programmed Death 1 receptor (PD-1) has been of particular interest. Many different types of tumors have been shown to overexpress PD-L1, which causes host immune cells that express the PD-1 receptor and bind PD-L1 to cease killing the tumor. Patients who have tumors exhibiting high levels of PD-L1 show poor prognosis compared to those who do not. Inhibition of the PD-L1 PD-1 binding axis has been shown to restore host immunity to the tumor, and recently many new drugs such as atezolizumab and pembrolizumab have been developed to target this interaction. Current methods of PD-L1 diagnosis have shown to vary based on the antibody, detection kit brand, antigen retrieval method, and clinically strict defined methods for use by the FDA for assessment. To refine detection of PD-L1, we have identified a PD-L1 specific peptide which can be used to detect PD-L1 expressing tumors using either conventional immunohistochemistry or flow cytometry. Immunohistochemistry using this peptide was tested against the FDA-approved PD-L1 (SP263) Rabbit monoclonal primary antibody on biopsied patient tissues. Flow cytometry was performed on both cultured cell lines and patient tissues. We have shown that our PD-L1 peptide shows specific staining in the tumor regions of FFPE tissues where the SP263 kit does not stain, and we can also detect PD-L1 expression in both cell samples and patient tissues using flow cytometry. Citation Format: Charles Caldwell, Cory Johnson, Richard Hammer, Raghuraman Kannan. Identification and validation of a PD-L1 specific peptide for determination of PD-L1 expression in 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 5625. doi:10.1158/1538-7445.AM2017-5625
Abstract 3967: High microsomal PGE2synthase-1 levels associate with low CD8 T cells and poorer melanoma patient survival
Authors: Sun-Hee Kim, Jason Roszik, Weiyi Peng, Suhendan Ekmekcioglu, Elizabeth A. Grimm
Journal: Cancer Research (2017)

Abstract COX-2 and its product PGE2 are reported to enhance carcinogenesis and tumor progression and to support immunosuppression, as reported by others in melanoma and other cancers. As most COX-2 inhibitors result in cardiotoxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is now also an alternative consideration for therapeutic targeting. Our previously published results (Kim, et al., 2016) showed that mPGES1 protein increased with melanoma patient clinical stage and that its intense expression was associated with reduced patient survival. We also reported that mPGES1 inhibition attenuated cell survival and increased apoptosis in human melanoma cells and significantly suppressed tumor growth in melanoma xenografts. This current study was designed to evaluate whether expression of mPGES1 contributes to immune evasion. Tumors in a Stage III melanoma TMA analysis demonstrated that high mPGES1 expression (intensity 3) was significantly associated with low CD8 levels (lower than median CD8 percent value) (r=-0.2722, p=0.0128). Importantly, stage III melanoma patients with this high mPGES1 and low CD8 signature had significantly increased risk of death as determined by Kaplan-Meier method and Univariate Cox proportional hazards regression models, and compared with patients with low mPGES1/low CD8 and low mPGES1/high CD8. Furthermore, the differential levels of several chemokines including CXCL1 and CXCL2 to regulate T cell migration were correlated the mPGES1 expression in the TCGA melanoma data set. Collectively, our study continues to resolve the potential role of mPGES1 in regulation of immune evasion and is designed as a preclinical approach to develop a rational therapeutic strategy targeting PGE2-driven inflammatory mediators as useful adjuvants for immune-based therapy. Citation Format: Sun-Hee Kim, Jason Roszik, Weiyi Peng, Suhendan Ekmekcioglu, Elizabeth A. Grimm. High microsomal PGE2synthase-1 levels associate with low CD8 T cells and poorer melanoma patient survival [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 3967. doi:10.1158/1538-7445.AM2017-3967
Abstract 4333: The role of cancer-associated fibroblast-induced chemokine ligand 11 in tumor microenvironment contributes to the progression of oral cancer
Authors: Shin Nieh
Journal: Cancer Research (2017)

Abstract Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer-related death in Taiwan and worldwide. The prognosis of OSCC is usually poor because of its propensity of extensive invasion, local recurrence and frequent regional lymph node metastasis, even at initial diagnosis. Recent studies showed carcinoma-associated fibroblasts (CAFs), a major type of tumor-surrounding stromal cell, generate certain mediators through which CAFs interact with tumors and contribute to cancer progression in numerous cancers. The orchestration between CAFs and cancer cells is complex and its underlying mechanism needs to be explored. In the present study, we used organotypic culture to investigate CAFs that promote aggressive behavior of cancer cells. Using microarray analysis, we detected abundant expression of chemokine (C-C motif) ligand 11(CCL11), also named Eotaxin, secreted by CAFs and further be identified as a critical mediator in CAF-induced invasiveness. We planned to validate that CCL11 played a major role in the crosstalk between fibroblasts and OSCC cells via the paracrine manner. CCL11was found upregulated in CAFs than in normal fibroblasts via Western blot analysis. Cells lines of OSCC, Fadu and TW204, treated with recombinant CCL11 increased capabilities of sphere formation in ten days. Administration of CCL11 promoted migration and invasion abilities through induction of the epithelial-to-mesenchymal transdifferentiation with corresponding morphological alterations of cancer cells. Counteracting CCL11 activity diminished the aggressive phenotype of cancer cells induced by CAFs. We further studied the relationship between the expression of CCL11 in both CAFs and OSCC cells and clinical outcome in the patients with OSCC. As a result, a high CCL11 expression level was associated with poor prognosis in terms of nodal metastasis and survival. These results indicate that CAFs promote cancer invasiveness via a paracrine effect on microenvironmental CCL11 signaling and suggest that CCL11 is a potential prognostic biomarker that may be considered in therapeutic strategies for the treatment of patients with OSCC. Citation Format: Shin Nieh. The role of cancer-associated fibroblast-induced chemokine ligand 11 in tumor microenvironment contributes to the progression of oral 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 4333. doi:10.1158/1538-7445.AM2017-4333
Abstract 4304: Feedback-phosphorylation of MKK4 by MAPKs promotes apoptosis
Authors: Hisashi Moriizumi
Journal: Cancer Research (2017)

Abstract Feedback-phosphorylation of MKK4 by MAPKs promotes apoptosis Moriizumi Hisashi, Takanori Nakamura and Mutsuhiro Takekawa Div. of Cell Signaling and Mol. Med., IMS, Tokyo Univ. The mitogen-activated protein (MAP) kinase pathway is an important system for cellular responses to extracellular stimuli. Each of the MAPK pathways is composed of MAPKKK, MAPKK and MAPK. In mammalian cells, at least three subfamilies of MAPKs, namely ERK, p38 and JNK, are present. The ERK pathway is activated in response to mitogenic stimuli and plays a key role in proliferation and differentiation. In contrast, the p38 and JNK pathways [collectively called stress-activated protein kinase (SAPK) pathways] regulate cellular stress responses such as apoptosis and cell cycle arrest. MKK4 is unique among the members of the mammalian SAPKK family (i.e., MKK3/4/6/7) in its ability to phosphorylate and activate both p38 and JNK. Interestingly, inactivating mutations of the MKK4 gene are frequently found in many types of cancer. Although MKK4 has been suggested as a tumor suppressor, the molecular mechanism by which MKK4 inhibits tumorigenesis remains unclear. Here we demonstrate that MKK4 can be phosphorylated at specific serine and/or threonine residues by downstream MAPKs(named the “feedback-phosphorylation”)and thereby regulates stress-induced apoptotic cell death. By generating antibodies specific to these phosphorylation sites, we found that under stress conditions both Thr and Ser residues of MKK4 were phosphorylated by JNK, while only the Ser residue was phosphorylated by ERK in response to mitogenic stimuli. In order to clarify physiological significance of the feedback-phosphorylation, we then generated a phosphorylation-deficient mutant of MKK4 (MKK4-AA) by substituting both Thr and Ser residues with Ala. Although the feedback-phosphorylation did not affect the enzymatic activity, stability and subcellular localization of MKK4, we found that cells expressing MKK4-AA mutant suppressed apoptosis induced by various stresses stimuli such as UV irradiation and anticancer drug treatment. These results suggest that feedback-phosphorylation of MKK4 regulates stress-induced apoptosis. Moreover, we are currently investigating the mechanism of how MKK4 affects apoptotic cell death in response to feedback-phosphorylation. Citation Format: Hisashi Moriizumi. Feedback-phosphorylation of MKK4 by MAPKs promotes apoptosis [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 4304. doi:10.1158/1538-7445.AM2017-4304
Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification
Authors: George Seed, Wei Yuan, Joaquin Mateo, Suzanne Carreira, Claudia Bertan, Maryou Lambros, Gunther Boysen, Roberta Ferraldeschi, Susana Miranda, Ines Figueiredo, Ruth Riisnaes, Mateus Crespo, Daniel Nava Rodrigues, Eric Talevich, Dan R. Robinson, Lakshmi P. Kunju, Yi-Mi Wu, Robert Lonigro, Shahneen Sandhu, Arul M. Chinnaiyan, Johann S. de Bono
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Precise detection of copy number aberrations (CNA) from tumor biopsies is critically important to the treatment of metastatic prostate cancer. The use of targeted panel next-generation sequencing (NGS) is inexpensive, high throughput, and easily feasible, allowing single-nucleotide variant calls, but CNA estimation from this remains challenging. Experimental Design: We evaluated CNVkit for CNA identification from amplicon-based targeted NGS in a cohort of 110 fresh castration-resistant prostate cancer biopsies and used capture-based whole-exome sequencing (WES), array comparative genomic hybridization (aCGH), and FISH to explore the viability of this approach. Results: We showed that this method produced highly reproducible CNA results (r = 0.92), with the use of pooled germline DNA as a coverage reference supporting precise CNA estimation. CNA estimates from targeted NGS were comparable with WES (r = 0.86) and aCGH (r = 0.7); for key selected genes (BRCA2, MYC, PIK3CA, PTEN, and RB1), CNA estimation correlated well with WES (r = 0.91) and aCGH (r = 0.84) results. The frequency of CNAs in our population was comparable with that previously described (i.e., deep deletions: BRCA2 4.5%; RB1 8.2%; PTEN 15.5%; amplification: AR 45.5%; gain: MYC 31.8%). We also showed, utilizing FISH, that CNA estimation can be impacted by intratumor heterogeneity and demonstrated that tumor microdissection allows NGS to provide more precise CNA estimates. Conclusions: Targeted NGS and CNVkit-based analyses provide a robust, precise, high-throughput, and cost-effective method for CNA estimation for the delivery of more precise patient care. Clin Cancer Res; 23(20); 6070–7. ©2017 AACR.
Colorectal endoscopic full-thickness resection using a novel, flat-base over-the-scope clip: a prospective study
Authors: Yara Backes, Wouter Kappelle, Luuk Berk, Arjun Koch, John Groen, Wouter de Vos tot Nederveen Cappel, Matthijs Schwartz, Marjon Kerkhof, Peter Siersema, Roland Schröder, T. Tan, Miangela Lacle, Frank Vleggaar, Leon Moons
Journal: Endoscopy (2017)

Abstract Background and study aims We aimed to evaluate the feasibility and safety of a new, flat-based over-the-scope clip (Padlock Clip) for colorectal endoscopic full-thickness resection (eFTR). Patients and methods We prospectively included 26 patients with lesions &lt; 20 mm. Indications for eFTR were re-resection of the scar of a low risk malignant polyp (n = 11), recurrent adenoma in a non-lifting scar (n = 10), non-lifting polyp (n = 4), and an adenoma located in a diverticulum (n = 1). Results Technical success rate and full-thickness resection rate were 100 % (26/26) and 92 % (24/26), respectively. Median procedure time was 43 minutes (IQR 27 – 56). No complications occurred during the procedure; 3 complications (12 %) occurred within 48 hours, of which one was a perforation requiring laparoscopic suturing. Specimen volumes from eFTR of scar tissue where the original polyp had been ≥ 20 mm (n = 13) were smaller compared with those from non-scar resections or scars where the original polyps had been &lt; 20 mm (n = 13) (median 0.8 vs. 1.5 cm3, P = 0.03). Conclusions In this first series of colorectal eFTR using the Padlock Clip, feasibility was demonstrated. It was relatively safe in view of surgery as the alternative treatment, but could still benefit from technical refinement. Future studies should explore for which indication this technique is most suitable. Trial registration: NTR5562 (Dutch Trial Register).
Abstract 5568A: A network based analysis for the treatment of triple negative breast cancer
Authors: Brett A. Fleisher, Sihem Ait-Oudhia
Journal: Cancer Research (2017)

Abstract Background: Triple-negative breast cancer (TNBC) is a complex heterogeneous disease characterized by the absence of three hallmark receptors: human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). Compared to other breast cancer subtypes, TNBC is more aggressive, has a higher prevalence in African Americans, and more frequently affects younger patients. Currently, TNBC lacks clinically-accepted targets for tailored therapy, warranting the need for candidate biomarkers. Methods: BiomarkerBase, a biomarker knowledgebase developed by Amplion uses a comprehensive list of synonyms to identify biomarkers registered in the records of clinical trials via the government website clinicaltrials.gov. Under each of the registered breast cancer biomarkers (with the exceptions of HER2, ER, and PR), sub-searches were conducted for clinical trials that explicitly used TNBC (or the full name, triple negative breast cancer) in the title of the biomarkers’ studies. Of note, most trials in this review were completed phase II or III. The selected candidate biomarkers were classified into four FDA biomarker categories (surrogate, prognostic, predictive, or pharmacodynamic (PD)) as well as by location (blood/plasma, cell surface, cytoplasm, or nucleus). Current literature about the biomarkers was further examined using PubMed. There, we sought to find papers that studied how the biomarkers may interact. These markers were further organized into a “cellular protein network” that demonstrates potential connectivity. Results: Blood biomarkers include VEGF/VEGFR and IL-8; cell surface biomarkers include EGFR, IGFBP, c-Kit, c-Met, and PD-L1; cytoplasm biomarkers include PIK3CA/AKT/mTOR-related metabolites (GPC, PCh, Lactate/ glucose), pPKM2, F1,6BP, SPHK1, STAT1/IRF2BP2, S6, p4E-BP1, SUV39H1, PTEN, and ALDH1; and nucleus biomarkers include BRCA1, the glucocorticoid receptor (GR), TP53, and Ki67. Table 1 provides an overview of the examined surrogate, prognostic, predictive, and PD biomarkers in TNBC in addition to current literature found in PubMed that provides support for their potential use. Conclusion: To date, there are no clinically-validated biomarkers for TNBC, which has hindered the development of tailored therapy for both chemosensitive and refractory TNBC. Before validation and use of these biomarkers occurs, stringent-clinical criteria must be met first. The list and cellular protein network provided is an inventory and reference point for promising biomarkers for breakthrough, targeted therapies in TNBC. Citation Format: Brett A. Fleisher, Sihem Ait-Oudhia. A network based analysis for the treatment of triple negative 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 5568A. doi:10.1158/1538-7445.AM2017-5568A
Abstract 514: Genetic load in cancer cell populations
Authors: Yuezheng Zhang, Xu Shen, Yawei Li, Tianqi Zhu, Yong Tao, Tao Li, Di Wang, Xueying Li, Qin Ma, Xuemei Lu, Hurng-Yi Wang, Chung-I Wu
Journal: Cancer Research (2017)

Abstract Populations accumulate deleterious mutations that have yet to be removed by natural selection. This mutated portion of the population that does not contribute to its fitness is called the genetic load and is proportional to the deleterious mutation rate. Given the genomic instability of cancer cells, the genetic load could be substantial if the instability indeed leads to loss of cell fitness. We hypothesize that because aneuploidy and copy number variations (CNVs) are the most common forms of genome instability, their fitness consequences may determine the genetic load in cancer cells. To test this hypothesis, we randomly selected single cells from a HeLa cell line and measured the cell growth rate via daily cell counting and an MTT cell proliferation assay. We then measured the genetic changes and resulting growth rate variation. We observed rapid generation of heterogeneity in the growth rate within the population. The growth rate of different progeny cells was stable indicating that it is genetically determined. Next, using whole genome sequencing of recently descended clones of a single HeLa cell, we found that cells with fewer newly acquired CNVs have higher proliferation rates vice versa. This indicated that CNV accumulation decreased cell fitness systematically. We next estimated the rate of CNV mutation by measuring the growth rate of two daughter cells from single proliferation and found that there is approximately 1 deleterious mutation in every 4 cell divisions. We speculated that due to a high, deleterious CNV mutation rate, tumor cells inevitably accumulate deleterious CNVs and a large percentage of tumor cells are genetically defective. Accordingly, we observed that the average growth rate of tumor cell populations decreased in the short term since defective cells accumulated in the population and the variation of cellular growth rates within the population increased. By modeling the process of mutation accumulation and measuring cell growth rate, we estimated that the deleterious mutation rate in HeLa cells is about 0.26-0.31 per cell division, and that HeLa cells reduce roughly 5%-6% of fitness for every cell division. The observations of a high proliferation rate and high genetic load in this representative tumor cell line indicates a “high risk, high reward” evolution strategy for tumor cells and suggests that increasing the level of genomic instability may cause the meltdown of tumor cell population by forcing cells to accelerate the cell cycle. Citation Format: Yuezheng Zhang, Xu Shen, Yawei Li, Tianqi Zhu, Yong Tao, Tao Li, Di Wang, Xueying Li, Qin Ma, Xuemei Lu, Hurng-Yi Wang, Chung-I Wu. Genetic load in cancer cell populations [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 514. doi:10.1158/1538-7445.AM2017-514
Abstract 3279: Circulating inflammatory biomarker C-reactive protein and radiotherapy-related pain in breast cancer patients
Authors: Eunkyung Lee, Omar L. Nelson, Carolina Puyana, Cristiane Takita, Jean L. Wright, Wei Zhao, Isildinha M. Reis, Rick Lin, Jennifer J. Hu
Journal: Cancer Research (2017)

Abstract Background: Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Post-surgery adjuvant radiotherapy (RT) significantly improves clinical outcomes. However, many patients develop treatment-related pain that negatively impacts quality of life. Methods: We evaluated an inflammatory biomarker, C-reactive protein (CRP) in RT-associated pain in a prospective study of 366 breast cancer patients (64% Hispanic whites, 20% African Americans, 16% non-Hispanic whites) undergoing RT. In each patient, we measured pre- and post-RT plasma CRP levels using a highly-sensitive ELISA kit. Pain score was assessed at pre- and post-RT as the mean of four pain severity items (i.e., pain at its worst, least, average, and now) from the Brief Pain Inventory. Pain scores of 4-10 were considered clinically-relevant pain. Association between pain and CRP levels was evaluated using logistic regression models after adjusting for potential confounders. Results: Overall, 16% patients at pre-RT and 31% patients at post-RT had pain. In multivariable analyses, RT-related pain score change &amp;gt;4 was significantly associated with CRP change &amp;gt;1 mg/L (OR=3.24, 95%CI=1.33, 7.88), age &amp;lt;50 (OR=3.27, 95%CI=1.20, 8.92), and 3+ comorbidity conditions (OR=5.91, 95%CI=1.33, 26.82). Conclusion: This is the first study to suggest that increased inflammatory biomarker, CRP level was associated with RT-related pain. Impact: Future larger studies are warranted to validate our findings and facilitate the discovery and development of anti-inflammatory agents to protect patients from RT-related pain and improve quality of life in breast cancer patients undergoing RT. Citation Format: Eunkyung Lee, Omar L. Nelson, Carolina Puyana, Cristiane Takita, Jean L. Wright, Wei Zhao, Isildinha M. Reis, Rick Lin, Jennifer J. Hu. Circulating inflammatory biomarker C-reactive protein and radiotherapy-related pain in breast cancer 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 3279. doi:10.1158/1538-7445.AM2017-3279