tbuckley/cabot-search huggingface dataset:
Abstract 1695: Exploiting the pancreatic cancer mutome for immune interception
Authors: Heather Kinkead, Eric Lutz, Thomas W. Dubensky, Elizabeth Jaffee
Journal: Cancer Research (2017)

Abstract This study aims to translate tumor-specific mutations identified by next-generation sequencing techniques into an effective anti-tumor vaccine for a classically non-immunogenic tumor, pancreatic ductal adenocarcinoma (PDA). Pancreatic ductal adenocarcinomas develop an average of 63 mutations during tumorigenesis, collectively referred to as the “mutome.” Of these, approximately 45 are amino acid point mutations. These mutations are not present in normal cells and provide a source of tumor-specific neoepitopes for targeted immunotherapy. Next-generation sequencing technologies allow for rapid identification of mutations present in patient tumors; however, methods for rapid identification of immunogenic neoepitopes which can be effectively targeted for tumor clearance, and optimized vaccination strategies for targeting them, still need to be developed. In this study, we are using a transplantable murine PDA model, Panc02, to develop vaccination strategies for inducing neoepitope-specific T cell antitumor responses, and to define parameters for selecting appropriate targets. Exome sequencing identified 878 nonsynonymous mutations in the Panc02 cell line. Three immunological epitope prediction servers identified 878 potentially immunogenic peptides in the Panc02 model, 29 of which were strong candidates (scores &amp;lt;50) and another 240 candidate epitopes within the limits of prediction (scores &amp;lt;1000). Panc02 neoepitope peptide vaccinations in mice confirmed 14% of the predicted epitopes to be immunogenic by IFNγ ELISPOT, which may include both CD8+ and CD4+ T cell responses. Tumor transplant experiments demonstrate that therapeutic vaccination against neoepitopes in combination with a human STING-activating cyclic dinucleotide adjuvant is capable of inducing a temporary regression of implanted tumors. After tumor escape and regrowth, flow cytometry reveals a large population of infiltrating lymphocytes, the majority of which are co-expressing the checkpoint molecules PD-1, Tim3, and Lag3, indicating that treatment of vaccinated animals with checkpoint blockade therapy may potentiate infiltrating lymphocytes and ultimately result in permanent tumor regression. Thus, a broad and unbiased approach for screening vaccine targets will allow for the evaluation of predictive algorithms and ultimately the development of more effective vaccination approaches for targeting the tumor mutome. Citation Format: Heather Kinkead, Eric Lutz, Thomas W. Dubensky, Elizabeth Jaffee. Exploiting the pancreatic cancer mutome for immune interception [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 1695. doi:10.1158/1538-7445.AM2017-1695
Abstract 459: Targeting MUC1 mediated nucleotide metabolism sensitizes pancreatic tumors to radiation therapy
Authors: VENUGOPAL GUNDA, Joshua Souchek, Jaime Abrego, Gennifer Goode, Enza Vernucci, Surendra K. Shukla, Aneesha DasGupta, Nina V. Chaika, Ryan King, Fang Yu, Tadayoshi Bessho, Chi Lin, Wang Shou, Li Sicong, Pankaj K. Singh
Journal: Cancer Research (2017)

Abstract Pancreatic cancer has the lowest survival rate of six perecent among all the cancers in the US and is projected to be the second leading cause of cancer related deaths in a decade. Radiation therapy provides only marginal increases in the survival rate in pancreatic cancer, due to poor responsiveness of pancreatic tumors. Clinical trials indicate a significant response to radiation only in twenty percent of primary pancreatic tumors. While multiple factors cause resistance to radiation therapy, the biological mechanisms mediating such innate resistance are currently being explored. Overexpression of MUC1 facilitates chemo and radiation resistance in pancreatic cancer. MUC1 overepxression also promotes pancreatic tumor growth through metabolic upregulation. We investigated the in vivo role of MUC1 mediated metabolic alterations in radiation response of pancreatic tumors. Our findings indicate that MUC1 expressing pancreatic tumors survive better upon radiation treatment. Metabolomic analysis through liquid chromatography coupled tandem mass spectrometry approach revealed that MUC1 expressing pancreatic tumors exhibit higher glycolytic and nucleotide metabolites upon irradiation. MUC1 expressing tumors also possess relatively higher PPP and nucleotide metabolites. Glycolytic inhibition using bromopyruvate revealed that MUC1 induced radiation resistance could be abrogated through inhibition of glucose carbon flux into nucleotide metabolism by BrPA. Treatment with BrPA effectively reduced glycolysis, pentose phosphate pathway and nucleotide levels in irradiated MUC1 expressing cells. Furthermore, a combination of BrPA and radiation reduced tumor growth in MUC1 expressing tumors. Metabolomic analysis showed a decrease in the glycolysis, PPP and nucleotide metabolites in MUC1 expressing tumors upon combination treatment with radiation and BrPA. Hence, our findings demonstrate that glycolytic inhibition could be used to effectively target MUC1 mediated radiation-resistance in pancreatic tumors. Citation Format: VENUGOPAL GUNDA, Joshua Souchek, Jaime Abrego, Gennifer Goode, Enza Vernucci, Surendra K. Shukla, Aneesha DasGupta, Nina V. Chaika, Ryan King, Fang Yu, Tadayoshi Bessho, Chi Lin, Wang Shou, Li Sicong, Pankaj K. Singh. Targeting MUC1 mediated nucleotide metabolism sensitizes pancreatic tumors to radiation 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 459. doi:10.1158/1538-7445.AM2017-459
Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study
Authors: P.B. Chapman, C. Robert, J. Larkin, J.B. Haanen, A. Ribas, D. Hogg, O. Hamid, P.A. Ascierto, A. Testori, P.C. Lorigan, R. Dummer, J.A. Sosman, K.T. Flaherty, I. Chang, S. Coleman, I. Caro, A. Hauschild, G.A. McArthur
Journal: Annals of Oncology (2017)

BackgroundThe BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation–positive metastatic melanoma. We present final OS data from BRIM-3.Patients and methodsPatients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib.ResultsBetween 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0–15.4] versus 9.7 months [95% CI 7.9–12.8; hazard ratio (HR) 0.81 [95% CI 0.67–0.98];P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0–15.4) versus 10.3 months (95% CI 9.1–12.8); HR 0.81 (95% CI 0.68–0.96);P = 0.01]. Kaplan–Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis.ConclusionsVemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies.ClinicalTrials.govNCT01006980.
Abstract 4280: <i>FH</i> (rs367543046, chr1:241661227 A/ATTT) heterozygous carrier status does not confer risk to hereditary leiomyomatosis and renal cell cancer (HLRCC) and prostate cancer
Authors: Michael F. Walsh, Diana Mandelker, Joseph Vijai, David Musheyev, Jennifer Kennedy, Zsofia Stadler, Yelena Kemel, Sabine Topka, Karen Cadoo, Maria Carlo, Marc Ladanyi, Mark Robson, Kenneth Offit, Liying Zhang
Journal: Cancer Research (2017)

Abstract Fumarate Hydratase (FH) mutations underpin the autosomal recessive syndrome Fumarate Hydratase deficiency and the autosomal dominant syndrome Hereditary Leiomyomatous and Renal Cell Carcinoma (HLRCC). The variant rs367543046, a duplication leading to p. Lys477_Asn478insLys in FH has strong evidence for risk towards fumarate hydratase deficiency when occurring in trans to another germline alteration in the FH gene. In addition, this variant in the heterozygous state has been reported in ClinVar to predispose to the autosomal dominant condition HLRCC, given other heterozygous mutations have shown to be pathogenic. Population level data is sparse to determine the variant’s impact in the heterozygous state. Here, we show in a series of 1375 cancer cases the (rs367543046, chr1: 241661227 A/ATTT), variant detected in 7 (0.5%) individuals with cancer. One patient with bladder cancer had a history of uterine leiomyomas, but the immunohistochemistry for 2SC was negative, suggesting that the leiomyomas were not associated with HLRCC. None of the other 6 carriers of this variant had any features of HLRCC. Notably, this variant was not detected in any of the patients with renal cancer (n=178) participating in the study. Since 4/7 prostrate cancer patients of Ashkenazi ethnicity harbored this variant, we performed a genetic epidemiology study using 856 Ashkenazi Jewish prostate cancer patients. The allele frequencies were compared with 557 Ashkenazi Jewish non-cancer controls. A fisher’s two sided exact test showed that the variant is not associated with prostate cancer in Jews (P=1, OR 1.12(CI 95% 0.21-7.25). Our findings suggest that the variant, which is pathogenic for autosomal recessive fumarate hydratase deficiency does not confer pathogenicity in the heterozygous form for Hereditary Leiomyomatous and Renal Cell Carcinoma or prostate cancer. Ashkenazi Jewish Prostate Cancer Patients vs Ashkenazi Jewish Non-Cancer PatientsAttributeAshkenazi Jewish Prostate Cancer PatientsAshkenazi Jewish Non-Cancer patientsCT53CC17071151 Citation Format: Michael F. Walsh, Diana Mandelker, Joseph Vijai, David Musheyev, Jennifer Kennedy, Zsofia Stadler, Yelena Kemel, Sabine Topka, Karen Cadoo, Maria Carlo, Marc Ladanyi, Mark Robson, Kenneth Offit, Liying Zhang. FH (rs367543046, chr1:241661227 A/ATTT) heterozygous carrier status does not confer risk to hereditary leiomyomatosis and renal cell cancer (HLRCC) and prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4280. doi:10.1158/1538-7445.AM2017-4280
Abstract 3808: <i>TM4SF1</i> regulates cell cycle and ROS status in bladder cancer cells by targeting FOXO3a via PPARγ-SIRT1 negative feedback loop
Authors: Rui Cao, Gang Wang, Kaiyu Qian, Liang Chen, Qingxuan Hu, Yu Xiao, Xinghuan Wang
Journal: Cancer Research (2017)

Abstract Transmembrane 4 superfamily member 1 (TM4SF1) is a member of tetraspanin family, which locates in the cell membrane, functions as signal transducer to regulate cell development, growth and motility. Currently, TM4SF1 has been reported to be overexpressed in liver cancer, pancreatic cancer and colorectal cancer, but its role in bladder cancer (BCa) has not been illustrated. We have found that TM4SF1 was strongly upregulated in human bladder cancer tissues at both transcription and translation levels, compared with the paracancerous tissues and normal bladder tissues. This result was corroborated with our transcriptome analysis. Moreover, the tissue array data showed that TM4SF1 closely related with survival rate of BCa as the patients with high expression of TM4SF1 have a poorer prognosis. Furthermore, in vitro and in vivo studies suggested that proliferation of BCa cells was significantly suppressed by knockdown of TM4SF1. Moreover, downregulation of TM4SF1 induced G0/G1 phase cell cycle arrest and apoptosis possibly via induced reactive oxygen species (ROS) status in BCa cells. In addition, we observed that phosphorylated/total SIRT1 proteins were considerably reduced in the BCa cells lacking TM4SF1. In contrast, PPARγ as well as its target phosphorylated/total FOXO3a were strongly increased, an important downstream transcriptional factor of PPARγ/SIRT1 negative feedback loop, regulating cell cycle, apoptosis and ROS metabolism. Therefore, we treated the TM4SF1-silencing BCa cells with GW9662 (antagonist of PPARγ) and resveratrol (activator of SIRT1), showing a recovery of the G0/G1 phase cell cycle arrest and scavenge of ROS status. Interestingly, the increase of phosphorylated/total FOXO3a by knockdown of TM4SF1 could also be rescued by using GW9662 and resveratrol. In conclusion, our results suggested that TM4SF1 may regulate cell cycle and ROS status of BCa cells by targeting FOXO3a via the PPARγ-SIRT1 negative feedback loop. Note: This abstract was not presented at the meeting. Citation Format: Rui Cao, Gang Wang, Kaiyu Qian, Liang Chen, Qingxuan Hu, Yu Xiao, Xinghuan Wang. TM4SF1 regulates cell cycle and ROS status in bladder cancer cells by targeting FOXO3a via PPARγ-SIRT1 negative feedback loop [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 3808. doi:10.1158/1538-7445.AM2017-3808
Abstract 2924: Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer
Authors: Alain R. Thierry, Brice Pastor, Zhi-Qin Camilla Jiang, anastasia Katsiampoura, Christine Parseghian, Jonathan Loree, Michael J. Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou, Scott Kopetz
Journal: Cancer Research (2017)

Abstract Malignant tumors shed cell free DNA into the blood stream. Analyzing this new biological source may have important implications in a shift towards personalized medicine for diagnosing and/or monitoring malignancies. We recently showed the first clinical validation and clinical utility of circulating DNA (cfDNA) analysis in oncology by testing RAS/BRAF hotspot mutations in plasma from metastatic colorectal cancer patients (mCRC) (Nat Med. 2014 Apr;20(4):430-5). In addition, liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. We evaluated under blinded conditions the ability of cfDNA to detect RAS/BRAF mutations in the plasma of 42 mCRC patients treated on a phase Ib/II trial of FOLFOX and dasatnib, with or without cetuximab. Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%). Our cfDNA assay was able to detect mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41/42 patients (98%) had a cfDNA detected RAS/BRAF mutation. Of 22 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (50%) developed a second mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild type tumors at baseline, 4/5 (80%) developed new mutations. Patients may harbor mutations at very low frequency down to 0.01% before initiation or during treatment revealing the need of a high sensitive technique to detect mutant subclones. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation. Combined qualitative and quantitative cfDNA analysis allows tracking acquired resistance by studying the real-time clonal evolution of the tumor and might help physicians to adjust patient treatment. Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway, demonstrating a convergent evolutionary pattern. Note: This abstract was not presented at the meeting. Citation Format: Alain R. Thierry, Brice Pastor, Zhi-Qin Camilla Jiang, anastasia Katsiampoura, Christine Parseghian, Jonathan Loree, Michael J. Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou, Scott Kopetz. Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal 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 2924. doi:10.1158/1538-7445.AM2017-2924
Abstract 3361: Methylome differences in differentiated thyroid cancers and benign adenomas
Authors: Josena K. Stephen, Kang Mei Chen, Jason Merritt, Indrani Datta, Dhananjay Chitale, George Divine, Maria J. Worsham
Journal: Cancer Research (2017)

Abstract Many recent studies examining aberrant DNA methylation in thyroid cancer are restricted to either candidate genes or genome-wide methylation in specific thyroid tumor subtypes. The goal of this study was to identify differentially methylated genes globally and their association with molecular pathways and signaling networks. Common mutations in papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), follicular adenoma (FA) and normal thyroid were also examined. Genome-wide methylation profiling using the Infinium HumanMethylation450FFPE (formalin fixed paraffin embedded) BeadChip Array was performed on 24 thyroid cases (8 PTC, 8 FTC, 4 FA and 4 normal thyroid). Ingenuity Pathway Analysis (IPA) was utilized to assess the roles of significantly differentially methylated genes in biological functions, signaling/metabolic pathways, and networks. Common mutations in 4 genes (BRAF, NRAS, HRAS, and KRAS) were assessed using TaqMan Mutation Detection assay. Twelve genes were significantly differentially methylated among 4 comparison groups: cancer vs normal, cancer vs adenoma, PTC vs normal, and PTC follicular variant (PTC-FV) vs PTC-Classic. CTU1 and HLA-DPB1 were significantly hypermethylated and AARS2, TMSB10, RNF216L, KIF15, KIAA1143, and SLC2A13 were significantly hypomethylated between cancer and normal. Significant differential hypermethylation was noted for PNPLA7 and NPC1L1 in cancer vs adenoma and SNX6 in PTC-FV vs PTC-Classic. NT5C1B was hypermethylated and AARS2 was hypomethylated in PTC vs normal. IPA identified 2 gene networks, involving 11/12 genes, characterized by 1) Cellular development, Cellular growth and proliferation, Connective tissue development and function and 2) Drug metabolism, Cell-mediated immune response, Cellular development. NT5C1B was involved in all 4 highly ranked canonical nucleotide degradation pathways. Several significant bio-functions involved NPC1L1. Mutations of NRAS codon 61 were identified in 1 sample each of FTC-Classic, PTC-FV and FA and BRAF V600E in one PTC-Classic sample. Differential methylation of AARS2, CTU1, HLA-DPB1, SLC2A13, PNPLA7, NPC1L1, NT5C1B and SNX6 suggest potential markers for discriminating thyroid cancers from adenomas and normal. NT5C1B was noted in highly ranked canonical pathways, suggesting a role in nucleotide degradation. Pathway analysis of differentially methylated genes support important biological processes in thyroid cancer pathogenesis. Supported by JFCI/CRAG A20038 Citation Format: Josena K. Stephen, Kang Mei Chen, Jason Merritt, Indrani Datta, Dhananjay Chitale, George Divine, Maria J. Worsham. Methylome differences in differentiated thyroid cancers and benign adenomas [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 3361. doi:10.1158/1538-7445.AM2017-3361
Abstract LB-249: Examination of analytical factors impacting concordance of plasma-tumor testing by next-generation sequencing (NGS)
Authors: Daniel Stetson, Brian Dougherty, Ambar Ahmed, Tristan Lubinski, Aleksandra Markovets, Kenneth Thress, Robert McEwen, Gaia Schiavon, David Whitston, Barrett Nuttall, J. Carl Barrett
Journal: Cancer Research (2017)

Abstract The increased usage of circulating tumor DNA (ctDNA) sequencing for oncology clinical research demonstrates a critical need for sensitive and specific testing. While we have observed a high degree of concordance between single tumor mutations in tumor and plasma, several recent studies have highlighted a lack of concordance between plasma and tumor panel NGS gene panel testing due to biological and technical factors. To explore further these factors and benchmark ctDNA NGS testing services, a set of matched plasma, tumor, and normal samples from 24 subjects were acquired from three biobanking companies. Replicate 2 ml-plasma samples were tested by four ctDNA sequencing companies, and matching tumor/normal samples were tested by two tumor sequencing companies. Concordance was measured by comparing plasma mutations to tumor mutations as well as comparing mutations among the same plasma tested by the ctDNA companies. While our experience with NGS of matched samples from clinical trials typically identifies ~30% of patients with no detectable mutation and therefore likely not shedding tumor DNA, with the retrospectively collected commercial samples ~60% lacked detectable high confidence mutations, likely due to quality control issues with sample collection. We also found variation in the concordance of ctDNA mutation detection rates among the four vendors, due to significant differences in DNA yield and assay sensitivity. While factors such as tumor heterogeneity and timing of plasma-tumor collection can lower concordance rates, the majority of discordance in our study was due to technical rather than biological variation. Assay analytical variance and the impact of reporting false positive variants are key factors that need to be addressed as plasma-based NGS testing is more widely incorporated into translational and clinical research. Examples illustrating the complexity of the analyses and giving support for confidence in ctDNA testing results will be given. Citation Format: Daniel Stetson, Brian Dougherty, Ambar Ahmed, Tristan Lubinski, Aleksandra Markovets, Kenneth Thress, Robert McEwen, Gaia Schiavon, David Whitston, Barrett Nuttall, J. Carl Barrett. Examination of analytical factors impacting concordance of plasma-tumor testing by next-generation sequencing (NGS) [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-249. doi:10.1158/1538-7445.AM2017-LB-249