tbuckley/cabot-search huggingface dataset:
Abstract 1380: Expression and functions of ASH1L in liver cancer
Authors: Lai Wei, Felice H. Tsang, Daniel Ho, Cheuk-Ting Law, Mengnuo Chen, Long-Hin Tsang, Carmen Cl Wong, Irene Ol Ng, Chun-Ming Wong
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is a common cancer and ranks the third lethal cancer worldwide. However, the detail molecular mechanisms underlying the initiation and progression of HCC remain poorly understood. Liver carcinogenesis is a multistep process that is driven by the accumulation of genetic and epigenetic alterations. Mutational landscape and driver mutations have recently been delineated by high-throughput sequencing studies. On the other hand, our current knowledge about epigenetic deregulation in human HCC is limited. Histone modification is a major component of epigenetic regulation, and deregulation of histone medication could alter local chromatin structure and gene expression. We hypothesized that deregulation of histone methyltransferases might contribute to HCC development. In this study, we showed that trithorax-group protein ASH1L was frequently up-regulated in human HCC. Overexpression of ASH1L was detected in 40% of primary HCCs and significantly associated with larger tumor size, present of venous invasion and tumor microsatellite formation. Up-regulation of ASH1L also correlated with increased Ki67 expression. ASH1L is a histone methyltransferase specific for catalyzing transcriptional-active H3K4 and H3K36 methylation. We showed that stable knockdown of ASH1L significantly suppressed HCC cell proliferation and colony formation. We further demonstrated that knockdown of ASH1L inhibited HCC cell migration. In addition, we investigated the underlying mechanisms contribute to ASH1L up-regulation. We showed that up-regulation of ASH1L in human HCC was contributed by chromosome amplification at chromosome 1q22. Furthermore, we showed that ASH1L was negatively regulated by miR-142. Therefore, down-regulation of miR-142 contributed to ASH1L up-regulation in HCC. In summary, our findings suggested that ASH1L was frequently up-regulated in human HCC due to chromosome amplification and miRNA deregulation. Citation Format: Lai Wei, Felice H. Tsang, Daniel Ho, Cheuk-Ting Law, Mengnuo Chen, Long-Hin Tsang, Carmen Cl Wong, Irene Ol Ng, Chun-Ming Wong. Expression and functions of ASH1L in liver 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 1380. doi:10.1158/1538-7445.AM2017-1380
Abstract 2249: Integrated multi-level omics-based biomarker models for ovarian cancer survival
Authors: Alan Fu, Shen-Chih Chang, Aileen Baecker, Helena R. Chang, Zuo-Feng Zhang
Journal: Cancer Research (2017)

Abstract Background: Although a number of prognostic biomarkers for ovarian cancer have been proposed, the pool of clinically useful biomarkers remains small. While the predictive power of individual biomarkers may be weak, the advent of more affordable high-throughput technologies and readily available “omics” level data point toward the possibility of high performance biomarker panels. In this study, we used tumor-based somatic mutation, mRNA and miRNA expression, and DNA methylation data from The Cancer Genome Atlas (TCGA) to construct integrated biomarker models for overall and progression-free survival. Methods: The somatic mutations, mRNA expression, and DNA methylation of 451 candidate genes, as well as the expression of the miRNAs targeting them, were individually analyzed for association with overall and progression-free survival in 488 TCGA serous cystadenocarcinoma patients of predominantly Caucasian descent. Following correction for multiple comparisons, molecular variations associated with survival were combined to construct integrated cross-validated prediction models for overall and progression-free survival. The discriminative power of these models was then evaluated for 1-, 3-, and 5-year overall and progression-free survival using ROC analysis. Results: Our cross-validated integrated molecular models were demonstrated to predict 5-year overall survival in the total patient pool with a ROC AUC of 0.801 and 5-year overall and progression-free survival in Caucasian patients with ROC AUCs of 0.866 and 0.809, respectively. Conclusions: Our findings suggest the potential utility of our multi-omics-based biomarker models in helping to inform clinical decisions following ovarian cancer diagnosis. Although extensive efforts were made to maximize the predictive potential of our models, further retrospective and prospective validation efforts are necessary before their clinical utility can be accurately assessed. Citation Format: Alan Fu, Shen-Chih Chang, Aileen Baecker, Helena R. Chang, Zuo-Feng Zhang. Integrated multi-level omics-based biomarker models for ovarian cancer 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 2249. doi:10.1158/1538-7445.AM2017-2249
Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy
Authors: Kranti A. Mapuskar, Kyle H. Flippo, Joshua D. Schoenfeld, Dennis P. Riley, Stefan Strack, Taher Abu Hejleh, Muhammad Furqan, Varun Monga, Frederick E. Domann, John M. Buatti, Prabhat C. Goswami, Douglas R. Spitz, Bryan G. Allen
Journal: Cancer Research (2017)

Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%-80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%-20% killing) and adult fibroblasts (20 years old; ∼10%-30% killing). Old fibroblasts also displayed significantly increased (2-4-fold) steady-state levels of O2•-, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40%-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2•- in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2•- and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. Cancer Res; 77(18); 5054-67. ©2017 AACR.
Abstract 3324: FATE1 promotes mitochondrial hyperfusion and supports maintenance of mitochondrial networks following apoptosis stimulation
Authors: Anne Hamacher-Brady, Verena Lang, Nathan R. Brady
Journal: Cancer Research (2017)

Abstract FATE1 (fetal and adult testis expressed 1), also known as the cancer-testis antigen BJ-HCC-2, is expressed in testis and tumor tissues. FATE1 was recently described as a major survival factor in tumor cells of various origins, by mediating the degradation of the pro-apoptotic BH3-only protein Bik (Maxfield et al., in Nat Commun 2015 Nov 16;6:8840) and through ER-mitochondrial uncoupling (Doghman-Bouguerra et al., in EMBO Rep 2016 Sep;17(9):1264-80). Interestingly, FATE1 shares high sequence homology with the mitochondrial Drp1 receptor MFF (mitochondrial fission factor). We thus investigated a possible role of FATE1 impact on mitochondrial morphology following the stimulation of apoptosis in cancer cells. We found that, similar to MFF, FATE1 is localized to outer mitochondrial membranes and, unlike MFF, additionally localized to the endoplasmic reticulum. Importantly, in contrast to MFF, FATE1 overexpression does not recruit Drp1 to mitochondria, and instead promotes hyperfusion of mitochondrial networks. Co-immunoprecipitation experiments and reconstitution of Mfn2 or Mfn1 in double knockout mouse embryonic fibroblasts indicate a role for the mitochondrial fusion protein Mfn2, but not Mfn1. As FATE1 overexpressing cancer cells were more resistant to mitochondrial fragmentation in response to TNF and valinomycin treatments, we propose FATE1 as a novel regulator of mitochondrial morphology changes occurring during apoptosis, with possible implications in FATE1-mediated resistance of cancer cells to chemotherapy. Citation Format: Anne Hamacher-Brady, Verena Lang, Nathan R. Brady. FATE1 promotes mitochondrial hyperfusion and supports maintenance of mitochondrial networks following apoptosis stimulation [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 3324. doi:10.1158/1538-7445.AM2017-3324
Abstract 4598: Triggering of OX40 on T cells by a novel monoclonal antibody elicits robust antitumor immunity&amp;lt;!–EndFragment–&amp;gt;
Authors: Hua Long, Ann White, Jie Wei, Brittany Jiang, Reid Feldman, Danielle Pappas, Aymen Al-Shamkhani, John Lin
Journal: Cancer Research (2017)

Abstract T cell costimulation is an attractive strategy for cancer treatment in addition to check point inhibitors. Costimulatory molecule OX40 is a member of the TNF receptor superfamily that is transiently expressed on activated T cells. Activation of OX40 leads to enhanced T cell proliferation and cytokine secretion and in turn results in better anti-tumor efficacy as shown by multiple mouse syngeneic tumor models. PF-04518600 (PF-8600) is a fully human IgG2 agonist antibody to human OX40 with high affinity and specificity. We used in vitro and in vivo methods to evaluate the co-stimulatory functions of PF-8600. PF-8600 demonstrated better agonist activity in a luciferase reporter cell line expressing OX40 and NFκB as compared to a human IgG1 antibody. In human primary T cells, PF-8600 dose dependently increased T cell proliferation and cytokine secretion in vitro. Furthermore in a mouse line expressing human OX40, PF-8600 in a mouse IgG1 framework increased the proliferation of OT1 cells and inhibited EG7 tumor growth as compared to isotype control antibody, further confirming the mechanism of action as an OX40 agonist. As regulatory T cells are a major inhibitory population in the tumor microenvironment, their specific depletion in the tumor is highly desirable. In an in vitro assay using monocyte derived macrophages as effector cells, PF-8600 mediated the depletion of OX40 expressing cells similar to a human IgG1 antibody, and this activity is dependent on the binding to hFcγRIIA. In human FcγR knock-in mice, anti-OX40-hIgG1 showed increased Treg reduction in the tumor comparing to anti-OX40-hIgG2, but less T cell proliferation and activation in the periphery. In combination with an anti-PD-L1 antibody, both anti-OX40-hIgG1 and hIgG2 showed similar enhanced anti-tumor activity in the MC38 colon carcinoma model as comparing to anti-PD-L1 alone. Both in vitro and in vivo results demonstrated PF-8600 enhanced T cells functions and inhibited tumor growth in a mouse syngeneic tumor model. The activity of the hIgG2 antibody is similar to that of an hIgG1 in both phagocytosis assays and hFcγR KI in vivo assays. Based on the mechanism of action and robust anti-tumor efficacy in preclinical models, PF-8600 is currently in clinical development in a broad spectrum of malignancies. Citation Format: Hua Long, Ann White, Jie Wei, Brittany Jiang, Reid Feldman, Danielle Pappas, Aymen Al-Shamkhani, John Lin. Triggering of OX40 on T cells by a novel monoclonal antibody elicits robust antitumor immunity&amp;lt;!–EndFragment–&amp;gt; [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 4598. doi:10.1158/1538-7445.AM2017-4598
Growth factor use and costs in breast cancer patients undergoing adjuvant therapy.
Authors: Hyun gi Noh, Dhakshila Paramanathan, Kiran Suryadevara, Kelly Choi, Augie Smith, William Kea, Eric V Schultz, Andrew Pecora, Stuart L. Goldberg
Journal: Journal of Clinical Oncology (2016)

e18277 Background: Myeloid growth factor support (GFs) reduces the incidence/duration of neutropenia and facilitates dose intensity. GFs is recommended by ASCO guidelines when the risk of chemotherapy induced febrile neutropenia (FN) exceeds 20% and may be considered for 10-20% FN risks. Most adjuvant breast cancer regimens fall into the 10-20% category. Methods: Retrospective review of insurance claims database. Results: 11,058 pts with breast cancer underwent biopsy/surgery between Jan 2011 – Sept 2015. Of these 3,541 received chemotherapy; 1048 met eligibility criteria (minimum 12 mo follow-up, no therapy for 3 mo prior to diagnosis, chemo duration < 10 months). 895 had regimens identified. 47 (5%) received > 20% FN incidence regimens per NCCN assessment with 44 (94%) receiving GFs. 812 (91%) received 10-20% FN incidence regimens with 692 (85%) receiving GFs. 36 (4%) received < 10% FN incidence regimens with 31 (86%) receiving GFs. Focusing on the cohort receiving 10-20% FN risk regimens, age was similar with/without GFs use (both median 60 yrs). Rates of ER visits were similar with/without GFs (0.3 mean, 0 median both cohorts). Hospitalization were similar with/without GFs (median 0 admissions both cohorts; mean 0.8 admissions both cohorts). Hospital days were similar (1.9 days mean [0 median] with GFs vs 2.1 day mean [0 median] without). Readmissions within 30 days were similar (0.7 mean, 0 median both cohorts). Total cost of 12 mo of care was higher in the GFs cohort (medical claims: median $214,572 vs $156,319; p < 0.05)(medical and pharmacy claims: median $220,081 vs $179,973; p < 0.05). The main differences were pharmacy costs (median $39,487 with GFs vs $4399 without; p < 0.05). Similar costs were noted for chemo ($25,488 vs $25,574), lab ($3883 vs $4396), medical ($7841 vs $5341), surgery ($11,045 vs $9008), and radiology ($1515 vs $1270). Conclusions: GFs usage is prevalent in breast cancer adjuvant chemo irrespective of regimen intensity. Although in the 10-20% FN regimen cohort total costs are higher with GFs, no differences in ER rates or hospitalizations were noted. Electronic health record based reviews with in-depth characterizations, including analysis of maintenance of delivered dose-intensity and relapse rate, are planned.
Abstract 4254: Improved understanding of the etiology of breast cancer in young women through evaluation of the genomic landscape
Authors: Matthew D. Wilkerson, Clifton L. Dalgard, Craig D. Shriver, Rachel E. Ellsworth
Journal: Cancer Research (2017)

Abstract Background Breast cancer is a disease where biological age and age at menopause are established risk factors, thus diagnosis of breast cancer in young women (&amp;lt;40 years, YW) is not common, representing ~6% of breast cancer diagnoses annually. Germline mutations in cancer predisposition genes accounts for ~20% of breast cancer diagnoses in YW, thus the etiology of breast tumors for the majority of YW is unknown. Methods Frozen tumor specimens and matched genomic DNA samples from 31 women diagnosed &amp;lt;40 years were available. Whole genome sequencing (WGS) was performed by generating sequencing libraries from 1 mg input using the TruSeq PCR-free library preparation workflow and sequencing on the HiSeq X Ten at triple lane depth with 150bp paired-end reads. WGS was analyzed using the Hiseq Analysis Software Tumor Normal Workflow, Bioconductor: deconstructSigs and ad hoc integrated analysis and hypothesis testing. Results Luminal A tumors from YW had significantly lower somatic mutational loads, copy number alterations and structural variants than other subtypes and structural variants on chromosome 17 were enriched in patients with the HER2-enriched subtype and HER2 status = 3+. Aging was the most common signature (28/31) followed by APOBEC activation (14/31). Signatures associated with defects in mismatch repair (9/31) and polymerase ϵ (10/31) were also detected in &amp;gt;25% of patient tumors. Of the six patients with BRCA defect signatures, three had germline mutations in BRCA2 and one had a CHEK2 mutation. Mutational signatures could cluster patients into two groups, with the youngest patients (&amp;lt;35 years) less likely to have signatures associated with aging but an enrichment in signatures of APOBEC, BRCA mutations and smoking; tumors within this group were more likely to be non-luminal A. Conclusions Profiling the genome of tumors from YW supports the idea that most tumors are not characterized by profiles associated with genetic predisposition but rather processes such aging, APOBEC activation, mismatch repair, and defects in DNA replication. Of note, breast tumors in the youngest patients (&amp;lt;35) have a different pattern of mutational signatures suggesting that even within YW, etiology differs by age. Citation Format: Matthew D. Wilkerson, Clifton L. Dalgard, Craig D. Shriver, Rachel E. Ellsworth. Improved understanding of the etiology of breast cancer in young women through evaluation of the genomic landscape [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 4254. doi:10.1158/1538-7445.AM2017-4254
Abstract 5597: Genomic profiling of syngeneic mouse cell lines and <i>in vitro</i> screen of the models against checkpoint inhibitors and target agents for preclinical application
Authors: Frank Xing, Wubin Qian, Chunlan Dong, Xiaoxi Xu, Sheng Guo, Qian Shi
Journal: Cancer Research (2017)

Abstract Cancer immunotherapy has provided substantial clinical benefit in a significant number of patients with advanced diseases. In pre-clinical studies, CrownBio has developed a large collection of syngeneic models to facilitate in vivo efficacy testing of immune-oncology agents in mice (MuScreenTM). To combine the ostensibly separate therapeutic strategies of activating immune cells against and targeting the unique genetic characteristics of a tumor model, we sought to thoroughly characterize the mutation profiles of these syngeneic mouse cell lines and examine drug response profiles of these cell line models. The goal of this work was to provide an in vitro system in evaluating combination effectiveness when targeting both immune checkpoint markers and oncogenic targets in preclinical studies. To this end, we investigated mutation and gene expression profiles of 18 mouse cancer cell lines out of the panel of 23 syngeneic mouse models included in the MuScreenTM for 50 well defined cancer-related mutations among 30,690 variants in exonic regions called by RNAseq (Illumina HiSeq X10). The somatic mutations revealed through the bioinformatics analysis include ALK (3 - frequency, same for the rest), BRAF (4), BRCA1 (7), BRCA2 (12), EGFR (3), ERBB2 (6), EGFR3 (2), FBXW7 (10), FLT3 (12), HRAS (1), KRAS (8), NRAS (1), PDGFRA (11), PTCH1 (9), PIK3CA (2), PTEN (6), RET (3), SETD2 (5), SMAD4 (3), SMO (13), TRP53 (13), TSC1 (3), and TSC2 (10). All of these oncogenic alterations are clinically actionable (Cancer Discovery 2, 82-93, 2012). The same set of genes was also subject to mRNA expression change analysis. We screened the 18 mouse cell lines with a few selected target therapy agents, and performed combination assays of these agents together with check point inhibitors such as aPD1, aPDL1, in a co-culture system with mouse T cells. An IncuCyte real-time imaging platform was used to distinguish activities on T cells and tumor cells. The results and the implications will be discussed. Citation Format: Frank Xing, Wubin Qian, Chunlan Dong, Xiaoxi Xu, Sheng Guo, Qian Shi. Genomic profiling of syngeneic mouse cell lines and in vitro screen of the models against checkpoint inhibitors and target agents for preclinical application [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 5597. doi:10.1158/1538-7445.AM2017-5597
Abstract 1666: Immune consequences of penfluridol treatment associated with inhibition of glioblastoma tumor growth
Authors: Alok Ranjan, Nehal Gupta, Sharavan Ramachandran, Stephen Wright, Sanjay Srivastava
Journal: Cancer Research (2017)

Abstract Glioblastoma is the most common and lethal brain tumor associated with only 12% median survival rate of patients. Despite the development of advanced surgical, radiation or use of combinations of anti-cancer drugs, treatment for glioblastoma patients is still a challenge. The major contributing factor in glioblastoma progression and resistive nature is its ability to evade the immune surveillance. Hence, modulating the immune system in glioblastoma tumors could be an important strategy for anticancer therapeutics. Penfluridol, an antipsychotic drug has been shown to have anti-cancer properties in our recently published studies. The present study evaluates the immune response of penfluridol in glioblastoma tumors. Our results demonstrated that penfluridol treatment significantly suppressed glioblastoma tumor growth. Our current results demonstrated about 72% suppression of myeloid derived suppressor cells (MDSCs) with penfluridol treatment in mouse bearing U87MG glioblastoma tumors. MDSCs are known to increase regulatory T cells (Treg), which are immunosuppressive in nature and suppresses M1 macrophages that are tumor suppressive in nature. Our results also showed suppression of regulatory T cells as well as elevation of M1 macrophages with penfluridol treatment by 58% and 57% respectively. Decrease in CCL4 as well as IFNγ with penfluridol treatment was also observed indicating decrease in overall tumor inflammation. This is the first report demonstrating immune modulations by penfluridol treatment associated with glioblastoma tumor growth suppression prompting further investigation to establish penfluridol as a treatment option for glioblastoma patients. [Studies supported in part by R01 grant CA129038, awarded by National Cancer Institute, NIH] Citation Format: Alok Ranjan, Nehal Gupta, Sharavan Ramachandran, Stephen Wright, Sanjay Srivastava. Immune consequences of penfluridol treatment associated with inhibition of glioblastoma tumor growth [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 1666. doi:10.1158/1538-7445.AM2017-1666