tbuckley/cabot-search huggingface dataset:
Abstract 3769: Stem cell-engineered invariant natural killer T cells for cancer therapy
Authors: Lili Yang, Drake Smith, Siyuan Liu, Sunjong Ji, Bo Liu
Journal: Cancer Research (2017)

Abstract Invariant natural killer T (iNKT) cells comprise a small population of αβ T lymphocytes. They bridge the innate and adaptive immune systems and mediate strong and rapid responses to many diseases, including cancer, infections, allergies and autoimmunity. However, the study of iNKT cell biology and the therapeutic applications of these cells are greatly limited by their small numbers in vivo (~0.01-1% in mouse and human blood). Here, we report a new method to generate large numbers of iNKT cells in mice through T cell receptor (TCR) gene engineering of hematopoietic stem cells (HSCs). We showed that iNKT TCR-engineered HSCs could generate a clonal population of iNKT cells. These HSC-engineered iNKT cells displayed the typical iNKT cell phenotype and functionality. They followed a two-stage developmental path, first in thymus and then in the periphery, resembling that of endogenous iNKT cells. When tested in a mouse melanoma lung metastasis model, the HSC-engineered iNKT cells effectively protected mice from tumor metastasis. This method provides a powerful and high-throughput tool to investigate the in vivo development and functionality of clonal iNKT cells in mice. More importantly, this method takes advantage of the self-renewal and longevity of HSCs to generate a long-term supply of engineered iNKT cells, thus opening up a new avenue for iNKT cell-based immunotherapy. Citation Format: Lili Yang, Drake Smith, Siyuan Liu, Sunjong Ji, Bo Liu. Stem cell-engineered invariant natural killer T cells for cancer therapy [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 3769. doi:10.1158/1538-7445.AM2017-3769
Abstract 5545: Integrated system-level analyses of androgen receptor variant networks to identify novel prostate cancer-relevant genes
Authors: Fiorella Magani, Eric R. Bray, Ning Zhao, Stephanie Peacock, Kerry L. Burnstein
Journal: Cancer Research (2017)

Abstract Unbiased high-throughput approaches provide a global view of the massive genetic and transcriptomic changes that occur in and potentially drive cancer. Such approaches permit the discovery of novel markers and therapeutic targets. Current treatments for advanced prostate cancer (PC) focus on inhibiting the androgen receptor (AR). However, PC inevitably progresses to a stage termed castration-resistant prostate cancer (CRPC), which is incurable. In CRPC, C-terminal truncated, constitutively active AR splice variants (such as AR-V7) play key transcription-regulatory roles resulting in treatment resistance and disease progression. However, designing high-affinity drugs to target the amino terminus of AR and AR variants is a major challenge due to the intrinsic disorganized structure of this region. Thus there is an imperative need to identify novel AR-V7 hub genes in PC that may serve as therapeutic targets. We performed an extensive and highly robust gene expression meta-analysis on PC patient samples. We defined gene modules correlated with disease progression using a powerful systems biology approach termed Weighted Gene-Co-expression Network Analysis (WGCNA). Further, we mapped the AR-V7 interactome for the first time using a novel high-throughput synthetic genetic array screening in yeast, known as Yeast Augmented Network Analysis (YANA). YANA was performed by crossing yeast expressing AR-V7 with a large collection of yeast strains lacking non-essential genes, and identifying those genes that caused a change in yeast growth (fitness). Human orthologs of the identified yeast genes were used to build an AR-V7 functional gene network. Finally, we combined the results from our independent system-level analyses with experimental data to identify hub genes that are upregulated in PC patients, regulated by AR-V7, and also functionally interact with AR-V7. The identified genes not only include select genes previously linked to PC, such as members of the cyclin and topoisomerase families, but also genes that have not been previously linked to AR-V7 activity or PC progression. Moreover, our gene expression signature predicts a higher risk of PC recurrence after primary treatment in patients. In sum, we show here an unbiased and novel gene discovery strategy using bioinformatics in concert with experimental approaches to identify new candidate genes in CRPC that may lead to prognostic markers and future targeted therapies. Citation Format: Fiorella Magani, Eric R. Bray, Ning Zhao, Stephanie Peacock, Kerry L. Burnstein. Integrated system-level analyses of androgen receptor variant networks to identify novel prostate cancer-relevant genes [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 5545. doi:10.1158/1538-7445.AM2017-5545
Abstract 1436: Identification of novel tumor suppressor candidates in familial cholangiocarcinoma using sequencing-based Megabase-scale haplotypes from germline and cancer genomes
Authors: Stephanie Greer, Lincoln Nadauld, Billy Lau, Laura Miotke, Erik Hopmans, Christina M. Wood, John M. Bell, David A. Jones, Hanlee P. Ji
Journal: Cancer Research (2017)

Abstract Cholangiocarcinoma (bile duct cancer) is a rare epithelial malignancy with an extremely poor prognosis characterized by a 5-year survival of less than 10%. While this tumor type can be amenable to specific combination chemotherapy regimens, it is typically diagnosed at an advanced stage and inevitably progresses towards distant metastasis. We identified a family with a predisposition to cholangiocarcinoma, having multiple affected family members, and sought to identify the underlying germline mutation(s). We employed linked-read sequencing, a microfluidic technology where high-molecular weight DNA molecules (&amp;gt;20 kb) are partitioned into droplets and labeled with unique barcodes, enabling computational reconstruction of the original large molecules following traditional short-read sequencing, to identify entire megabase-scale regions of the genome that segregate with the disease. We applied this technology to an entire generation of a family predisposed to cholangiocarcinoma, including a mix of 8 affected and unaffected siblings. We additionally utilized each affected individual’s cancer genome to search for a common second hit that would serve as further confirmation. Our analysis yielded a small set of four candidate pathogenic variants. Functional validation of the candidate genes in a zebrafish model, using morpholino-based gene silencing, identified one candidate whose silencing led to a reproducible phenotype consistent with known aspects of the candidate gene’s function. The candidate variant occurs in a TGF family-interacting domain, and has not been extensively characterized in other cancers. Cross-validation with TCGA datasets showed the gene was altered in 5% of cholangiocarcinomas, all of which displayed homozygous deletions. This identification of a germline allele associated with familial cholangiocarcinoma represents a unique discovery with clinical implications for the described family and warrants further investigation in other patients who display features of an inherited cholagniocarcinoma. This finding also raises the possibility of TGF pathway targeting as a therapeutic strategy in select cholangiocarcinomas, and highlights the power of whole-genome phasing to discover novel inherited tumor suppressor variants. Citation Format: Stephanie Greer, Lincoln Nadauld, Billy Lau, Laura Miotke, Erik Hopmans, Christina M. Wood, John M. Bell, David A. Jones, Hanlee P. Ji. Identification of novel tumor suppressor candidates in familial cholangiocarcinoma using sequencing-based Megabase-scale haplotypes from germline and cancer genomes [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 1436. doi:10.1158/1538-7445.AM2017-1436
Aptavalve-gated Mesoporous Carbon Nanospheres image Cellular Mucin and provide On-demand Targeted Drug Delivery
Authors: Chengyi Li, Min Qian, Shanshan Wang, Huilin Jiang, Yilin Du, Jianxin Wang, Weiyue Lu, Niren Murthy, Rongqin Huang
Journal: Theranostics (2017)

In this report, we present a mesoporous carbon nanosphere that can target drugs to tumors and image tumor biomarkers. A single-strand DNA (P0 aptamer) aptavalve was capped on the surface of doxorubicin-loaded oxide mesoporous carbon nanospheres (Dox-OMCN-P0) through π-π stacking for real-time imaging-guided on-demand targeting drug delivery. The Dox-OMCN-P0 could not only realize the detection of MUC1 tumor marker with a wide linear range (0.1 - 10.6 μmol/L) and a low detection limit (17.5 nmol) based on different apparatuses, but also achieve in-situ targeting imaging of cellular MUC1 concentration in vitro and in vivo via "off-on" fluorescence biosensing. Much attractively, as a real-time feedback of the diagnostic/imaging outcomes, Dox-OMCN-P0 accomplished the on-demand targeting drug delivery in quantitative response to MUC1. Controllable chemotherapy with sustained release and pH-sensitiveness, together with the potential photothermal therapy, were also clearly demonstrated. This is a simple but advanced platform, which could well achieve the real-time switchable imaging of cellular mucin for targeting cancer therapy.
IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation
Authors: Stanley C. Jordan, Tomas Lorant, Jua Choi, Christian Kjellman, Lena Winstedt, Mats Bengtsson, Xiaohai Zhang, Torsten Eich, Mieko Toyoda, Britt-Marie Eriksson, Shili Ge, Alice Peng, Sofia Järnum, Kathryn J. Wood, Torbjorn Lundgren, Lars Wennberg, Lars Bäckman, Erik Larsson, Rafael Villicana, Joe Kahwaji, Sabrina Louie, Alexis Kang, Mark Haas, Cynthia Nast, Ashley Vo, Gunnar Tufveson
Journal: New England Journal of Medicine (2017)

Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor.We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound.Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred.IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).
Abstract 2540: miR-196b as a potential biomarker for human esophageal cancer
Authors: Xiaohui Tan, Tao Chen, Robert Siegel, Sidney Fu
Journal: Cancer Research (2017)

Abstract Esophageal cancer is the sixth most common cause of cancer related death. Although multiple genetic and epigenetic alterations have been detected in esophageal cancer, molecular markers for early diagnosis and prediction of prognosis or treatment responses are quite limited. microRNA (miRNA) is a class of small-regulatory non-coding RNA, acting as either a tumor suppressor or oncogene by regulating gene expression through pairing with complementary seed of the targeted messenger RNAs (mRNA). A number of miRNA expression profiling studies have been conducted in esophageal. In our current study, we analyzed the most recent studies on miRNAs expression profiles in esophageal cancer. Consistently dysregulated miRNAs have been identified in esophageal cancer, including upregulation of miR-196b, miR-135a, and downregulation of miR-141, miR-200a-5p, miR-200b-3p, miR-27b, miR-210. We first assessed expression of miRNAs in esophageal cancer cell lines and primary esophageal cancer tissues by real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). Significantly overexpressed miR-196b was observed in human esophageal squamous cell carcinoma KYSE-70 and KYSE-180 compared with normal esophageal squamous cell line, HET-1A. Furthermore, overexpression of miR-196b was detected in 12 out of 14 (86%) cancer tissues compared to the matched normal tissues. Forced expression of miR-196b promotes the proliferation and invasion in esophageal cancer cell lines. TargetScanS and miRanda were used to identify the target genes of miR-196b. A list of targets genes were predicted, including GATA6, ARHGAP28, EPS15 and EPHA7. Forced expression of miR-196b resulted in significant downregulated EPS15 and EPHA7 expression in esophageal cancer cell lines. Our present work suggested that miR-196b acts as an oncomiR by regulating EPS15 and EPHA7. Therefore, miR-196b could be used as a biomarker for esophageal cancer. Citation Format: Xiaohui Tan, Tao Chen, Robert Siegel, Sidney Fu. miR-196b as a potential biomarker for human esophageal 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 2540. doi:10.1158/1538-7445.AM2017-2540
Abstract 2541: Two miR-34 loci, miR-34a and miR-34b/c, have differential anticancer effects in lung adenocarcinomas
Authors: Jeong Seon Kim, Young-Ho Ahn
Journal: Cancer Research (2017)

Abstract Three miR-34 family members (miR-34a, miR-34b, and miR-34c) are clustered on two different chromosomal loci, miR-34a and miR-34b/c, and have identical seed-sequences predicted to target the same set of genes; however, miR-34a and miR-34c have different sets of negatively correlated genes in TCGA data of human lung adenocarcinomas. Therefore, we hypothesized that miR-34 family members, which are tumor suppressive miRNAs, might have differential effects on lung tumorigenesis. To prove this, we overexpressed each miR-34 cluster, miR-34a and miR-34b/c, in murine lung cancer cells. miR-34b/c enhanced cancer cell attachment and suppressed cell growth and invasion compared with miR-34a. In a syngeneic mouse model, both miR-34a and miR-34b/c blocked lung metastasis; whereas, miR-34b/c suppressed tumor growth more than miR-34a. miR-34b/c also decreased mesenchymal markers (Cdh2 and Fn1), and increased epithelial markers (Inadl, Crb3, Ocln, and Dsp) and miR-200 family members better than miR-34a, implying that miR-34b and miR-34c partially inhibit EMT. Furthermore, miR-34b and miR-34c are better prognostic markers than miR-34a in human lung adenocarcinoma patients. Collectively, we suggest that miR-34b and miR-34c are more effective tumor suppressors than miR-34a. Citation Format: Jeong Seon Kim, Young-Ho Ahn. Two miR-34 loci, miR-34a and miR-34b/c, have differential anticancer effects in lung adenocarcinomas [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 2541. doi:10.1158/1538-7445.AM2017-2541
Abstract 1324: Profile of common prostate cancer risk variants in an unscreened Romanian population
Authors: Paul D. Iordache, Bjarni Halldórsson, Andrei Manolescu, Dana Mates, Radu Ursu, Viorel Jinga
Journal: Cancer Research (2017)

Abstract In the present study we investigated for the first time the profile of common prostate cancer risk variants in an unscreened Romanian population. The study population consisted of 990 unrelated histopathologically confirmed prostate cancer (PCa) cases and 1,034 male controls consisting of patients admitted for urological and surgical conditions, excluding cancer. DNA was extracted from whole blood at deCODE Genetics (Reykjavik, Iceland) and genotyped using Illumina SNP arrays, 24.295.558 variants were imputed using the 1000 Genomes dataset in the 2,024 Romanian subjects. A systematic literature review for variants associated with prostate cancer identified in previous GWAS‘ was done using the NHGRI catalog as a starting point, identifying 238 unique variants from 28 studies. None of the tested variants in a Romanian only GWAS reached a genome wide significance (p-value lower than 5x10-8) but 807 markers reached p-values of 1x10-6. Thirty-one of the previously-reported SNPs replicated in the Romanian cohort, with the strongest associations seen at: 8q24.21, 11q13.3, 6q25.3, 5p15.33, 22q13.2, 17q12 and 3q13.2. The most signficantly replicated variants in Romania are rs1016343 at 8q24.21 (P = 2.2x10-4), rs7929962 at 11q13.3 (P = 2.7x10-4) and rs9364554 at 6q25.2 (P = 4.7x10-4). Our present study is the first GWAS on prostate cancer performed on a Romanian cohort. The high proportion of clinically significant disease in the Romanian prostate cancer cases will allow the dissection of the association between genetic variation and severe disease. Acknowledgements: This study was funded in part by the European Union FP7 Program (ProMark project 202059) and by the EEA grant (ROMCAN project RO14-0017; EEA-JRP-RO-NO-20131-10191). Citation Format: Paul D. Iordache, Bjarni Halldórsson, Andrei Manolescu, Dana Mates, Radu Ursu, Viorel Jinga. Profile of common prostate cancer risk variants in an unscreened Romanian population [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 1324. doi:10.1158/1538-7445.AM2017-1324
Abstract 5192: Selection of radiosensitizers based on HRAS mutation in head and neck cancer
Authors: Michael M. Fisher, Adam D. Swick, Kwangok P. Nickel, Randall J. Kimple
Journal: Cancer Research (2017)

Abstract Purpose/Objective(s): The ability of activated HRAS to promote radiation resistance and predict for sensitivity to potential radiosensitizers was tested in a head and neck cancer model system. Materials/Methods: Mutations in HRAS, KRAS, and NRAS were analyzed using cBioPortal in a head and neck cancer cohort. The Illumina TruSeq Amplicon Cancer panel was used to screen a panel of head and neck cancer cell lines for mutations in RAS-family genes. Cell growth and radiation survival was assessed by clonogenic survival assay. Immunoblots were used to confirm target activation/knockdown in overexpression and knockdown studies. A tumor control dose 50% (TCD50) assay was employed to investigate radiosensitization of a mutated-HRAS head and neck cancer cell line in a flank xenograft model in nude mice. Results: Activating mutations in one of the three RAS genes are seen in 5-10% of head and neck cancer patients. Mutations in HRAS represent over 50% of these. Screening our panel of head and neck cancer cell lines identified a canonical activating mutation in HRAS (i.e. G12V) in SCC22B. Consistent with known roles for activated HRASG12V, SCC22B is relatively insensitive to both cetuximab and radiation. Using both in vitro and in vivo studies, cetuximab exhibited no ability to radiosensitize SCC22B. Cetuximab treatment decreased AKT, but not ERK activation. Direct inhibition pathways downstream of HRAS by selumetinib (MEK/ERK) or BEZ235 (PI3K/MTOR) decreased target protein activation and resulted in significant growth inhibition compared to control (p&amp;lt;0.05). Treatment with either selumetinib or BEZ235 radiosensitized HRASG12V expressing cells (SER 1.3-1.8) but had more modest effects on cells with wildtype HRAS. siRNA knockdown of HRAS radiosensitized SCC22B, but not SCC1 or SCC6 cells relative to non-targeting control. Overexpression of HRASG12V conferred relative radioresistance in wildtype cell lines. In vivo assessment of the radiosensitizing effects of these compounds (TCD50) is pending. Conclusion: More than 5% of head and neck cancers harbor activating mutations in one of the RAS family of genes. These mutations lead to resistance to cetuximab, either as a single agent, or as a radiosensitizer. Inhibition of downstream targets such as the MEK/ERK and PI3K/MTOR pathways can radiosensitize tumors harboring activating mutations in HRAS. Identification of additional mutation/drug combinations that result in radiosensitization may be valuable to advance the design of personalized radiation therapy. Citation Format: Michael M. Fisher, Adam D. Swick, Kwangok P. Nickel, Randall J. Kimple. Selection of radiosensitizers based on HRAS mutation in head and neck 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 5192. doi:10.1158/1538-7445.AM2017-5192
Abstract SY25-03: From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy
Authors: Padmanee Sharma
Journal: Cancer Research (2017)

Abstract Immune checkpoint therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1, have led to significant clinical responses in cancer patients. To investigate immunologic changes and mechanistic pathways that are elicited by these therapies, we conducted presurgical and tissue-based clinical trials, which permit access to tumor tissues for laboratory studies. To compare and contrast data, we chose one tumor type that responds well to immune checkpoint therapy and one that does not. The first presurgical trial was conducted with anti-CTLA-4 (ipilimumab) in a cohort of patients with localized bladder cancer. The second presurgical trial was conducted with anti-CTLA-4 (ipilimumab) in patients with localized prostate cancer. In addition, we evaluated data from patients with melanoma who received immune checkpoint therapy. These data enabled us to identify the ICOS/ICOSL pathway as relevant for antitumor immune responses in the setting of anti-CTLA-4 therapy. We also identified resistance mechanisms, including expression of other immune inhibitory pathways such as VISTA and loss of the IFNγ signaling pathway in tumor cells. These data will be discussed in greater detail. Citation Format: Padmanee Sharma. From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy [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 SY25-03. doi:10.1158/1538-7445.AM2017-SY25-03