bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B38: Radiation enhances intracellular delivery of anti-MGMT oligomers to reduce protein expression in vitro and in a xenograft model
Authors: Wu Jeffrey , Ambady Prakash , Morris DreeAnna , Pagel Michael , Woltjer Randy , Walker Joshua , Muldoon Leslie , Neuwelt Edward 
Published: April 2017

Abstract
High levels of DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) in glioblastoma tumor are associated with temozolomide resistance and poor prognosis. MGMT provides a promising therapeutic target to overcome chemo-resistance and improve overall survival in cancer patients. In this study, we investigate the enhanced delivery of anti-MGMT morpholino oligonucleotide (AMON) using a sub-therapeutic dose of radiation to reduce MGMT expression of human cancer cells (T98G glioma and H460 and A549 non-small cell lung carcinoma) in vitro and in vivo. Compared to standard transfection techniques, sub-therapeutic dose of radiation enhanced intracellular AMON delivery and transiently reduced MGMT protein expression at 3 d in vitro. The optimal radiation dosage was cancer cell type dependent and ranged from 1-12 Gy. In addition, AMON delivered using sub-therapeutic dose of radiation increased cytotoxicity of T98G cells in response to temozolomide compared to radiation and temozolomide alone in vitro. In a H460 subcutaneous xenograft tumor model, intravenous AMON administration reduced MGMT protein level by 50% in irradiated tumors but not in contralateral non-irradiated lesions within the same animal. Tumor MGMT protein downregulation by AMON did not alter DNA promoter methylation status. Our results demonstrate for the first time the use of radiation to enhance the intracellular delivery of antisense oligonucleotides to modulate MGMT protein expression in vitro and in vivo. We have previously shown that antisense nucleotides can be delivered to the brain parenchyma using osmotic blood brain barrier disruption. Therefore, we believe that cancer patients with MGMT overexpression, unmethylated DNA promoter and/or resistance to DNA alkylating agents may benefit from this novel antisense therapeutic technology to improve overall survival.
Citation Format: Jeffrey Wu, Prakash Ambady, DreeAnna Morris, Michael Pagel, Randy Woltjer, Joshua Walker, Leslie Muldoon, Edward Neuwelt. Radiation enhances intracellular delivery of anti-MGMT oligomers to reduce protein expression in vitro and in a xenograft model [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B38.
Abstract B39: Tumor hypoxia induces DNA repair vulnerabilities through contextual “loss-of- heterozygosity”
Authors: Mahamud Osman , Chua Melvin L.K , Lo Winnie , Zafarana Gaetano , Bristow Robert G. 
Published: April 2017

Abstract
Introduction: Intratumoral hypoxia leads to decreased expression in DNA damage response (DDR) and repair pathways. Given the “two-hit” model for loss of gene function, we hypothesize that hypoxia-mediated down-regulation of gene expression and function, coupled with an already inactive allele may ultimately give rise to an exploitable contextual “loss-of-heterozygosity” phenotype.
Method: To interrogate this relationship, isogenic DLD-1 cells heterozygous and homozygous null for BRCA2, were placed under normoxic (21% O2) or hypoxic (0.2% O2) conditions for 72 hours. Hypoxia-mediated changes in DDR response and DNA repair were evaluated by cell proliferation, cell cycle analysis, western blots, qPCR, immunofluorescence, clonogenic assays and repair assays.
Results: No differences in proliferation and cell survival were observed between oxic and hypoxic cells (72 hours - 0.2% O2). Under chronic hypoxic conditions, confirmed by the up-regulation of VEGF and HIF1α, mRNA and protein expression of key homologous recombination (HR) genes (BRCA1, BRCA2, RAD51) were down-regulated. Functionally, BRCA2(-/-) null cells proved unable to recruit Rad51 foci and resultantly presented a profound sensitivity to PARP inhibition. Conversely, heterozygote BRCA2(+/-) cells retained the ability to recruit Rad51 foci under both oxic and hypoxic conditions, however, exposure to chronic hypoxia resulted in a reduction in the number of foci formed. Chronically hypoxic BRCA2(+/-) cells exhibited a 30 to 40% increase in sensitivity to PARP inhibition when compared to their oxic counterparts. Preliminary data shows a similar synthetically lethal relationship in genetic and tumor microenvironment induced HR deficient cells, when challenged with DNA damage response (DDR) kinase inhibitors ATRi and DNAPKi.
Conclusions: Herein we illustrate through a novel mechanism of contextual “loss-of heterozygosity”, which marries the tumor microenvironment and innate genetic alterations, increased sensitivity to DDR kinase inhibitors and PARPi.
Citation Format: Osman Mahamud, Melvin L.K Chua, Winnie Lo, Gaetano Zafarana, Robert G. Bristow. Tumor hypoxia induces DNA repair vulnerabilities through contextual “loss-of- heterozygosity” [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B39.
Abstract B40: [10]-gingerol as a pro-apoptotic molecule in triple negative breast cancer
Authors: Martin Ana Carolina B. M. , Tomasin Rebeka , Becceneri Amanda Blanque , Fuzer Angelina , Vieira Paulo Cezar , Cominetti Marcia Regina 
Published: April 2017

Abstract
The aim of this work was to study the pro-apoptotic effects of [10]-gingerol and connect them to anti-tumor and anti-metastatic activities in triple negative breast cancer (TNBC) cell lines and in an spontaneous triple negative breast cancer model in vivo.
Breast cancer has the highest incidence among women and metastasis is the major cause of death in cancer. TNBC affects 20% of women with breast cancer. This cancer type is very aggressive and has a high propensity to form lung and brain metastases. Nowadays, there is no effective treatment for TNBC and therefore, new therapies are required. Studies to discovery new molecules to be used in more efficient treatments for this disease are essential. Molecules that can interfere with cell proliferation, migration, invasion, apoptosis and cell cycle can be used as a model or tools to develop new anti-metastatic drugs. Epidemiologic studies have shown that Asian populations have lower incidence of breast cancer comparing to western populations. This has been attributed in part to differences in dietary habits. In particular, gingerols, natural compounds extracted from ginger rhizomes, have been shown to present anti-cancer properties against various tumor cell types in vitro and in vivo.
MTT assay was performed to verify the inhibitory effects of [10]-gingerol on cell proliferation. To investigate [10]-gingerol mechanisms of action, apoptosis, cell cycle assays and TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) were performed. For the in vivo data an spontaneous model of breast cancer metastasis was used.
Results: [10]-gingerol was able to inhibit cell proliferation in different cell lines. In the murine cell line (4T1Br4), [10]-gingerol induced apoptosis, cell cycle arrest at sub-G0 phase and also induced DNA damage demonstrated by TUNEL assay, therefore interfering with DNA and provoking its damage. [10]-gingerol inhibited lung, bone and brain metastases in an intra-mammary fat pad spontaneous breast cancer model.
Conclusion: [10]-gingerol showed to be a non-toxic compound with anti-proliferative and DNA damaging effects, inducing cell apoptosis in vitro and also inhibiting lung, bone and brain metastases in a spontaneous TNBC model in vivo. Patent deposit: BR 10 2015 024093 7. Approved by ethical committee – E507 and 3224-1.
Citation Format: Ana Carolina B. M. Martin, Rebeka Tomasin, Amanda Blanque Becceneri, Angelina Fuzer, Paulo Cezar Vieira, Marcia Regina Cominetti. [10]-gingerol as a pro-apoptotic molecule in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B40.
Abstract B41: REV7 is a possible prognostic predictor and a potential therapeutic target in human malignancy
Authors: Murakumo Yoshiki , Niimi Kaoru , Okina Sosei 
Published: April 2017

Abstract
Human REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene transcription and carcinogenesis, and is a key protein in translesion DNA synthesis. Here, we present our study to evaluate the significance of REV7 expression in human malignancy and its possibility to be a molecular target for cancer therapy. REV7 expression was assessed in epithelial ovarian cancer (EOC) and diffuse large B-cell lymphoma (DLBCL) by immunohistochemical staining. REV7 expression was detected in the majority of EOCs (92.0%) with especially high levels of expression frequently observed in ovarian clear cell carcinomas (CCCs) (73.5%) compared with that of non-CCCs (53.4%). Enhanced immunoreactivity to REV7 was associated with poor prognosis represented by reduced progression-free survival in advanced stage (stages II to IV) EOC. REV7 expression was also assessed in DLBCL, the most common type of non-Hodgkin lymphoma, in which high REV7 expression was associated with significantly shorter overall survival and progression-free survival. The effects of REV7 knockdown on cell proliferation and chemosensitivity in CCC cells were also analyzed in vitro and in vivo. REV7 knockdown in CCC cells decreased cell proliferation without affecting cell cycle distribution. Additionally, the number of apoptotic cells and DNA damaged cells were increased after cisplatin treatment. In a nude mouse tumor xenograft model, inoculated REV7-knockdown tumors showed significantly reduced tumor volumes after cisplatin treatment compared with those of the control group. These findings indicate that high REV7 expression is associated with poor prognosis in EOC and DLBCL, and depletion of REV7 enhances sensitivity to cisplatin treatment in CCC, suggesting that REV7 is a candidate for molecular target in human malignancy.
Citation Format: Yoshiki Murakumo, Kaoru Niimi, Sosei Okina. REV7 is a possible prognostic predictor and a potential therapeutic target in human malignancy [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B41.
Abstract B43: RECQ1, a breast cancer susceptibility gene, is upregulated by cancer therapeutics in a p53-dependent manner
Authors: Lu Xing , Parvathaneni Swetha , Sharma Sudha 
Published: April 2017

Abstract
Sensitivity of cancer cells to DNA-damaging chemotherapeutics is determined by DNA repair processes. Consequently, cancer cells may upregulate expression of certain DNA repair genes as a mechanism to promote chemoresistance. Here, we report identification of RECQ1, a breast cancer susceptibility gene that encodes the most abundant RecQ helicase in humans, as a p53-regulated target potentially acting as a defense against DNA-damaging agents. Quantitative RT-PCR analysis in a variety of cancer cell lines revealed RECQ1 to be upregulated following DNA damage, which was confirmed by Western blot experiments. Significant increase in RECQ1 mRNA level was observed following treatment with alkylating agent methylmethanesulfonate (MMS) as well as the representative chemotherapeutic drugs doxorubicin, temozolomide and fotemustine. Upregulation of RECQ1 expression also appeared to depend on the nature of DNA lesion. Induction of RECQ1 by genotoxins requires p53 since it was observed in p53 wild-type but not in p53 null cells. Consistent with that, the RECQ1 promoter is bound by endogenous p53 and is responsive to p53 in luciferase assay. Knocking down RECQ1 expression in cancer cells resulted in increased sensitivity to MMS, fotemustine and temozolomide supporting the hypothesis that RECQ1 is involved in the recovery of cells from DNA damage. Notably, RECQ1 is frequently overexpressed and amplified in a variety of cancers. As RECQ1 efficiently protects cells from genomic instability through repair of DNA lesions including those induced by alkylating and other chemotherapeutic agents, RECQ1 overexpression may provide resistance to anti-cancer drugs. RECQ1 expression level may therefore serve to predict chemotherapeutic response of cancer patients and timely implementation of alternative therapeutic strategies.
Citation Format: Xing Lu, Swetha Parvathaneni, Sudha Sharma. RECQ1, a breast cancer susceptibility gene, is upregulated by cancer therapeutics in a p53-dependent manner [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B43.
Abstract B44: Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer
Authors: Toulany Mahmoud , Ilda Mari , Wheeler Deric L. , Rodemann H. Peter 
Published: April 2017

Abstract
Introduction: One of the major mechanisms of radioresistance in solid tumors is the activa-tion of the PI3K/Akt pathway in which Akt facilitates the repair of DNA double-strand breaks (DSBs) through stimulation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). As it is known that the PI3K/Akt pathway is hyperactivated in K-RAS mutated (K-RASmut), we investigated if targeting PI3K would be a potential approach for enhancing radiosensitivity of K-RASmut cells non-small lung cancer (NSCLC).
Methods: The K-RASmut NSCLC cell lines A549 and H460 were utilized to examine the effect of PI3K inhibition on Akt signaling, non-homologous end joining (NHEJ) repair of DSBs, and post-irradiation cell survival.
Results: Short-term (1-2 h) pre-treatment of K-RASmut cells with the PI3K inhibitor PI-103 (1 µM) inhibited Akt/DNA-PKcs activity, blocked DSBs repair and induced radiosensitivity, while long-term (24 h) pre-treatment did not. Lack of an effect in K-RASmut cells after 24 h of PI-103 pre-treatment was due to reactivation of K-Ras/MEK/ERK-dependent Akt. However, long-term treatment with PI-103 together MEK inhibitor PD98059 completely blocked reactivation of Akt and impaired DSBs repair through NHEJ leading to radiosensitization. The effect of PI3K inhibition on Akt signaling was also tested in A549 mouse xenografts in vivo. Akt and P-DNA-PKcs activity was inhibited 30 min post-irradiation in xenografts, which were pre-treated by PI-103 30 min before irradiation. However, after a 24 h pretreatment with PI-103, a significant reactivation of Akt was achieved 24 h after irradiation.
Conclusion: Due to ERK-dependent reactivation of Akt in K-RAS mutated NSCLC cells, dual targeting of PI3K and MEK is an effective approach to induce radiosensitization.
Acknowledgement: This work was supported by grants from the Deutsche Forschungsge-meinschaft (DFG, RO 527/7-1) awarded to HPR /MT and GRK 1302/2 (T11) awarded to MT/HPR.
Citation Format: Mahmoud Toulany, Mari Ilda, Deric L. Wheeler, H. Peter Rodemann. Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B44.
Abstract IA01: Advancing the field of mutational signatures: Mechanisms and clinical applications
Authors: Nik-Zainal Serena 
Published: April 2017

Abstract
Mutational signatures are the imprints of the biological processes that have gone awry in human cells. We previously outlined the methods for identifying and quantifying base substitution mutational signatures present in primary human cancers (http://cancer.sanger.ac.uk/cosmic/signatures). Here, using a highly-curated cohort of 560 whole genome sequenced breast cancers, we extend the understanding of mutational signatures to include six novel rearrangement signatures. Diving into the detail of individual mutational signatures, we reveal intriguing mechanistic insights into the DNA damage and repair processes that mark the landscape of cancer genomes. Furthermore, we highlight how these mutational signatures distinguish clinical cohorts in breast cancer and have potential clinical applications.
Citation Format: Serena Nik-Zainal. Advancing the field of mutational signatures: Mechanisms and clinical applications [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA01.
Abstract IA02: Defects in DNA repair genes revealed by clinical sequencing of advanced cancer patients
Authors: Chinnaiyan Arul 
Published: April 2017

Abstract
In 2011, we introduced the Mi-Oncoseq program, an IRB-approved protocol to carry out integrative sequencing of advanced cancer patients. It was one of the first comprehensive DNA and RNA sequencing programs offered for cancer patients. The purpose of this program was to determine the utility of genomic sequencing of tumors and germline coupled with a multi-disciplinary Precision Medicine Tumor Board (PMTB) in the management of advanced cancer patients. Collectively across all patient cohorts we have enrolled over 1500 patients since inception of Mi-Oncoseq where molecular results for both somatic and germline aberrations are returned to physicians. Both common and rare mutations were identified in numerous cellular pathways that are involved in carcinogenesis including those in the DNA repair pathway. We identified homozygous deletions, deleterious mutations and/or LOH in genes including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2 that are potentially actionable. For example, a multi-institutional, collaborative SU2C-PCF study of men with metastatic castrate-resistant prostate cancer (mCRPC) found that treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate (Mateo et al. NEJM, 2015). Additionally, a follow-up study found 11.8% of mCRPC patients had a germline mutation in a DNA-repair gene, including moderate risk genes (ATM, CHEK2, PALB2, RAD51D) for which clinical testing criteria do not exist (Pritchard et al, NEJM, 2016). Most of these patients would not qualify for germline genetic testing under current clinical care models. Our studies demonstrate that DNA repair mutations are common in mCRPC patients who may benefit from therapies such as PARP inhibitors and when identified in the germline, could have a significant impact on their family members where early cancer screening could be implemented as appropriate.
Citation Format: Arul Chinnaiyan. Defects in DNA repair genes revealed by clinical sequencing of advanced cancer patients [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA02.
Abstract IA05: Prospective identification of vulnerabilities to DNA repair inhibitors
Authors: Durocher Daniel 
Published: April 2017

Abstract
The advent of CRISPR/Cas9 as a gene editing tool has enable the development of genome-scale libraries of single-guide RNAs that can be used to probe biological processes. CRISPR/Cas9 screens can be used to profile the essential gene complement of cancer cell lines, map genetic interactions and chart the response to drugs. During my presentation, I will present our efforts to map the genetic networks that govern the DNA damage response and will discuss our work aimed at mapping the genetic architecture of the response to PARP inhibitors. Our work revealed new types of genetic vulnerabilities to PARP inhibition and in particular, I will discuss a type DNA lesion that could act as the elusive inhibited-PARP “trap”.
Citation Format: Daniel Durocher. Prospective identification of vulnerabilities to DNA repair inhibitors [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA05.
Abstract IA06: The Fanconi anemia-BRCA pathway and cancer
Authors: Taniguchi Toshiyasu 
Published: April 2017

Abstract
The Fanconi anemia (FA)-BRCA pathway has emerged as an important pathway in cancer biology. FA is a rare genetic disease characterized by chromosomal instability, cancer-susceptibility and cellular sensitivity to interstrand DNA crosslink (ICL)-inducing agents. The FA proteins including breast/ovarian cancer susceptibility proteins, BRCA1(FANCS) and BRCA2(FANCD1), cooperate in a common pathway (the FA-BRCA pathway) required for cellular resistance to ICL-inducing agents. The main function of the pathway is to coordinate multiple DNA repair mechanisms during ICL repair, although many of the components of the pathway also play critical roles in protecting replication forks.
Inactivation of this pathway in cancer cells can lead to sensitivity to anti-cancer ICL-inducing agents, such as cisplatin and carboplatin, while reactivation of this pathway is implicated in acquired resistance to ICL-inducing agents. Therefore, inhibition of the pathway is an attractive therapeutic strategy to overcome DNA-crosslinker resistance of tumor cells.
In this talk, I will introduce what the FA-BRCA pathway is and how this pathway is inactivated in human cancer. I will also mention some of the mechanisms of acquired resistance to cisplatin and PARP inhibitors in cancer cells, related to the FA-BRCA pathway. I will also discuss our recent findings about the regulation of the FA-BRCA pathway by FANCI protein and a deubiquitinating enzyme, USP28.
Citation Format: Toshiyasu Taniguchi. The Fanconi anemia-BRCA pathway and cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA06.