tbuckley/cabot-search huggingface dataset:
Abstract 5355: Multiple mutations to the same gene are selected for and cooperate to drive cancer
Authors: Alexander N. Gorelick, Ed Reznik, Yanyan Cai, Craig Bielski, Chaitanya Bandlamudi, Alexander Penson, Philip Jonsson, Konnor La, Maurizio Scaltriti, Nikolaus Schultz, Barry S. Taylor
Journal: Cancer Research (2018)

Abstract Cancers accumulate oncogenic mutations whose biochemical impact depends upon other germline and somatic variants in the cell. It stands to reason that the consequence of a somatic mutation is mediated by the presence of additional genetic variants within the same gene, and by the allele on which they arise. We have undertaken integrative analyses of 27,534 human tumors, including 19,640 prospectively sequenced advanced and metastatic cancers, and revealed a startling rate of multiple non-synonymous somatic mutations in the same cancer gene and tumor, hereafter referred to as multiple mutations. Overall, 26% of primary and metastatic tumors had at least one cancer gene with two or more somatic mutations. A minority of multiple mutations arose from somatic hypermutation or as secondary mutations driving resistance to molecularly targeted therapy. Clonality analysis further indicated that the majority of multiple mutations were present in the same cell. Multiple cancer genes were enriched for a greater burden of multiple mutations than would be expected in the absence of selection, including APC, B2M, EGFR, and TERT. The allelic configuration of these mutations indicated that while multiple mutations in trans arose predominantly in tumor suppressor genes, consistent with the selective pressure for biallelic inactivation, the majority of phaseable mutations arose in cis in both tumor suppressors and oncogenes, implying a selective pressure exists for a biochemical function distinct from individual driver mutations in the same gene. Collectively, these data argue that multiple genetic variants within a gene and their allelic configurations can interact to drive cancers. Citation Format: Alexander N. Gorelick, Ed Reznik, Yanyan Cai, Craig Bielski, Chaitanya Bandlamudi, Alexander Penson, Philip Jonsson, Konnor La, Maurizio Scaltriti, Nikolaus Schultz, Barry S. Taylor. Multiple mutations to the same gene are selected for and cooperate to drive cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5355.
Abstract 3691: Collagen 1 fiber content may predict for recurrence in non-small cell lung cancer
Authors: Samata Kakkad, Peng Huang, Malcolm Brock, Balaji Krishnamachary, Zaver M. Bhujwalla
Journal: Cancer Research (2018)

Abstract Non-small cell lung carcinoma (NSCLC) comprises 85% of all lung cancers. Approximately 30-50% of NSCLC recur despite curative resection. There is a major unmet need to identify NSCLC that are likely to recur so that these patients may be treated with more aggressive therapies. Collagen 1 (Col1) fibers are a major structural component of the extracellular matrix (ECM) of tumors. While increased Col1 fibers have been associated with increased metastasis in breast cancer, the role of Col1 in NSCLC and its relationship to recurrence has not been previously examined. We performed a blinded second harmonic generation (SHG) microscopy study on tumor tissue obtained from 5 patients with nonrecurrent NSCLC and 5 patients with recurrent NSCLC. Col1 fibers were detected with SHG microscopy that detects an intrinsic signal derived from the noncentrosymmetric molecular structure of Col1 fibers. SHG microscopy of tumor regions was performed on the H&amp;E sections to quantify Col1 fiber volume and inter fiber distance in the tumors. At least 10 fields of view were analyzed from 1-2 sections obtained from each tumor. We additionally performed Haralick feature analyses to further analyze Col1 fiber patterns. Adjacent sections were immunostained for CD44 and α-SMA to identify cancer associated fibroblasts (CAFs) and understand their role in these tumors. We observed a significant increase of Col1 fiber volume and a significant decrease of inter fiber distance in recurrent NSCLC. Four Haralick features (orientation, contrast, energy and homogeneity) were also significantly higher in the recurrent tumors compared to the non recurrent tumors. We are currently analyzing the CAFs in the tumor sections to understand their role in the significant differences observed in Col1 fibers between recurrent and nonrecurrent tumors. If these preliminary data are confirmed in an expanded sample set, Col1 fiber analysis may provide a companion diagnostic test that can be performed rapidly on H&amp;E tumor sections, using a confocal microscope, to evaluate the likelihood of tumor recurrence. These studies provide new insights into the role of the tumor microenvironment in NSCLC recurrence, and identify new targets for future therapeutic strategies. This work was supported in part by NIH R35CA209960. Citation Format: Samata Kakkad, Peng Huang, Malcolm Brock, Balaji Krishnamachary, Zaver M. Bhujwalla. Collagen 1 fiber content may predict for recurrence in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3691.
Sunitinib Prior to Planned Nephrectomy in Metastatic Renal Cell Carcinoma: Angiogenesis Biomarkers Predict Clinical Outcome in the Prospective Phase II PREINSUT Trial
Authors: Laetitia Mauge, Arnaud Mejean, Laure Fournier, Helena Pereira, Marie-Christine Etienne-Grimaldi, Emeline Levionnois, Armelle Caty, Sophie Abadie-Lacourtoisie, Stéphane Culine, Sylvestre Le Moulec, Claude Linassier, Christine Théodore, Alain Ravaud, Laurence Albiges, Abel Grine, Eric Tartour, Gérard Milano, Anne-Sophie Gille, Virginie Verkarre, Dominique Helley, Stéphane Oudard
Journal: Clinical Cancer Research (2018)

Purpose: The PREINSUT study characterized factors predictive of response to sunitinib given before planned nephrectomy in patients with metastatic renal cell carcinoma (mRCC).Patients and Methods: This French multicenter, prospective, open-label, phase II trial (NCT00930345) included treatment-naïve patients with clear-cell mRCC. Patients received two cycles of sunitinib before nephrectomy. The primary objective was to evaluate the potential of circulating angiogenesis-related biomarkers measured before and on treatment for identifying responders based on primary renal tumor (PRT) size change. Secondary objectives were to evaluate the ability of biomarkers to predict progression-free survival (PFS) and overall survival (OS).Results: Thirty-two patients were enrolled. The median PFS was 4.5 months, and the median OS was 12.4 months. OS was significantly longer in responding patients (28.8 vs. 11.1 months; P = 0.03). Of 27 patients evaluable for PRT response, nine (33.3%) had a ≥10% decrease in PRT size. Baseline biomarkers significantly associated with outcome were endothelial progenitor cells (PRT response); vascular endothelial growth factor (VEGF)-A, stromal cell-derived factor-1 (SDF-1), soluble VEGF receptors (sVEGFR)1 and 2 (PFS); and SDF-1 and sVEGFR1 (OS). During treatment, changes in biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response), sVEGFR2 (PFS), and SDF-1 and sVEGFR1 (OS). There was no correlation between plasma sunitinib or its active metabolite steady-state trough concentrations and clinical outcome.Conclusions: Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. As blood biomarkers are not subjected to tumor heterogeneity and allow longitudinal follow-up, circulating angiogenesis profile has a promising place in antiangiogenic therapy guidance. Clin Cancer Res; 24(22); 5534-42. ©2018 AACR.
Sodium Restriction Shifts Circadian Rhythm of Blood Pressure From Nondipper to Dipper in Essential Hypertension
Authors: TakashiUzu, KazuhikoIshikawa, TakashiFujii, SatokoNakamura, TakashiInenaga, GenjiroKimura
Journal: Circulation (1997)

Background Sodium restriction has been widely used for treatment of hypertension and renal diseases. Whether sodium restriction can transform the circadian rhythm of blood pressure from nondipper to dipper is examined. Methods and Results Patients (n=42) with essential hypertension were maintained on a high-sodium diet (12 to 15 g of NaCl per day) and a low-sodium diet (1 to 3 g/d) for 1 week each. On the last day of each diet, blood pressures were measured noninvasively every hour for 24 hours with an automatic oscillometric device. Twenty-one patients were classified as non–sodium sensitive whereas 21 were classified as sodium sensitive on the basis of a ≥10% change in 24-hour mean arterial pressure caused by sodium restriction. Nocturnal blood pressure fall was significant in the non–sodium sensitive subjects but not in sodium-sensitive subjects. There was a significant interaction between sodium restriction and nocturnal fall in blood pressure only in the sodium-sensitive subjects, indicating that the...
Abstract 1511: Differential expression analysis and biomarker identification in five salivary gland carcinoma types
Authors: Kathryn J. Brayer, Yoshitsugu Mitani, Adel El-Naggar, Scott A. Ness
Journal: Cancer Research (2018)

Abstract Significant morphologic overlap can exist between distinct salivary gland neoplasms, making differential diagnosis challenging, even with the use of new immunohistochemistry stains and FISH probes (Griffith et al., Arch Pathol Lab Med 2017). RNA-sequencing (RNAseq) technology is increasingly being used as a tool for identify diagnostic molecular signatures in a wide variety of diseases (Byron et al., Nat Rev Genet 2016). Furthermore, transcriptomics data are being used to develop biomarkers that can be used in drug discovery assays. Using an unbiased RNAseq analysis pipeline (Brayer et al., Cancer Discov 2016; Brown et al., PLos One 2017), we developed molecular profiles for 126 salivary gland tumors with accompanying clinical data–68 adenoid cystic carcinoma (ACC), 23 acinic cell carcinoma (Acinic), 5 basal cell adenoma (BCA), 20 basal cell adenocarcinoma (BCAC), and 10 secretory carcinoma (SC)–and have identified distinct gene expression patterns for each neoplasm. Additionally, a detailed analysis within each cancer type has revealed heterogeneous gene expression patterns, with altered signaling pathways, suggesting molecular subtypes exist. In both ACC and Acinic samples we identified unique molecular signatures found in patients with poor overall survival. Transcripts within each molecular signature that are independent of gender, age, and cancer stage, but correlated with clinical outcome data, are being identified for use as diagnostic or prognostic biomarkers and for use in drug discovery assays. Preliminary results to identify biomarkers for these neoplasms will also be presented. Citation Format: Kathryn J. Brayer, Yoshitsugu Mitani, Adel El-Naggar, Scott A. Ness. Differential expression analysis and biomarker identification in five salivary gland carcinoma types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1511.
Abstract 12526: AKAP150-Mobilized PKC Activation Mediates Myocardial Dysfunction in Diabetes
Authors: ZengChao, JinyiWang, NaLi, MingzhiShen, HaichangWang, QiujunYu
Journal: Circulation (2014)

Background: Chronic activation of conventional PKC (cPKC) is a key signaling that directs the cardiac toxicity of hyperglycemia. AKAP150, a scaffold protein of the A-kinase anchoring proteins (AKAPs) family, is less defined regarding its capability to anchor and regulate cPKC signaling in cardiomyocytes. This study was aimed to investigate the role of AKAP150 in cPKC-mediated cardiac injury in diabetes. Methods and Results: In cardiac tissues from streptozotocin-induced diabetic rats and high-glucose treated neonatal rat cardiomyocytes, expression of AKAP150 increased significantly at both mRNA and protein levels, with a marked elevation in expression and activity of cPKC and phosphorylation levels of p65NF-κB and p47phox. AKAP150 knockdown was established via intramyocardial injection in vivo and transfection in vitro of adenovirus carrying AKAP150 targeted shRNA. Downregulation of AKAP150 reversed diabetes-induced diastolic dysfunction, as evidenced by decreased left ventricular end-diastolic diameter a...
Abstract 731: A minigene platform to validate novel immunogenic peptides arising from somatic mutations as therapeutic cancer vaccines
Authors: Xiaoshan Shi, Vasumathi Kode, Kayla Lee, Amit Chaudhuri, Papia Chakraborty
Journal: Cancer Research (2018)

Abstract Cancer vaccines have shown promise in treating late-stage cancers that have failed traditional therapies. Somatic mutations provide a rich source of potential cancer vaccines with minimal T-cell tolerance. We have built a robust screening assay to test somatic mutations for CD8+ T cell activation in a T cell-dendritic cell co-culture assay with synthetic peptides added from outside. Our screening assay revealed that non-mutated wild-type peptides in many instances induced T-cell activation, although their HLA binding affinity was weak. We suspect that addition of high concentration of the peptides from outside may overcome their weak HLA-binding property, allowing them to bind HLA and activate T cells. To reduce the bias of artificial HLA presentation, we have built a minigene platform to screen pairs of wild-type and mutant peptides to assess their immunogenicity. We applied our proprietary cancer vaccine prediction platform to a set of somatic single-nucleotide variants (SNVs) and indels and selected immunogenic peptides by a combination of features that include TCR binding, HLA binding, gene expression and proteasomal processing. Predicted mutant immunogenic peptides and their wild-type counterpart were cloned as minigenes and expressed in HLA restricted antigen-presenting cells (APCs). The minigene-expressing APCs were co-cultured with allogenic CD8+ T cells and activation was monitored by the combined expression of IFN-gamma, TNF-alpha and granzyme-A (CTL phenotype of T cells) by flow cytometry. Our screening assay reveals that a significant number of indels are not presented when they are expressed as a longer peptide because of the stability of the transcripts. However, their presentation and immunogenicity are preserved when they are expressed as short 9-mer peptides with engineered proteasomal cleavage sites. Our study also reveals a range of HLA-binding affinities for peptide presentation. In conclusion, our analysis demonstrates that the two approaches for investigating immunogenicity of peptides—minigene approach and external addition of peptide approach—have differential utilities for testing and validating the immunogenicity of indels and SNVs. Citation Format: Xiaoshan Shi, Vasumathi Kode, Kayla Lee, Amit Chaudhuri, Papia Chakraborty. A minigene platform to validate novel immunogenic peptides arising from somatic mutations as therapeutic cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 731.
Abstract 5749: Interleukin-1 (IL-1) induces a treatment-resistant gene expression pattern in prostate cancer (PCa)
Authors: Shayna Elizabeth Thomas-Jardin, Mohammed Kanchwala, Joan Jacob, Rachel Meade, Nagham Gahnim, Nikki Delk
Journal: Cancer Research (2018)

Abstract Inflammation promotes the development and progression of cancer, where inflammatory cytokines secreted by infiltrating immune cells and tumor cell autocrine signaling are usurped to promote tumor cell survival and disease progression. The interleukin-1 (IL-1) inflammatory cytokine is elevated in prostate cancer (PCa) patient tissue and serum, where it promotes PCa metastasis and bone colonization. Performing in vitro analysis on PCa cell lines and RNA sequencing, we found that IL-1 concomitantly upregulates many pro-survival and lineage proteins, and represses the hormone receptor, androgen receptor (AR). Despite AR loss, a subpopulation of PCa cells remain viable. Our observation could reflect a role for IL-1 in the de novo accumulation of AR- PCa subpopulations. Indeed, AR- PCa subpopulations, such as stem and neuroendocrine cells, are implicated in PCa resistance to AR-targeted therapies. Thus, we hypothesize that IL-1 may reprogram AR+ PCa cells into treatment-resistant AR- PCa cells that survive hormone receptor repression through the upregulation of pro-survival pathways. To begin to address this hypothesis, we performed RNA sequencing and pathway analysis to identify an IL-1-conferred expression pattern in the LNCaP AR+ PCa cell line that mimics the PC3 AR- PCa cell line. We identified canonical inflammatory and immune response pathways, including NFκB, IL-8, and iNOS signaling cascades, likely facilitating PCa cell survival in an inflammatory tumor microenvironment. We also identified novel IL-1-regulated proteins that are known to promote PCa cell survival, such as SQSTM1/p62, SOX9, and ELF3. Experiments are underway to determine the functional significance of our IL-1-conferred gene expression profile in cell line and PDX models. Our investigation will provide insight into the mechanistic function of IL-1 in PCa resistance to AR-targeted therapies Citation Format: Shayna Elizabeth Thomas-Jardin, Mohammed Kanchwala, Joan Jacob, Rachel Meade, Nagham Gahnim, Nikki Delk. Interleukin-1 (IL-1) induces a treatment-resistant gene expression pattern in prostate cancer (PCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5749.
Abstract LB-276: Application of a CRISPR/Cas9 screen to identify novel therapeutic strategies with CDK4/6 inhibitors in pancreatic cancer
Authors: Craig Goodwin, Sehrish Javaid, Adrienne D. Cox, Kris Wood, Channing Der
Journal: Cancer Research (2018)

Abstract While mutational activation of KRAS occurs in nearly all pancreatic ductal adenocarcinomas (PDAC), clinically relevant agents directly targeting KRAS remain elusive. The second most frequent aberration in PDAC is loss of the tumor suppressor CDKN2A, which encodes INK4A, an endogenous inhibitor of the CDK4 and CDK6 cell cycle regulatory proteins that promote G1 cell cycle progression. KRAS and INK4A mutations cooperate to accelerate PDAC metastatic development, in part, by converging to block RB tumor suppressor activity. While no anti-KRAS targeted therapies have reached the clinic, pharmacologic restoration of CDKN2A function by inhibition of CDK4/6 may be an effective anti-KRAS therapeutic strategy. We found that CDK4/6 inhibitors (e.g., palbociclib) elicited single-agent activity in a subset of tested PDAC cell lines. Furthermore, concurrent treatment with the ERK inhibitor SCH772984 caused a potent synergistic reduction in anchorage-dependent and -independent cell growth, induced apoptosis, and increased senescence and G1 arrest. We next sought to identify novel genes that regulate sensitivity to palbociclib. Using a CRISPR/Cas9 loss-of-function screen, we individually silenced expression of 2500 genes from the “druggable genome” in combination with palbociclib. We identified genes that caused synergistic growth suppression in combination, suggesting small molecule combinations to overcome de novo or acquired CDK4/6 inhibitor resistance in the clinic. We also identified genes whose loss imparts a survival advantage, suggesting possible resistance mechanisms to single-agent CDK4/6 inhibition. In total, these data suggest that CDK4/6 inhibitors alone, or in combination, may benefit patients clinically. Citation Format: Craig Goodwin, Sehrish Javaid, Adrienne D. Cox, Kris Wood, Channing Der. Application of a CRISPR/Cas9 screen to identify novel therapeutic strategies with CDK4/6 inhibitors in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-276.
Abstract 3177: mTOR inhibitor augments the antitumor effect of p53-expressing oncolytic adenovirus in human neuroblastoma cells
Authors: Terutaka Tanimoto, Hiroshi Tazawa, Hiroshi Noso, Morimichi Tani, Takanori Oyama, Yasuo Urata, Shunsuke Kagawa, Takuo Noda, Toshiyoshi Fujiwara
Journal: Cancer Research (2018)

Abstract Background: Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. High-risk NB patients show an unfavorable clinical outcome, even after treatment with intensive chemotherapy and aggressive surgical resection. Therefore, a novel therapeutic strategy is needed for the treatment of high-risk NB patients. We developed a tumor-specific replication-competent oncolytic adenovirus OBP-702, in which the hTERT promoter drives the expression of the viral E1A and E1B genes for tumor-specific viral replication and the Egr-1 promoter induces p53 expression. Preclinical studies demonstrated that OBP-702 induces autophagy-related cell death in human NB cell lines. To enhance OBP-702-induced autophagy-related cell death, we hypothesized that a mTOR inhibitor temsirolimus, which is well-known autophagy inducer, may promote autophagy-related cell death by OBP-702 infection. In this study, we investigated the antitumor effect of OBP-702 in combination with temsirolimus in human NB cell lines. Methods: We used 3 human NB cell lines, including IMR-32, CHP-134 and SK-N-SH. The antitumor effect of OBP-702 and temsirolimus was evaluated using XTT assay. In vitro synergistic effect was calculated with CalcuSyn software (BioSoft, Inc.). Virus-mediated cell death and p53 expression were analyzed by Western blot analysis. Ad-p53, a replication-defective adenovirus expressing p53 gene, was used to assess the effect of p53 in combination with temsirolimus. The combined effect of OBP-702 and temsirolimus was further evaluated using a subcutaneous CHP-134 xenograft tumor model. Results: Combination with OBP-702 and temsirolimus exhibited a synergistic antitumor effect in all NB cell lines in vitro. We confirmed that combination with these drugs enhanced autophagy. In addition, temsirolimus showed an effect to stabilize p53 protein induced by OBP-702. Ad-p53 also showed synergistic effect in combination with temsirolimus. The combination treatment significantly inhibited tumor growth, as compared to monotherapy, in NB xenograft tumor model. Conclusions: These results suggest that p53-expressing oncolytic adenovirus and mTOR inhibitor synergistically induce autophagic cell death and may be a promising strategy in NB patients. Citation Format: Terutaka Tanimoto, Hiroshi Tazawa, Hiroshi Noso, Morimichi Tani, Takanori Oyama, Yasuo Urata, Shunsuke Kagawa, Takuo Noda, Toshiyoshi Fujiwara. mTOR inhibitor augments the antitumor effect of p53-expressing oncolytic adenovirus in human neuroblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3177.