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

Abstract IA09: Replication fork stability confers chemoresistance in BRCA-deficient cells
Brca1- and Brca2-deficient cells have reduced capacity to repair DNA double strand breaks (DSBs) by homologous recombination (HR) and consequently are hypersensitive to DNA damaging agents including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein PTIP protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore HR activity at DSBs. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn, protects nascent DNA...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Chaudhuri, A. R., Callen, E., Ding, X., Gogola, E., Duarte, A. A., Lee, J.-E., Wong, N., Lafarga, V., Calvo, J. A., Panzarino, N. J., John, S., Day, A., Crespo, A. V., Shen, B., Starnes, L. M., Ruiter, J. R. d., Daniel, J. A., Konstantinopoulos, P. A., Co Tags: Synthetic Lethality and Viability: Oral Presentations - Invited Abstracts Source Type: research

Abstract B09: DNA damage inducible phosphorylation of ATR at threonine 1989 and quantitative analysis of the effect of ATR inhibition on DNA damage signaling using PTMScan
DNA repair pathways and checkpoint control are crucial in the maintenance of genome integrity. Agents that cause DNA damage, and agents that perturb DNA repair pathways, have been used successfully in the treatment of human cancer.The PI3K-like protein kinases ATR (ATM and Rad3-related) and ATM (ataxia telangiectasia mutated) are critical regulators of the DNA damage response (DDR), signaling to downstream effector molecules that in turn regulate cellular responses such as DNA repair, cell cycle arrest, and cell death.ATM is activated in response to DNA damage in part via autophosphorylation at serine 1981. ATR was long th...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Roberts, H. J., Stokes, M. P., Jia, X., Lee, K. A., Keezer, S. M. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA08: Synthetic viability due to BRCA2 and PARP1 loss
It is very well established that BRCA1 and BRCA2 deficient cells are hypersensitive to PARP inhibitors (PARPi) due to synthetic lethality. Because Parp1 parylates proteins involved in a wide range of biological processes, we hypothesized that inhibiting PARP activity may have detrimental effect on cells that are HR proficient and do not undergo synthetic lethality. We have demonstrated that although Brca2 null ES cells are not viable, they can survive after ES cells expressing a conditional allele of Brca2 are treated with olaparib prior to Cre-mediated deletion of the conditional allele. We also found that while Parp1 los...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Sharan, S. K. Tags: Synthetic Lethality and Viability: Oral Presentations - Invited Abstracts Source Type: research

Abstract A08: PARP1-mediated E2F1 regulation of DNA repair capacity
PARP1 holds two major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Notably, PARP1 has been found to be a key modulator of androgen receptor (AR) function and AR-dependent phenotypes, which is a driving factor in prostate cancer (PCa) biology and therapeutic management. Recent studies indicate an unanticipated prevalence of DNA repair alterations in advanced PCa and showed that PARP1 inhibitors (PARPi) can effectively manage of a subset of these tumors. Despite the functions of PARP1 in DNA repair having been exploited as a therapeutic target ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Schiewer, M. J., Mandigo, A. C., Gordon, N., Han, S., Zhao, S., Evans, J., Parsons, T., Birbe, R., McCue, P., Visakorpi, T., Raj, G., Rubin, M., Bono, J. d., Lallas, C., Trabulsi, E., Gomella, L. G., Dicker, A. P., Kelly, W. K., Feng, F. Y., Knudsen, K. E Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR07: Identifying factors mediating response and resistance to chemotherapy through a chemical-genetic interaction map
Nearly every cancer patient, especially those with highly lethal and aggressive tumor types, is treated with cytotoxic chemotherapy. Currently, the selection of chemotherapy is based on average responses over a large number of patients. This belies our understanding of DNA repair that has demonstrated that the inability of a tumor cell to properly repair particular types of DNA damage has a dramatic influence on cell survival. Here, we report the generation of a quantitative chemical-genetic interaction map to chart the influence of knockdown of 625 genes on sensitivity to 30 FDA approved chemotherapeutic agents in breast ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hu, H.-M., Bandyopadhyay, S. Tags: Synthetic Lethality and Viability: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA07: Genetic determinants of tumor development, therapy response and resistance in mouse models of BRCA-deficient breast cancer
Heterozygous germline mutations in BRCA1 or BRCA2 strongly predispose to development of breast and ovarian cancer (as well as other cancer types) via loss of the remaining wildtype allele. BRCA1/2-deficient cancers are defective in DNA double-strand break (DSB) repair via homologous recombination (HR) and therefore hypersensitive to DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors. However, these treatments do not result in tumor eradication and eventually resistance develops. To maximize therapeutic efficacy of these drugs and achieve durable remissions, it is important to un...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Jonkers, J. Tags: Synthetic Lethality and Viability: Oral Presentations - Invited Abstracts Source Type: research

Abstract B07: Learning from human tumors: Modeling of Mre11 complex patient mutations in yeast
The Mre11 complex plays a central role in the eukaryotic DNA damage response (DDR) in which it acts as a sensor of DNA double strand breaks (DSBs), and thereby governs DNA damage signaling as well as DSB repair. The complex is comprised of Mre11, Rad50, and Nbs1 (or Xrs2 in budding yeast), with dimers of Rad50 and Mre11 forming its core and a Nbs1/Xrs2 protomer binding to each Mre11. The Mre11 complex globular domain harbors all enzymatic and DNA binding functions of the Mre11 complex and is a very dynamic domain regulated by conformational changes induced by Rad50 ATP binding and hydrolysis cycles. It was suggested that t...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hohl, M., Inagaki, A., Petrini, J. H. J. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A07: The RAD51 paralog complex SWS1-SWSAP1 is critical for homologous recombination in the mouse
Homologous recombination (HR), also termed homology-directed repair, is a major pathway for the repair of DNA double-strand breaks (DSBs) generated by DNA damaging agents, replication fork collapse and during meiosis. Failure to repair DSBs correctly causes genomic instability, leading to mutagenesis, and developmental defects. Moreover, defects in HR impact the response to many therapeutics. Components of the HR machinery include BRCA2 and five RAD51 paralogs, which are critical for RAD51 assembly onto single-stranded DNA, an important intermediate for homologous strand invasion. Disruption of these HR genes in mice resul...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Prakash, R., Abreu, C. M., Keeney, S., Jasin, M. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR06: Targeted chemotherapy for Homologous Repair Defects (HRD) in molecularly profiled cancer patients
Precision Medicine Tumor Boards (PMTB) are now established at many academic institutions and provide a forum for multidisciplinary teams to discuss tumor profiling results to aid treatment choices for cancer patients. PMTBs typically focus on kinase mutations and well defined translocations, mostly because of limited gene panels explored. Established treatments exist for some of these genetic aberrations and multiple clinical trials have been initiated for specific kinase-targeted investigational drugs in development.The Yale 409 Gene Panel (Ion Torrent; AmpliSeq Comprehensive Cancer Panel) includes a large set of Homologo...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Eder, J. P., McLaughlin, J. F., Sklar, J., Walther, Z., Finberg, K., Minnella, A., Juergensmeier, J. M. Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA06: The Fanconi anemia-BRCA pathway and cancer
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 pl...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Taniguchi, T. Tags: Homologous Recombination Defects: Oral Presentations - Invited Abstracts Source Type: research

Abstract A06: Regulation of homologous recombination by the SUMO ligase NSMCE2
Conclusions: The hyper-accumulation of RAD51 at stalled forks we observed in NSMCE2-deficient cells suggests the sumoylation of one or more substrates by NSMCE2 is required for the remodeling of stalled forks that normally leads to unloading of RAD51 at the fork, strand breakage, and repair by HR. We suggest that the RAD51 accumulation that is observed in a substantial fraction of cancers may not be sufficient to demonstrate that the cells are HR proficient. Based on our data, RPA staining combined with RAD51 may be able to distinguish HR-proficient and deficient cells.Citation Format: Kelvin W. Pond, Christelle DeRenty, M...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Pond, K. W., DeRenty, C., Yagle, M., Ellis, N. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR05: Distinct BRCA1- and BRCA2-specific functions at stalled replication forks: Clinical implications for differences between BRCA1 and BRCA2 mutation-driven cancer
BRCA1 and BRCA2 are tumor suppressor genes, and germ line mutations in these two genes increase the risk of breast cancer. Both BRCA1 and BRCA2 are required for stabilization and repair of stalled replication forks. Stalled forks, when not resolved, lead to mutations, or collapse into double strand breaks (DSBs). Both outcomes result in what is commonly referred to as replication stress (RS), which, when chronic, is a driving force behind cancer development. However, it is not clear what are the differences, if any, between BRCA1 and BRCA2 dependent stabilization and repair of stalled replication fork. Getting a better und...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Duan, H., Reed, R., Garber, J., Pathania, S. Tags: Replication Stress: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA05: Prospective identification of vulnerabilities to DNA repair inhibitors
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 partic...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Durocher, D. Tags: Homologous Recombination Defects: Oral Presentations - Invited Abstracts Source Type: research

Abstract A05: Improving outcome in homologous recombination competent epithelial ovarian cancer: Hyperthemia and surgeon's perspective
Conclusions: Personalized surgical and chemotherapeutic strategies may be developed for HR stratified EOCs. Primary surgery may be the preferred approach in HRC due to poor chemoresponse and resources should be optimized to achieve complete cytoreduction anticipating difficult resection. Intra-operative hyperthermic treatment and selective HR inhibitors (HSP90) may improve subsequent chemoresponse in HRC. Pre-clinical studies on patient tissues and after HIPEC procedures are proposed in ongoing studies to consolidate our hypothesis.1. Epithelial ovarian cancer: HR assay to stratify as HRD and HRC2. HRC: Primary surgery+ HI...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mukhopadhyay, A., Abdulrahman, G., Davison, E., Matheson, E., Drew, Y., Curtin, N. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR04: Mechanism for PARPi resistance: Homologous recombination without BRCA1
Approximately 15-20% of all epithelial ovarian cancers harbor germline or somatic mutations in BRCA1/2. Despite PARP inhibitor induce synthetic lethality in non-cancerous mouse embryo fibroblast cells that harbor BRCA1/2 mutations, a substantial fraction of BRCA1/2-mutated tumors patients do not respond to PARPi treatment, and a large fraction of BRCA1/2-mutated tumors patients eventually develop resistance to PARPi suggest significant frequency of acquired mutation lead to PARPi resistance preventing complete cure.We use CRISPR based library screen identified ATMIN/DYNLL1 loss as strong candidate for PARPi and cisplatin r...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: He, Y. J., Meghani, K., Chowdhury, D. Tags: Synthetic Lethality and Viability: Oral Presentations - Proffered Abstracts Source Type: research

Abstract A04: Phosphorylation and ubiquitylation on the RPA-ssDNA platform promote homologous recombination
Replication stress is an important source of genome instability in cancer cells. Impediments to replication fork progression stimulate the accumulation of RPA-coated single-stranded DNA (RPA-ssDNA). RPA-ssDNA then recruits and activates a large number of genome maintenance factors including the master checkpoint kinase ATR to protect genomic integrity. Amongst the factors recruited onto RPA-ssDNA, we have previously shown that the E3 ubiquitin ligase PRP19, in addition to its central role as an RNA splicing factor, plays an integral part in the elicitation of the DDR during replication stress. Specifically, the ubiquitin l...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Dubois, J.-C., Clement, G., Cappadocia, L., Gaudreau, L., Zou, L., Marechal, A. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA03: Targeting the DNA damage response to generate new medicines for cancer treatment
Cancers are characterized by high levels of genomic instability and endogenous DNA damage. Traditional cancer therapies include radiotherapy and DNA-damaging chemotherapy, but these treatments are associated with significant damage to normal tissue. These unwanted side effects may be reduced by using targeted treatment approaches that preferentially affect tumor cells with specific mutations. The DNA damage response (DDR) in cancer cells differs in at least three aspects to those of normal cells, namely the loss of one or more DDR pathway or capability, increased levels of replication stress and higher levels of endogenous...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: O'Connor, M. J. Tags: Keynote Presentations: Oral Presentations - Invited Abstracts Source Type: research

Abstract A03: The EMSY threonine 207 phospho-site is required for EMSY-driven suppression of DNA damage repair
Conclusions: EMSY-overexpressing cells show decreased HDR activity, demonstrating EMSY's relevance to the HDR pathway. Our data support the notion that EMSY-driven HDR impairment is BRCA2-interaction-independent and challenges the currently held impression that EMSY overexpression mimics the BRCA2-depleted phenotype via direct interaction. We found a new phospho-site at EMSY T207 and identified PKA as a targeting kinase. Phosphorylation of EMSY at T207, but not S209 phospho-site is necessary for EMSY-driven suppression of HDR. We suggest that an increase in EMSY's T207 phosphorylation in patients bearing EMSY¬-amplifie...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Jelinic, P., Eccles, L., Tseng, J., Cybulska, P., Powell, S. N., Levine, D. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR02: Small molecules that specifically inhibit the D-loop activity of RAD51
RAD51 plays a central role in homologous recombination (HR), which maintains genome integrity. RAD51 is commonly overexpressed in cancer cells relative to normal tissue and is considered a therapeutic target in oncology. One potential challenge for targeting RAD51 pharmacologically is that it mediates functions in both double-strand DNA break (DSB) repair and stabilization of stalled replication forks.In order to distinguish compound-mediated effects on these RAD51 functions, we developed a novel class of RAD51 inhibitors. In contrast to many previously reported RAD51 inhibitors, we sought to develop compounds that do not ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Budke, B., Lv, W., Tueckmantel, W., Kozikowski, A., Connell, P. Tags: Homologous Recombination Defects: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA02: Defects in DNA repair genes revealed by clinical sequencing of advanced cancer patients
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 a...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Chinnaiyan, A. Tags: Keynote Presentations: Oral Presentations - Invited Abstracts Source Type: research

Abstract B02: DNA repair landscape in High Grade Ovarian Cancer (HGOC) and evolution with neo-adjuvant chemotherapy
Background: HGOC is frequently diagnosed at an advanced stage where NeoAdjuvant Chemotherapy (NACT) provides an essential component of the treatment strategy. HGOC are initially very chemosensitive, putatively due to DNA repair defects. While BRCA mutations explain impaired homologous recombination in 12% to 15% of HGOC, loss of other DNA repair proteins may also be relevant. Unfortunately despite initial response rates of 80%, most invariably relapse. Chemo-resistance mechanisms are poorly understood and previous studies have only focused on the characterization at diagnosis. However given their chemosensitivity, profilin...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Auguste, A., Mesnage, S., Formal, A. L., Cojocaru, E., Drusch, F., Adam, J., Gouy, S., Bentivegna, E., Lhomme, C., Pautier, P., Genestie, C., Leary, A. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR01: Mechanisms of regulation of the tumor suppressor PALB2
One typical mechanism to promote genomic instability, a hallmark of cancer, is to inactivate tumor suppressors, such as PALB2. It has recently been reported that mutations in PALB2 increase the risk of breast cancer by 8-9 fold. PALB2 was identified BRCA2 interacting protein, essential for BRCA2 anchorage to nuclear structures and for its function in double-strand break repair. Inherited mutations in PALB2 are associated with a predisposition for ovarian, breast and pancreatic cancers. The basis of the tumorigenic potential of PALB2 is thought to be related to functions in homologous recombination.Therefore, the regulation...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Couturier, A., Buisson, R., Pauty, J., Rodrigue, A., Joshi, N., Caron, M.-C., Coulombe, Y., Zou, L., Masson, J.-Y. Tags: DNA Damage Signaling: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA01: Advancing the field of mutational signatures: Mechanisms and clinical applications
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 ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Nik-Zainal, S. Tags: Keynote Presentations: Oral Presentations - Invited Abstracts Source Type: research

Abstract B01: Histone acetyltransferase 1 contributes to colon cancer initiating cell chemoresistance through DNA damage repair pathways
Despite advances in treatment, Colorectal cancer (CRC) remains a leading cause of cancer related deaths in North America. Most CRCs contain a subset of self-renewing colon cancer-initiating cells (CC-ICs) responsible for tumor initiation and maintenance. CC-ICs are relatively chemoresistant as compared to the bulk tumor cells, however the mechanisms of this chemoresistance are poorly understood. An increasing amount of evidence suggests that epigenetic regulators may be playing a central role in driving CC-IC chemoresistance; one such example being histone acetyltransferase (HAT1), which plays an important role in cancer c...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Agro, L., Leung, C., Wang, Y., Lima-Fernandes, E., O'Brien, C. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research

IGF-1 Receptor Modulates FoxO1-Mediated Tamoxifen Response in Breast Cancer Cells
Tamoxifen is a common adjuvant treatment for estrogen receptor (ER)α-positive patients with breast cancer; however, acquired resistance abrogates the efficacy of this therapeutic approach. We recently demonstrated that G protein–coupled estrogen receptor 1 (GPER1) mediates tamoxifen action in breast cancer cells by inducing insulin-like growth factor–binding protein-1 (IGFBP-1) to inhibit IGF-1–dependent signaling. To determine whether dysregulation of IGFBP-1 induction is associated with tamoxifen resistance, IGFBP-1 transcription was measured in tamoxifen-resistant MCF-7 cells (TamR) after tamoxif...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Vaziri-Gohar, A., Zheng, Y., Houston, K. D. Tags: Signal Transduction Source Type: research

Potent EMT and CSC Phenotypes Are Induced By Oncostatin-M in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is referred to as a silent killer due to the lack of clear symptoms, a lack of early detection methods, and a high frequency of metastasis at diagnosis. In addition, pancreatic cancer is remarkably resistant to chemotherapy, and clinical treatment options remain limited. The tumor microenvironment (TME) and associated factors are important determinants of metastatic capacity and drug resistance. Here, oncostatin M (OSM), an IL6 cytokine family member, was identified as an important driver of mesenchymal and cancer stem cell (CSC) phenotypes. Furthermore, the generation of cells that ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Smigiel, J. M., Parameswaran, N., Jackson, M. W. Tags: Signal Transduction Source Type: research

Inflammatory Molecule, PSGL-1, Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NF{kappa}B Signaling
P-selectin glycoprotein ligand 1 (SELPLG/PSGL-1) is an inflammatory molecule that is functionally related to immune cell differentiation and leukocyte mobilization. However, the role of PSGL-1 in tumor development remains unknown. Therefore, this study investigates the mechanistic role of PSGL-1 in the development of intestinal tumors in colorectal cancer. ApcMin/+ mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a ApcMin/+;PSGL-1–/– genotype. The incidence and pathologic features of the intestinal tumors w...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Li, J., Zhou, Z., Zhang, X., Zheng, L., He, D., Ye, Y., Zhang, Q.-Q., Qi, C.-L., He, X.-D., Yu, C., Shao, C.-k., Qiao, L., Wang, L. Tags: Oncogenes and Tumor Suppressors Source Type: research

Bone Microenvironment Changes in Latexin Expression Promote Chemoresistance
This study suggests that the LXN pathway should be further explored as a viable target for preventing or reversing taxane resistance in prostate cancer. Mol Cancer Res; 15(4); 457–66. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Zhang, M., Osisami, M., Dai, J., Keller, J. M., Escara-Wilke, J., Mizokami, A., Keller, E. T. Tags: Oncogenes and Tumor Suppressors Source Type: research

miR-211-5p Suppresses Metastatic Behavior by Targeting SNAI1 in Renal Cancer
The Snail family transcriptional repressor 1 (SNAI1) is known to promote metastatic phenotypes in renal cell carcinoma (RCC). However, the mechanism by which SNAI1 promotes RCC metastasis remains largely unexplored. Here, bioinformatics and quantitative validation revealed that miR-211-5p was downregulated in metastatic RCC clinical specimens compared with nonmetastatic RCC tissues. Overexpression of miR-211-5p suppressed RCC cell migration and invasion via downregulation of SNAI1 expression. Luciferase reporter assays demonstrated that miR-211-5p directly targeted 3'-UTR of SNAI1. Furthermore, miR-211-5p decreased xenogra...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Wang, K., Jin, W., Jin, P., Fei, X., Wang, X., Chen, X. Tags: Oncogenes and Tumor Suppressors Source Type: research

Metabolic Profiling in Formalin-Fixed and Paraffin-Embedded Prostate Cancer Tissues
Metabolite profiling has significantly contributed to a deeper understanding of the biochemical metabolic networks and pathways in cancer cells. Metabolomics-based biomarker discovery would greatly benefit from the ability to interrogate retrospective annotated clinical specimens archived as formalin-fixed, paraffin-embedded (FFPE) material. Mass spectrometry–based metabolomic analysis was performed in matched frozen and FFPE human prostate cancers as well as isogenic prostate cancer cell lines. A total of 352 and 460 metabolites were profiled in human tissues and cell lines, respectively. Classes and physical–...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Cacciatore, S., Zadra, G., Bango, C., Penney, K. L., Tyekucheva, S., Yanes, O., Loda, M. Tags: Metabolism Source Type: research

Immunophenotyping and Transcriptomic Outcomes in PDX-Derived TNBC Tissue
Cancer tissue functions as an ecosystem of a diverse set of cells that interact in a complex tumor microenvironment. Genomic tools applied to biopsies in bulk fail to account for this tumor heterogeneity, whereas single-cell imaging methods limit the number of cells which can be assessed or are very resource intensive. The current study presents methods based on flow cytometric analysis and cell sorting using known cell surface markers (CXCR4/CD184, CD24, THY1/CD90) to identify and interrogate distinct groups of cells in triple-negative breast cancer clinical biopsy specimens from patient-derived xenograft (PDX) models. Th...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Snowden, E., Porter, W., Hahn, F., Ferguson, M., Tong, F., Parker, J. S., Middlebrook, A., Ghanekar, S., Dillmore, W. S., Blaesius, R. Tags: Genomics Source Type: research

14-3-3{sigma} Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2
In this study, we tested the hypothesis that 14-3-3 causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2–M phase following DNA-damaging treatments. We showed that 14-3-3 contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2–M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3–mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the ot...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Chen, Y., Li, Z., Dong, Z., Beebe, J., Yang, K., Fu, L., Zhang, J.-T. Tags: DNA Damage and Repair Source Type: research

EZH2 or HDAC1 Inhibition Reverses Multiple Myeloma-Induced Epigenetic Suppression of Osteoblast Differentiation
This study suggests that therapeutically targeting EZH2 or HDAC1 activity may reverse the profound multiple myeloma–induced osteoblast suppression and allow repair of the lytic lesions. Mol Cancer Res; 15(4); 405–17. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Adamik, J., Jin, S., Sun, Q., Zhang, P., Weiss, K. R., Anderson, J. L., Silbermann, R., Roodman, G. D., Galson, D. L. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma
Elucidation of TNF-directed mechanisms for cell death induction and maintenance of tumor growth has revealed a role for receptor-interacting protein kinases 1 and 3 (RIPK1/RIP1 and RIPK3/RIP3), components of the necrosome complex, as determinants of cell fate. Here, the participation of TNF signaling was analyzed with regard to the cytotoxic action of different DNA-damaging agents in a panel of colon cancer cells. While most of these cell lines were insensitive to TNF, combination with these drugs increased sensitivity by inducing cell death and DNA damage, especially in the case of the topoisomerase inhibitor SN38. Change...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Cabal-Hierro, L., O'Dwyer, P. J. Tags: Cell Death and Survival Source Type: research

A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance
TRAIL is a potent death-inducing ligand that mediates apoptosis through the extrinsic pathway and serves as an important endogenous tumor suppressor mechanism. Because tumor cells are often killed by TRAIL and normal cells are not, drugs that activate the TRAIL pathway have been thought to have potential clinical value. However, to date, most TRAIL-related clinical trials have largely failed due to the tumor cells having intrinsic or acquired resistance to TRAIL-induced apoptosis. Previous studies to identify resistance mechanisms have focused on targeted analysis of the canonical apoptosis pathway and other known regulato...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Dimberg, L. Y., Towers, C. G., Behbakht, K., Hotz, T. J., Kim, J., Fosmire, S., Porter, C. C., Tan, A.-C., Thorburn, A., Ford, H. L. Tags: Cell Death and Survival Source Type: research