Abstract B15: Dissecting the molecular mechanism of dianhydrogalactitol (VAL-083) activity in cancer treatment
Conclusions: VAL-083 displayed broad anti-neoplastic activity in different lung and prostate cancer cells through the replication-dependent DSBs. Elucidation of the molecular mechanisms underlying VAL-083 cytotoxicity provides guidance for improved treatment strategies for cancer patients with VAL-083 in either single or combination regimens.Citation Format: Beibei Zhai, Anne Steino, Jeffrey Bacha, Dennis Brown, Mads Daugaard. Dissecting the molecular mechanism of dianhydrogalactitol (VAL-083) activity in cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therap...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Zhai, B., Steino, A., Bacha, J., Brown, D., Daugaard, M. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA14: Mechanisms of the ATR-dependent replication stress response
Replication stress can be caused by DNA damage, difficult to replicate DNA sequences, collisions between replication and transcriptional machineries, and aberrations in the replication timing or other regulatory mechanisms. Cancer cells often have elevated levels of replication stress driven by oncogenes. Replication stress response pathways are important in these contexts to allow cells to complete replication, maintain genome stability, and remain viable. Drugs that increase the replication stress burden or inactivate components of the replication stress response pathway can be useful as cancer therapeutics. For example,...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Cortez, D. Tags: Replication Stress: Oral Presentations - Invited Abstracts Source Type: research
Abstract B14: A novel role for BRD9 in regulating cellular growth and DNA damage response pathways
We examined if SWI/SNF chromatin remodeling activity was dependent on BRD9 status and how this correlated with the growth phenotype. Nucleosome accessibility was significantly decreased when BRD9 was depleted indicating chromatin exists in a more compacted conformation. However, BRD9 knockdown does not result in alterations in assembly or stability of the SWI/SNF complex. Though loss of BRD9 does not perturb SWI/SNF dynamics, it may be required for complex recruitment to chromatin directly or by tethering through protein-protein interactions. Identification of novel BRD9-interacting proteins that target recruitment was car...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Vallaster, C., Gharadaghi, F., Cocozaki, A., Jacques, K., Price, B., Guichard, S. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA13: Replication stress in cancer pathogenesis: Mechanisms and treatment opportunities
Replication stress (RS) induced by activated oncogenes and loss of some tumor suppressors is emerging as one of the hallmarks of cancer. The RS-induced DNA damage and the ensuing activation of cell cycle checkpoints commonly induce cellular senescence or cell death of the nascent tumor cells, providing an inducible intrinsic barrier to cancer progression. On the other hand, this scenario creates an environment that favors outgrowth of tumor cell clones featuring p53 mutations and other checkpoint defects such as those in ATM or Chk2 kinases, events that allow tumor growth at the expense of enhanced genomic instability. The...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Bartek, J., Bartkova, J. Tags: Replication Stress: Oral Presentations - Invited Abstracts Source Type: research
Abstract B13: Involvement of PAF1 complex in the DNA damage response
PAF1 complex is a transcriptional complex composed of PAF1, CTR9, CDC73, LEO1, RTF1 and SKI8 in human. It plays a key role in the regulation of every step of transcription, from initiation to termination. PAF1 complex associates with RNA polymerase II during transcription, and regulates modification patterns of surrounding histones or chromatin structure via recruitment of histone modifying enzymes or chromatin remodeling factors to the actively transcribed site. In yeast, PAF1 complex has been also proposed to involve in other DNA associated processes, like DNA recombination, replication, and repair. However, detailed mol...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Park, G., Kim, N., Yoo, J.-Y. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA12: Poisoning cancer with oxidized nucleotides by targeting MTH1
This study exemplifies a new general therapeutic approach to convert oxidative stress to cytotoxic DNA damage and cancer cell death. Here, I will present the progression of MTH1 inhibitors from pre-clinical development into early clinical trials.References:Gad et al 2014 Nature. 508(7495):215-21.Citation Format: Thomas Helleday. Poisoning cancer with oxidized nucleotides by targeting MTH1 [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 IA12. (Source: ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Helleday, T. Tags: Replication Stress: Oral Presentations - Invited Abstracts Source Type: research
Abstract B12: Effect of Ganoderma lucidum on DNA damage and DNA repair in colorectal cancer cell lines
Colorectal carcinoma (CRC) is the third most common type of cancer in the world and second most common cause of cancer related deaths in Europe. Countries of Central Europe (Czech Republic, Slovakia and Hungary) have one of the highest rates both for incidence and mortality of CRC and this disease therefore possesses a serious health, social and economic problem.CRC is a complex disease that develops as consequence of environmental and health risk factors with particular involvement of suboptimal DNA repair, resulting in accumulation of DNA damage. Reactive oxygen species (ROS) represent a group of highly reactive molecule...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Opattova, A., Cumova, A., Vodenkova, S., Macinga, P., Horak, J., Sliva, D., Vodicka, P. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A12: CTCF facilitates DNA double-strand break repair by homologous recombination
The repair of DNA double strand breaks (DSB) is mediated via two major pathways, non-homologous end joining (NHEJ) or homologous recombination repair (HRR). Such repair is critical for cell survival and genome stability. Here, we report a new role for the multifunctional protein CTCF in facilitating the repair of DSB via the HRR pathway. CTCF is recruited to DSB through its zinc finger domain independently of poly(ADP-ribose) polymers catalyzed by PARP-1. CTCF ensures proper DSB repair kinetics in response to gamma-irradiation, and potentiates activation of the G2/M checkpoint. We find that CTCF regulates HRR through facil...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hilmi, K., Zhang, C., Yu, Z., Saad, A., Richard, S., McCaffrey, L., Alaoui-Jamali, M. A., Witcher, M. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA11: Signatures of mutational processes in human cancer
All cancers are caused by somatic mutations. These mutations may be the consequence of the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, enzymatic modification of DNA, or defective DNA repair. In some cancer types, a substantial proportion of somatic mutations are known to be generated by exogenous arcinogens, for example, tobacco smoking in lung cancers and ultraviolet light in skin cancers, or by abnormalities of DNA maintenance, for example, defective DNA mismatch repair in some colorectal cancers.Each biological process causing mutations leaves a characteristic...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Alexandrov, L. B. Tags: DNA Repair Gene Mutations in Cancer Genomes: Oral Presentations - Invited Abstracts Source Type: research
Abstract A11: RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1
The retinoblastoma (RB) tumor suppressor is widely recognized as a master regulator of the transcriptional program that controls entry into the S phase of the cell cycle. Its loss, which is a hallmark of cancer, leads to uncontrolled cell proliferation. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers and remodelers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double strand breaks (DSBs) dependent on E2F1 and ATM kinase activity. RB promotes DNA end resection and DSB repair through homologous recombination (HR), and its loss res...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Velez-Cruz, R., Manickavinayaham, S., Biswas, A. K., Clary, R. W., Johnson, D. G. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR10: Ionizing radiation-induced tumorigenesis is associated with exome-wide mutational signatures conserved in mice and humans
Conclusions: IR-induced tumorigenesis is associated with stable trinucleotide-based mutational signatures that are conserved in human malignancies and mouse malignancies. These signatures are highly distinguishable from that associated with UV. These conserved signatures, developing in multiple irradiated tissue types, may reflect mutational processes associated with in vivo IR exposure and possibly demonstrate non-lethal but pathogenic somatic variants related to DNA repair.This abstract is also being presented as Poster B42.Citation Format: Philip Davidson, Amy Sherborne, Barry Taylor, Alice Nakamura, Jean Nakamura. Ioni...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Davidson, P., Sherborne, A., Taylor, B., Nakamura, A., Nakamura, J. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Oral Presentations - Proffered Abstracts Source Type: research
Abstract IA10: DNA repair mutations in ovarian carcinoma and relationship to therapeutic response
Ovarian carcinomas with germline or somatic mutations in BRCA1 and BRCA2 are sensitive to platinum chemotherapy and to PARP inhibitors. The therapeutic role of damaging mutations in other homologous recombination genes is less certain. We will review various measures of homologous recombination deficiency in ovarian cancer and their correlation with efficacy of PARP inhibitor therapy in the relapsed setting.Citation Format: Elizabeth M. Swisher. DNA repair mutations in ovarian carcinoma and relationship to therapeutic response [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and T...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Swisher, E. M. Tags: DNA Repair Gene Mutations in Cancer Genomes: Oral Presentations - Invited Abstracts Source Type: research
Abstract B10: The role of Down syndrome's DYRK1A kinase in repair of the DNA double strand breaks
The function of DYRK1A protein kinase is regulated by its gene dosage whereby both gains and losses of one copy of DYRK1A gene on chromosome 21 result in developmental abnormalities. In order to better understand the function and regulation of DYRK1A, we applied a highly sensitive MudPIT proteomic approach to identify DYRK1A-interacting proteins in human cells. Four biological replicate MudPIT experiments were performed and the proteins reproducibly detected in the DYRK1A immunoprecipitates but not in the controls, were identified. Six proteins detected in all four biological replicate experiments were also most highly enr...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Menon, V. R., Ananthapadmanabhan, V., Litovchick, L. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A10: The impact of cancer-associated RAD51C mutations in homologous recombination
Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks (DSBs). Loss of function of key HR repair proteins have been linked to diseases characterized by genomic instability including cancers and Fanconi anemia. Regulation of RAD51 filaments is critical during HR repair and is mediated by several factors including the RAD51 paralogs, a group of proteins that share sequence homology with RAD51. The RAD51 paralog family consists of five proteins in humans, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. The RAD51 paralog, RAD51C, has recently become a key protein of interest as RAD51C mutations h...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Sullivan, M. R., Prakash, R., Jasin, M., Bernstein, K. A. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR09: APOBEC3A sensitizes leukemia cells to inhibitors of the replication checkpoint
The human APOBEC3 family of DNA-cytosine deaminases comprises seven members (A3A-A3H) that act on single-stranded DNA (ssDNA). The APOBEC3 enzymes are best defined by their capacity to restrict viral infection, however several family members are also capable of causing cellular DNA damage that leads to activation of DNA damage responses. Mutational signatures consistent with APOBEC3 activity have been identified in cancer genomes, and elevated expression of APOBEC3 enzymes has been observed in solid tumors. These findings point to a role for APOBEC3 enzymes in cancer-associated mutagenesis, however the impact of APOBEC3 ac...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Green, A. M., Budagyan, K., Hayer, K. E., Weitzman, M. D. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Proffered Abstracts Source Type: research
