Abstract B40: [10]-gingerol as a pro-apoptotic molecule in triple negative breast cancer
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 Devel...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Martin, A. C. B. M., Tomasin, R., Becceneri, A. B., Fuzer, A., Vieira, P. C., Cominetti, M. R. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A40: Profile of DNA repair status in a recently established panel of patient-derived ovarian carcinoma xenografts
Conclusions: These data suggest the mRNA expression levels of targeted DNA repair pathway-related genes as PALB2, XPF and CDK12 predict the response to a platinum based therapy in ovarian cancer, even if they need to be prospectively validated in cohort of ovarian cancer patients.Citation Format: Federica Guffanti, Maddalena Fratelli, Monica Ganzinelli, Francesca Ricci, Maria Rosa Cappelletti, Damiele Generali, Francesca Bizzaro, Raffaella Giavazzi, Giovanna Damia. Profile of DNA repair status in a recently established panel of patient-derived ovarian carcinoma xenografts [abstract]. In: Proceedings of the AACR Special Con...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Guffanti, F., Fratelli, M., Ganzinelli, M., Ricci, F., Cappelletti, M. R., Generali, D., Bizzaro, F., Giavazzi, R., Damia, G. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B39: Tumor hypoxia induces DNA repair vulnerabilities through contextual "loss-of- heterozygosity"
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...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mahamud, O., Chua, M. L. K., Lo, W., Zafarana, G., Bristow, R. G. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A39: Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetorchore-microtubule attachments
The DAB2IP tumor suppressor protein is a member of the Ras GTPase-activating protein family and is often downregulated by epigenetic silencing in many advanced cancer types. Current literature indicates that DAB2IP plays a crucial role in suppression of the PI3K-Akt pathway and epithelial-mesenchymal transition. Loss of DAB2IP is often detected in advanced prostate cancer (PCa) and is associated with increased androgen receptor signaling and poor patient prognosis. Here we report that loss of DAB2IP is also resulted in chromosomal instability due to defects in kinetochore-microtubule (KT-MT) attachment and the spindle asse...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Yu, L., Shang, Z.-F., Chen, B. P. C., Saha, D. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B38: Radiation enhances intracellular delivery of anti-MGMT oligomers to reduce protein expression in vitro and in a xenograft model
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...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Wu, J., Ambady, P., Morris, D., Pagel, M., Woltjer, R., Walker, J., Muldoon, L., Neuwelt, E. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A38: Targeting Microenvironment Damage Responses via PARP inhibition to Enhance Prostate Cancer Therapy
Conclusions: PARP inhibitors, developed primarily to target vulnerabilities in tumor cells directly, may provide additional anti-tumor effects via DDSP and repurposing PARPi to suppress the DDSP could augment responses to radiation and chemotherapy via microenvironment modulation. In addition to PARP1, our ongoing studies are designed to evaluate other PARP family members including PARP5 and PARP10 that may influence damage responses.Citation Format: Payel Chatterjee, Peter Nelson. Targeting Microenvironment Damage Responses via PARP inhibition to Enhance Prostate Cancer Therapy [abstract]. In: Proceedings of the AACR Spec...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Chatterjee, P., Nelson, P. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B37: PARP inhibitor olaparib induces genomic instability in normal mammalian cells
Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA damage response pathways to be targeted by specific inhibitors for clinical benefit. Tumors with defects in homologous recombination (HR) are hypersensitive to PARP inhibitors (PARPi), and early phase clinical trials have been promising in patients with advanced BRCA1 and BRCA2-associated breast, ovary and prostate cancer. Unlike HR-defective cells, HR-proficient cells manifest low cytotoxicity when exposed to PARPi. Nonetheless, they mount a DNA damage response and show a genomic instability phenotype as demonstrated by an increased frequ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Vanoli, F., Ito, S., Frock, R. L., Alt, F. W., Moynahan, M. E., Jasin, M. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A37: Development of screening methods to identify Translesion DNA Synthesis inhibitors
Translesion DNA synthesis (TLS) is a DNA damage tolerance process that employs specialized polymerases to bypass DNA damage during replication. Recent evidence indicates that TLS is a key process that promotes the development of resistance to cancer treatments that induce DNA damage (i.e. Cisplatin). Thus, the inhibition of TLS emerges as a promising strategy for cancer therapy. However, to date, specific chemical inhibitors of TLS are not available.The main goal of our project is to identify specific inhibitors of TLS that can be used as a proof of concept in cancer therapy by developing cell-based assays that explore TLS...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Villafanez, F., Garcia, A. I., Pansa, M. F., Carbajosa, S., Bocco, J. L., Soria, G. Tags: Replication Stress: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B36: Targeting BRCA1 through natural HSP90 inhibitors to reverse platinum resistance in TNBC
Background: Triple-negative breast cancers (TNBCs) are highly associated with an aggressive clinical course, resistance to chemotherapy, and poor prognosis compared to other breast cancer subtypes. However, breast cancers arising in BRCA1 mutation carriers appear to be particularly sensitive to platinum-based chemotherapy agents. The tumor suppressor BRCA1 (breast cancer type 1 susceptibility protein) is part of a protein complex that repairs DNA damage by homologous recombination. Recent studies have shown that tumor cells expressing high levels of BRCA1 are resistant to both ionizing radiation (IR) and platinum-based che...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Valdez, K., Ramamoorthy, P., Anant, S., Jensen, R. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B34: Development of novel small molecule inhibitors targeting DNA repair proteins
More than 1.6 million new cases of cancer will be diagnosed in the US in 2016 and a third of these will be from solid tumor of the lung, pancreas, breast, and ovary. These cancers represent a continuing clinical challenge in treatment and together account for over 250,000 deaths in the US alone, representing over 40% of all cancer deaths. There are limited therapeutic options for these patients, and targeted and combination therapies remain necessary for treating these aggressive cancers. The opportunity exists to exploit recent scientific advances in our knowledge of the underlying biology behind these cancers to create n...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Pawelczak, K. S., Gavande, N., VanderVere-Carozza, P., Turchi, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B33: PARP-dependent co-modulation of DNA repair and microglial activity as a dual-pronged anti-glioblastoma treatment strategy
Conclusion: Preliminary results show that Olaparib is effective in sensitizing GBM cells to chemotherapy while microglia appear to enhance this effect. Further studies linking this combination therapy with microglia-mediated GBM elimination will help to elucidate the mechanism of this bimodal effect. This study emphasizes the importance of: (1) identifying novel effects of PARP inhibition on microglia in association with GBM and (2) the importance of developing microglia-mediated immunotherapeutic intervention to overcome the limitations of current therapies to significantly improve patient outcome.Citation Format: Asha Si...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Sinha, A., Katyal, S., Kauppinen, T. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A33: Defect in S phase cell cycle checkpoint renders tumours vulnerable to CHK1 inhibitor single-agent treatment in vitro and in vivo
CHK1 inhibitors are being investigated as chemosensitizing agents with agents that increase replication stress. Here we have investigated the molecular basis of sensitivity to CHK1 inhibitors as single agents in melanoma and lung cancer. We have found that sensitivity in vitro and in vivo to single agent CHK1 inhibitor is loss of the S phase cell cycle checkpoint response. This is through a number of mechanisms including the uncoupling of CHK1 activation with the destabilization of CDC25A. Loss of checkpoint by over-expressing components of the checkpoint or inhibition of Wee1, covert CHK1 inhibitor insensitive cells to se...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Oo, Z. Y., Stevenson, A., Lanagan, C., Spoerri, L., Larsen, J., Gabrielli, B. Tags: Replication Stress: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B32: CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, combined with DDR agents provides a novel approach to increasing therapeutic index
Topoisomerase I inhibitors are used as standard-of-care chemotherapy in many types of cancer but are associated with significant toxicities. There is potential to improve their efficacy further by combining with inhibitors of the DNA damage response, such as the poly ADP ribose polymerase (PARP) inhibitor olaparib. However, while preclinical data highlight the improved efficacy of this combination, subsequent clinical trials have struggled due to dose limiting myelotoxicity.CRLX101 is an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a potent topoisomerase I inhibitor. This agent is ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: O'Connor, L. O., Wang, A. T., Jones, D., Odedra, R., Spreadborough, M., Wilson, J., Smith, A., Cotton, P., Reens, J., Barnes, J., Sheridan, V., Tellez, A., Lau, A., Sadler, C., O'Connor, M. J., Eliasof, S. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A32: Exploring the interplay between nucleotide excision repair and DNA replicative stress
Ultraviolet (UV) light causes highly genotoxic DNA lesions that are removed by nucleotide excision repair (NER), and NER is critical for preventing UV-associated skin cancers. UV-induced DNA lesions block the progression of DNA polymerases, leading to replicative stress and genomic instability. Upon UV, the ataxia-telangectasia and rad3 related (ATR) kinase is rapidly activated, leading to cell-cycle arrest, inhibition of replication origin firing, and stabilization of blocked replication forks. Intriguingly, previous data indicated that reduced ATR activity causes profound NER defects specifically in S phase cells. Moreov...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Drobetsky, E., Belanger, F., Angers, J.-P., Fortier, E., Costantino, S., Wurtele, H. Tags: Replication Stress: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B31: Poly(ADP-ribose) Polymerase 1 as a novel target for alpha-particle therapy in high-risk neuroblastoma
Conclusion: 211At-MM4 is a small molecule PARP inhibitor functionalized with an alpha emitting radionuclide astatine-211 that can effectively deliver alpha-particles to the nucleus of cancer cells. The neuroblastoma cell lines evaluated showed differential sensitivities and in vitro results translated into in vivo models. Furthermore we have characterized a novel therapy for high-risk neuroblastoma and aim for future clinical translation.Citation Format: Mehran Makvandi, Catherine Hou, Kuiying Xu, Redmond-Craig Anderson, Samuel Ander-Effron, Robert H. Mach, John M. Maris, Daniel A. Pryma. Poly(ADP-ribose) Polymerase 1 as a...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Makvandi, M., Hou, C., Xu, K., Anderson, R.-C., Ander-Effron, S., Mach, R. H., Maris, J. M., Pryma, D. A. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B30: Talazoparib efficacy is enhanced by noncytotoxic doses of temozolomide-mediated DNA damage in prostate cancer cell lines
Conclusion: Talazoparib is cytotoxic to prostate cancer cells as a single agent in nonclinical cell based models. Herein, we demonstrate that combining noncytotoxic doses of TMZ with talazoparib improves efficacy in killing of LNCaP and 22RV1 cells. The increased efficacy corresponds with increased DNA-damage and increased trapped PARP-DNA complexes. Low, noncytotoxic doses of TMZ are shown to generate DNA damage sites in vitro and in treated LNCaP cells, providing a mechanistic basis for the combination effect of talazoparib and TMZ. Together, these nonclinical data provide scientific rationale for a clinical trial strate...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lindquist, J. N., Phan, V. T., Riquelme, E., Mukherjee, K., Farias, O., Gupta, A., Raja, M., Rai, R., Uppal, H., Protter, A. A. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A28: Mutational landscape of TP53 in localized prostate cancer
Conclusions: This is the first comprehensive interrogation of the mutational landscape of TP53 in localized prostate cancer. Our findings suggest that functional TP53 loss at both the copy number and transcription level accounts for a subset of non-indolent localized prostate cancer.Citation Format: Osman Mahamud, Melvin L.K Chua, Stephane Supiot, Emilie Lalonde, Alan Dal Pra, Alejandro Berlin, Michèle Orain, Valerie Picard, Helene Hovington, Alain Bergeron, Yves Fradet, Bernard Têtu, Gaetano Zafarana, Alice Meng, Julie Livingstone, Melania Pintilie, Michael Fraser, Theodorus van der Kwast, Paul C. Boutros, Br...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mahamud, O., Chua, M. L. K., Supiot, S., Lalonde, E., Pra, A. D., Berlin, A., Orain, M., Picard, V., Hovington, H., Bergeron, A., Fradet, Y., Tetu, B., Zafarana, G., Meng, A., Livingstone, J., Pintilie, M., Fraser, M., Kwast, T. v. d., Boutros, P. C., Rob Tags: DNA Repair Gene Mutations in Cancer Genomes: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA27: Exploiting the inhibition of cullin-RING-ligases in DSB repair as a therapeutic strategy
While single component E3 ubiquitin ligases have established roles in DNA double-strand break (DSB) repair, the function of multicomponent cullin-RING-ligases (CRL) in DSB repair is only beginning to emerge. FBXW7 is a substrate recognition component of Skp1-Cullin1-F-box E3 ubiquitin ligases previously known only to regulate the proteasomal degradation of substrates such as Cyclin E and MCL1. Given that FBXW7 loss promotes genomic instability, we hypothesized that FBXW7 may have a direct function in DSB repair. To establish the functions of FBXW7 in DSB repair, we first demonstrated the rapid localization of FBXW7 to DSB ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Morgan, M. Tags: Novel Approaches to Targeting DNA Repair: Oral Presentations - Invited Abstracts Source Type: research

Abstract B27: Co-inhibition of ATM and TDP1 as a novel chemosensitization strategy against malignant brain tumors
Conclusions: ATM and TDP1 co-inhibition represents an effective two-pronged approach to chemoradiosensitize CNS tumors. As TDP1 antagonizes Top1cc formation and efficacy of Top1 poisons such as the camptothecin (CPT) cohort of drugs, our findings will improve existing Top1-mediated anti-cancer strategies by enhancing tumor cell killing while reducing clinical doses and patient side-effects. Furthermore, these findings also suggest an alternative avenue in the clinical management of GBM.Citation Format: Matthew Packer, Ali Saleh, Sachin Katyal. Co-inhibition of ATM and TDP1 as a novel chemosensitization strategy against mal...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Packer, M., Saleh, A., Katyal, S. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A27: Assessing somatic tumor-associated RAD51 mutations and screening for novel dominant-interfering RAD51 proteins
The responsiveness of cancer cells to chemotherapy and targeted treatment, as well as the development of resistance, is determined by the state of DNA damage response pathways. Homology-directed repair (HDR) is crucial for error-free repair of DNA double-strand breaks that arise during replication stress or are induced by exogenous genotoxins. Therefore, HDR efficacy status in cancer cells could potentially be utilized as an indicator to predict tumor responsiveness to standard chemotherapies and to poly(ADP-ribose) polymerases (PARP) inhibitors. We are interested in understanding the influence of different levels of funct...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lim, P. X., Sutherland, J., Noonan, R., Dananberg, A., Holloman, W., Smogorzewska, A., Jasin, M. Tags: DNA Repair Gene Mutations in Cancer Genomes: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA26: Dual functions of PARP1 in prostate cancer: mechanisms and implications for therapeutic intervention
Prostatic adenocarcinoma (PCa) is the 2nd leading cause of cancer death in US men. Organ-confined PCa can be effectively managed, but there is no durable treatment for advanced disease. Advanced PCa is treated through androgen deprivation therapy, often coupled with direct AR antagonists, as PCa is exquisitely dependent on androgen receptor (AR) activity for survival. Furthermore, recent studies identified AR as a major effector of DNA repair, manifest through the ability of the receptor to regulate DNAPK expression and activity. While AR directed therapeutics effectively suppress the pro-proliferative, pro-survival, and p...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Knudsen, K. E. Tags: Novel Approaches to Targeting DNA Repair: Oral Presentations - Invited Abstracts Source Type: research

Abstract B26: Development of a proximity ligation assay for the detection of PARP-1 trapped to chromatin
Conclusion: The PLA trapping assay provides an improved methodology for evaluation of endogenous PARP-1 complexes bound to chromatin and may have utility for clinical tissue specimens where detection of PARP-1 trapping may lead to insights regarding efficacy and tolerability of PARP inhibitors.Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.Citation Format: Todd Hopkins, Barrett Ainsworth, Vivek Abraham, David Maag, Eric Johnson, Julie Wilsb...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hopkins, T., Ainsworth, B., Abraham, V., Maag, D., Johnson, E., Wilsbacher, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A26: High frequency of Cytosine to Adenine mutations in neuroblastoma correlates with genomic aberrations in 8-Oxo-Guanine repair pathway
Conclusion: We identified a subset of neuroblastoma tumors with a high CtoA mutation frequency, which correlates with losses of glycosylases involved in the repair of CtoA mutations. 8-Oxo-Guanine levels are elevated in cell lines with loss of OGG1 or MUTYH, which can be rescued by overexpression of OGG1 or MUTYH respectively.Citation Format: Anne Hakkert, Marli E. Ebus, Rogier Versteeg, Caron N. Huib, Jan Koster, Jan J. Molenaar. High frequency of Cytosine to Adenine mutations in neuroblastoma correlates with genomic aberrations in 8-Oxo-Guanine repair pathway [abstract]. In: Proceedings of the AACR Special Conference on ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hakkert, A., Ebus, M. E., Versteeg, R., Huib, C. N., Koster, J., Molenaar, J. J. Tags: DNA Repair Gene Mutations in Cancer Genomes: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA25: Novel mechanisms of PARP-inhibitor resistance in tumors with defects in the Fanconi Anemia/BRCA pathway
Large-scale genomic studies have demonstrated that approximately 50% of high-grade serous ovarian cancers (HGSOCs) harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. HRR alterations have also been identified, albeit less frequently, in other human malignancies including triple negative breast, prostate, and pancreatic cancers. The most commonly altered HRR genes are BRCA1 and BRCA2 followed by other Fanconi Anemia (FA) genes (e.g. PALB2, FANCA, FANCI, FANCL, and FANCC), core RAD genes (e.g. RAD50, RAD51, RAD51C, and RAD54L) and DNA damage response genes involved in HRR, such a...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: D'Andrea, A. D. Tags: Novel Approaches to Targeting DNA Repair: Oral Presentations - Invited Abstracts Source Type: research

Abstract B25: "TargetDBR"--A DNA repair drug and target discovery collaboration: Exploiting synthetic lethal, high content, and functional cellular reporter assays to accelerate DNA repair targeted drug discovery
Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Inhibition of DSB repair sensitizes cells to these therapies. Mutations have been reported in nearly every DNA repair pathway and these pathways often exhibit redundancy. Inhibition of functional repair factors can induce synthetic lethality in repair-deficient tumors even in the absence of exogenous DNA damage and whilst sparing healthy tissue. We demonstrate a compound and target discovery platform comprising the integration...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hollick, J. J., Abriola, L., Bono, F., Hegan, D., Klingbeil, P., Liu, Y., Sundaram, R., Surovtseva, Y. V., Whittaker, M., Bindra, R. S., Glazer, P. M. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A25: Investigating the co-occurrence of potentially pathogenic DNA repair pathways alleles in BRCA1 or BRCA2 mutation carrier women with ovarian cancer.
Recurrent mutations in BRCA1 and BRCA2, which are genes that play a major role in the homologous recombination (HR) DNA repair pathway, account for a significant proportion of hereditary breast cancer (HBC) and or breast-ovarian cancer (HBOC) families of French Canadian (FC) descent due to common founders. This has facilitated genetic testing for establishing germline mutation carrier status in hereditary cancer clinics in Quebec for offering cancer surveillance and prevention options for women at risk for hereditary breast and other cancers. Recent evidence suggests that rare germline mutations in other members of HR path...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Alenezi, W. M., Revil, T., Badescu, D., Arcand, S. L., Rouleau, G., Ragoussis, I., Tonin, P. N. Tags: DNA Repair Gene Mutations in Cancer Genomes: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA24: Targeting Chk1
The majority of traditional anticancer drugs inhibit DNA synthesis either by directly damaging DNA or by inhibiting synthesis of deoxyribonucleotide precursors. DNA damage induces cell cycle arrest through activation of cell cycle checkpoints whose goal is to prevent further DNA synthesis or mitosis until the damage is repaired. These checkpoints have undergone intense investigation as potential therapeutic targets, and Chk1 inhibitors (Chk1i) have emerged as promising novel therapeutic agents (1). Chk1 was initially recognized as a regulator of the DNA damage-induced S and G2 checkpoints, and its inhibition forced S phase...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Eastman, A. R. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Invited Abstracts Source Type: research

Abstract B24: Genomic prediction of response to PARP inhibition in breast cancer
In conclusion, we identified a gene set involved with DNA repair, cell-cycle, and programmed cell death, which was associated with poor outcomes in triple-negative breast cancer patients that could potentially benefit from anti-PARP therapy.Citation Format: Saima Hassan, Amanda Esch, Laura M. Heiser, Joe W. Gray. Genomic prediction of response to PARP inhibition in 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 B24. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hassan, S., Esch, A., Heiser, L. M., Gray, J. W. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A24: A genome-wide RNAi screen identifies synthetic lethality of CX-5461 with homologous recombination repair deficiency in ovarian cancer
Cancer is characterized by deregulated cell growth and proliferation, both of which are associated with hyperactivation of ribosome biogenesis. Inhibition of ribosome biogenesis using CX-5461, a specific inhibitor of RNA polymerase I-dependent transcription, has shown therapeutic efficacy in a MYC driven B-cell lymphoma mouse model, which is enhanced when used in combination with the mTORC1 inhibitor Everolimus. However, the therapeutic potential of CX-5461 in solid cancers is yet to be determined.Our preliminary data utilizing a panel of 36 ovarian cancer (OVCA) cell lines suggest that acute CX-5461 treatment results in c...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Yan, S., Chan, K. T., Simpson, K. J., Sanij, E., Sheppard, K. E., Hannan, K. M., Hannan, R. D., Pearson, R. B. Tags: Synthetic Lethality and Viability: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA23: Using PARP inhibitors to target ATM-deficient cancers
The Ataxia-Telangiectasia Mutated (ATM) serine/threonine protein kinase plays an important role in orchestrating the cellular response to DNA double strand breaks (DSBs). Germline loss of ATM function results in Ataxia-Telangiectasia (A-T), a devastating childhood syndrome characterized by progressive loss of neuromuscular control, immune deficiency and cancer predisposition. ATM is also deleted in a large proportion of human mantle cell lymphoma (MCL) and other lymphomas and recent studies have revealed that ATM is altered in many sporadic cancers including lung, colorectal, breast and prostate cancer. We previously showe...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lees-Miller, S. P. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Invited Abstracts Source Type: research

Abstract A23: BRCA1 mutations in the BRCT domain can be removed through alternative splicing and induce PARP inhibitor resistance
Conclusions: Our findings indicate that alternative splicing can remove deleterious mutations that disrupt BRCT peptide folding, generating more truncated but functional proteins capable of restoring residual DNA repair and PARPi resistance.Citation Format: Yifan Wang, Andrea J. Bernhardy, Neil Johnson. BRCA1 mutations in the BRCT domain can be removed through alternative splicing and induce PARP inhibitor resistance [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...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Wang, Y., Bernhardy, A. J., Johnson, N. Tags: Synthetic Lethality and Viability: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA22: The role of ATM in tumor and endothelial cells in mediating the response of cancer to radiation therapy
Fibroblasts isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation and mice lacking the gene mutated in ataxia telangiectasia (ATM) are sensitive to total-body irradiation. Kinase inhibitors of ATM can sensitize tumor cells to radiation, but these inhibitors may also sensitize normal tissues to radiation toxicity. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but whether endothelial cell death plays an important role in tumor response to radiation therapy has remained unclear. To clarify the role of endothelial cells i...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Kirsch, D. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Invited Abstracts Source Type: research

Abstract PR21: DEK is critical for homologous recombination and its loss is synthetic lethal with DNA-PK inhibition
DEK is a highly conserved chromatin-bound protein whose upregulation across different cancer types directly correlates with genotoxic therapy resistance. While DEK loss induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair, the role of DEK remains incompletely understood. To this end we previously determined that loss of DEK moderately attenuates non-homologous end-joining repair (NHEJ). However, the observed partial decrease in NHEJ activity is likely insufficient to fully explain the sensitivity of DEK-deficient cells to radiation and chemotherapy. Thus, we h...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Smith, E. A., Gole, B., Willis, N. A., Eric, K. F., Jegga, A. G., Ali, A. M., Guo, H., Meetei, A. R., Andreassen, P. R., Kappes, F., Scully, R., Wiesmüller, L., Susanne, W. I. Tags: Homologous Recombination Defects: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA21: Targeting WEE1 kinase to potentiate chemoradiation in the treatment of pancreatic cancer
Pancreas cancer is projected to cause approximately 42,000 deaths in 2016, making it the third greatest cause of cancer mortality (behind lung and colorectal, but greater even than breast). Systemic failure remains the dominant cause of death, although local failure is responsible for up to 1/3 of the pancreatic cancer related mortality. We have focused on improving the treatment of locally advanced pancreatic cancer, defined as disease which cannot be resected but has not overtly metastasized, where the issue of local control becomes even more important, and have hypothesized that the treatment of locally advanced pancrea...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lawrence, T. S., Morgan, M. A. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Invited Abstracts Source Type: research

Abstract B21: The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma
Glioblastoma (GBM) represents one of the most aggressive cancer types with the vast majority of patients succumbing to disease within the first five years. This dire prognosis reflects the limited efficacy of our frontline therapies which include radiation therapy and temozolomide (TMZ) chemotherapy. The cellular response to these therapies is critically mediated by DNA damage response signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR). Preliminary studies from our laboratory suggest the ATR inhibitor VX-970 has single agent efficacy in both...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Burgenske, D., Mladek, A., Sarkaria, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A21: Enhancing chemotherapeutic responses in CNS malignancy through suppression of hyperactive DNA damage repair pathways
Introduction: We are targeting DNA repair pathways to enhance existing chemoradiotherapeutic strategies against medulloblastoma (MB) and malignant glioma (MG), two highly invasive tumors of the central nervous system (CNS). Current methods to treat childhood medulloblastoma are highly intrusive and lead to poor quality of life while the three-year survival rate of patients afflicted with malignant glioma remains abysmal (
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mostafizar, M., Katyal, S. Tags: Synthetic Lethality and Viability: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR20: A 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms
The tumor suppressor protein 53BP1 was first identified as a p53-interacting protein over two decades ago, however its direct contribution to p53-dependent cellular activities has remained enigmatic. Having reinvestigated the link between 53BP1 and p53, we now show 53BP1 plays an important role in directly stimulating genome-wide p53-dependent gene transactivation and repression events in response to ionizing radiation (IR) and synthetic p53 activation. We have also fine-mapped the domains in 53BP1 that modulate p53 activity and reveal it requires both auto-oligomerization and its tandem-BRCT domain-mediated bivalent inter...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Cuella-Martin, R., Oliveira, C., Lockstone, H. E., Snellenberg, S., Grolmusova, N., Chapman, J. R. Tags: DNA Damage Signaling: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA20: Phosphorylation of BRCA1 by CHK2 mediates resection activity and recruitment of BRCA2
There is genetic evidence that Chk2, BRCA1 and BRCA2 are functioning in the same pathway of DNA repair, but the links between the proteins are poorly understood. We have previously shown that BRCA1's regulation of homologous recombination (HR) is dependent on Chk2-mediated phosphorylation of BRCA1 at serine 988 (BRCA1-S988). We also found that BRCA1 regulates BRCA2 recruitment in response to DNA damage, which is also dependent on the phosphorylation of BRCA1 at Serine-988. Furthermore, in HCT116/Chk2-/- cells and in MCF7 cells with depleted Chk2, the same effects on HR and BRCA2 recruitment has been found as found in cells...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Powell, S. N. Tags: DNA Damage Signaling: Oral Presentations - Invited Abstracts Source Type: research

Abstract B20: Schedule-dependent activation of DNA helicases by Checkpoint Kinase 1 inhibition following dNTP depletion causes CDK2-independent replication catastrophe
DNA damaging agents are standard of care therapies for many cancers, but frequently produce poor outcomes in many patients. Using DNA damage checkpoint inhibitors to sensitize cancer cells to standard therapies is a rapidly emerging strategy. Understanding the mechanism behind sensitization will help clinicians develop rational combinations and schedules to improve cancer care. Additionally, understanding how defects in the DNA damage response affect treatment outcomes may help identify which patients will respond to treatment. We have previously demonstrated that inhibition of Checkpoint Kinase 1 (Chk1) with MK8776 sensit...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Warren, N. J., Eastman, A. R. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A20: Synthetic lethality induced by pharmacological inhibition of ATM and PARP1
DNA double-stranded breaks (DSBs) are highly deleterious and need to be repaired for maintaining genomic stability and viability. Cells resolve DSBs via non-homologous end-joining or homologous recombination repair (HRR). The simultaneous downregulation of both repair mechanisms induces synthetic lethality. Accordingly, PARP1 inhibitors (PARPi) are being used to target cancers with defective HRR such as cancers with BRCA1/2 mutations. Similar to BRCA1/2, ATM is involved in HRR; and ATM deficiency enhances sensitivity towards PARPi. But unlike BRCA1/2, ATM can be targeted using various small-molecule inhibitors (ATMi) in ca...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mak, J. P. Y., Poon, R. Y. C. Tags: Synthetic Lethality and Viability: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR19: Targeting DNA double-strand break repair to potentiate radio- and chemo-therapy of glioblastoma
Glioblastomas (GBMs) are lethal brain tumors which are treated with ionizing radiation (IR) in combination with the DNA alkylating agent temozolomide (TMZ). Unfortunately, not all GBMs respond to therapy, and most of them quickly acquire resistance to TMZ and recur. In order to better understand the molecular basis for therapy-driven TMZ resistance, mice bearing orthotopic GBM xenografts were subjected to protracted TMZ treatment, and cell lines were generated from the primary (untreated) and recurrent (TMZ-treated) tumors. We found that cell lines derived from recurrent tumors were more resistant to TMZ in vitro compared ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mukherjee, B., Alcazar, C. G. d., Todorova, P., Burma, S. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA19: PARP trapping and Schlafen 11
Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARP inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models. Resist...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Pommier, Y., Murai, J. Tags: DNA Damage Signaling: Oral Presentations - Invited Abstracts Source Type: research

Abstract B19: The ATR inhibitor, AZD6738, synergizes with other DNA damage response inhibitors and genotoxic drugs in pancreatic ductal adenocarcinoma cell lines: Opportunities for new therapeutic combinations
Mutations in oncogenes, tumor suppressor and DNA damage response (DDR) mediator genes drive or permit malignant transformation but also increase endogenous replication stress. The serine/threonine kinase ATR plays a critical role in safeguarding genome integrity from such replication stress and several studies have demonstrated the increased reliance of cancer cells on ATR function. We investigated the therapeutic opportunities for the ATR inhibitor, AZD6738, in combination with DNA damaging or DDR-targeted agents, in the context of pancreatic ductal adenocarcinoma (PDAC).We evaluated four DNA-damaging agents (gemcitabine,...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Wallez, Y., Koh, S.-B., Bhogadi, V. S. V., Lau, A., Richards, F. M., Jodrell, D. I. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR18: Somatic ERCC2 mutations, nucleotide excision repair (NER) function, and cisplatin response in muscle-invasive bladder cancer (MIBC)
ERCC2 is a core member of the nucleotide excision repair (NER) pathway, a highly conserved and remarkably versatile DNA repair pathway responsible for repairing intrastrand DNA adducts created by genotoxic agents such as UV irradiation and platinum-based chemotherapies. Recent large-scale genomic efforts have shown that somatic ERCC2 missense mutations are present in approximately 20% of all primary muscle-invasive bladder cancers (MIBC). We previously showed that ERCC2 mutations are associated with treatment response and overall survival in MIBC patients treated with cisplatin-based chemotherapy. Initial functional studie...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mouw, K., Lazaro, J.-B., Damish, A., Reznichenko, E., Frazier, Z., Liu, D., Kim, J., Polak, P., Garraway, L., Getz, G., Rosenberg, J., Allen, E. V., D'Andrea, A. Tags: DNA Repair Gene Mutations in Cancer Genomes: Oral Presentations - Proffered Abstracts Source Type: research

Abstract PR17: The transcriptional repressor Slug promotes the DNA damage response
The transcriptional repressor Slug/SNAI2 orchestrates epigenetic programs indispensable for tissue self-renewal and tumorigenesis. Although Slug-deficient animals are highly sensitive to lethal irradiation, the direct biological relationship between Slug and the DNA damage response remains largely unexplored. Here we report that Slug interacts with DNA repair proteins, including FANCI, BCCIP and PARP1, in a mass spectrometry screen for Slug binding partners. In response to double-strand breaks (DSBs) induced by irradiation, Slug-deficient cells exhibited a marked delay in the resolution of H2ax foci. Furthermore, we showed...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Zhou, W., Ouyang, J., Huber, K., Kuperwasser, C. Tags: DNA Damage Signaling: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA17: Non-canonical aspects of ATM and p53 signaling pathways
The ATM protein kinase and p53 protein are both central mediators of many aspects of DNA damage and cellular stress signaling. While there is a clear, direct relationship between ATM and p53, ATM has numerous substrates in addition to p53 and, conversely, p53 can be activated by selected stresses without ATM. We have identified novel aspects of stress response signaling independently involving either ATM or p53. Though ATM plays a central role in mediating cellular responses to DNA breakage, some of the clinical abnormalities in the cancer-prone disorder, Ataxia-telangiectasia (A-T), are difficult to attribute directly to ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Kastan, M. B., Scarbrough, P., Chen, J., Brown, A., Crutchley, J., Fleenor, D. Tags: DNA Damage Signaling: Oral Presentations - Invited Abstracts Source Type: research

Abstract B17: Development of novel, potent orally available Wee1 inhibitors with robust antitumor efficacy in vivo
In this study, we describe the development of novel and highly potent small molecule inhibitors of Wee1 emanating from 2 distinct chemical series (ADC730, ADC999). These inhibitors exhibit single digit nM IC50 values versus the enzyme and good selectivity profiles against the kinome. In cells, target engagement was demonstrated through the inhibition of both CDC2- and CDK2-dependent Wee1 phosphorylation. In line with the mechanism of action, gH2AX and apoptosis induction was also observed in a dose-dependent manner. Further profiling in panels of cell lines indicated strong anti-proliferative activity both in combination w...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Gavory, G., O'Dowd, C., Rozycka, E., Boyd, C., Gorges, B., McLean, E., Rountree, S., Sheperd, S., Burton, S., McFarland, M., Janssen, D., Treder, A., Wilkinson, A., Burkamp, F., Harrison, T. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR16: Normal and neoplastic tissues with partial Hus1 impairment show hypersensitivity to cisplatin in vivo
The DNA damage response (DDR) factor HUS1 is vital for proper functioning of the ATR checkpoint pathway. Following DNA damage, HUS1 forms a heterotrimeric complex with RAD9 and RAD1 and works with other checkpoint and scaffold proteins to activate ATR and CHK1 kinases. HUS1 also has separate functions that promote DNA repair. Due to its essential nature and diverse roles in genome maintenance, we hypothesized that HUS1 would be critical in the response of normal and neoplastic tissues to the DNA-damaging chemotherapeutic, cisplatin. Cisplatin is a widely used chemotherapeutic that damages DNA via platinated adducts, which ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Noe, T. E., Siderides, C. C., Gallastegui, A., Cheung, J. M., Abratte, T., Hume, K. R. Tags: DNA Damage Signaling: Oral Presentations - Proffered Abstracts Source Type: research

Abstract A16: Potent and selective ATR inhibitors for the treatment of homologous-recombination deficient and PARPi-resistant cancers
We report the generation of a novel class of highly potent and specific ATR inhibitors (ATRN series) that exhibit low nanomolar activity in cultured cells (IC50 = 2-8 nM) and do not detectably inhibit ATM, DNA-PK or mTOR (IC50> 10 µM). In side-by-side comparisons, both the potency and selectivity of the ATRN series is superior to previously reported ATR inhibitors (VE821, VE822, AZD20, AZD6738, ETP-46464). In addition, the ATRN series has sufficient bioavailability and stability for in vivo application. Our lead compound (ATRN-119) slows progression of human BRCA2-deficient PDAC (CAPAN1) and RAS oncogene-driven p5...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Butler, L. R., Ragland, R. L., Breslin, H. J., George, E., Gill, T., Scheiwer, M., Gordon, N., Knudsen, K., Simpkins, F., Gilad, O., Brown, E. J. Tags: Synthetic Lethality and Viability: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR15: Cas9/RNA-based forward genetic screenings in mouse embryonic stem cells uncovered the role of genes mediating resistance to ATR inhibitors
Mouse embryonic stem cells (mESCs) represent an excellent platform to study processes of developmental biology, model disease in vitro and in vivo or perform drug discoveries. In the last few years, the development of precise genome engineering tools based on the RNA-guided Cas9 nuclease from the type II prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system, has enabled efficient and easy to engineer targeted genome modifications in mammalian cells. Using this technology, we generated a highly controlled doxycycline-inducible Cas9 mESC line, which harbor one single copy of Ca...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Ruiz, S., Mayor-Ruiz, C., Lafarga, V., Murga, M., Vega, M., Ortega, S., Fernandez-Capetillo, O. Tags: Replication Stress: Oral Presentations - Proffered Abstracts Source Type: research