Dysregulated GPCR Signaling and Therapeutic Options in Uveal Melanoma
Uveal melanoma is the most common primary intraocular malignant tumor in adults and arises from the transformation of melanocytes in the uveal tract. Even after treatment of the primary tumor, up to 50% of patients succumb to metastatic disease. The liver is the predominant organ of metastasis. There is an important need to provide effective treatment options for advanced stage uveal melanoma. To provide the preclinical basis for new treatments, it is important to understand the molecular underpinnings of the disease. Recent genomic studies have shown that mutations within components of G protein–coupled receptor (GP...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Chua, V., Lapadula, D., Randolph, C., Benovic, J. L., Wedegaertner, P. B., Aplin, A. E. Tags: Minireview Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
Abstract A46: Nup153 and Nup50 promote recruitment of 53BP1 to DNA repair foci by antagonizing BRCA1-dependent events
This study focuses on an unexpected role for particular nuclear pore proteins in the antagonism between the DNA repair factors BRCA1 and 53BP1, and the impact this has on the response to poly(A) ribose polymerase (PARP) inhibition. Repair of DNA double strand breaks, a cornerstone of genomic integrity, typically follows one of two distinct pathways: the high fidelity process of homologous recombination (HR) repair, in which BRCA1 plays a key role, and the more error-prone process of non-homologous end joining (NHEJ), which relies on 53BP1. The balance between NHEJ and HR depends, in part, on whether 53BP1 predominates in b...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mackay, D. R., Ullman, K. S. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B45: A genome-scale screen identifies the microcephaly gene, ZNF335, as a regulator of DNA end resection
We examined the recruitment of known resection factors to DSB sites and determined that the localization of CtIP and BLM were impaired in cells depleted of ZNF335. Our data suggests that ZNF335 plays an important role in promoting resection and ATR activation in response to DSBs.Citation Format: Jordan Young, Mikhail Bashkurov, Andrea McEwan, Thomas Sun, Alessandro Datti, Daniel Durocher. A genome-scale screen identifies the microcephaly gene, ZNF335, as a regulator of DNA end resection [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montre...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Young, J., Bashkurov, M., McEwan, A., Sun, T., Datti, A., Durocher, D. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B44: Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer
Conclusion: Due to ERK-dependent reactivation of Akt in K-RAS mutated NSCLC cells, dual targeting of PI3K and MEK is an effective approach to induce radiosensitization.Acknowledgement: This work was supported by grants from the Deutsche Forschungsge-meinschaft (DFG, RO 527/7-1) awarded to HPR /MT and GRK 1302/2 (T11) awarded to MT/HPR.Citation Format: Mahmoud Toulany, Mari Ilda, Deric L. Wheeler, H. Peter Rodemann. Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Confe...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Toulany, M., Ilda, M., Wheeler, D. L., Rodemann, H. P. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A44: The identification of germline mutations in DNA repair genes in Brazilian individuals at-risk for hereditary breast cancer
Hereditary breast cancer corresponds to 10-15% of all diagnosed cases of breast cancer in the world. The majority germline mutations are identified in BRCA1/2 genes, however the application of multigene panels has increased the number of pathogenic variations detected in DNA repair genes. According to the current version of NCCN Guideline, mutations in BRCA1/2, TP53 and PTEN confers high risk to develop breast cancer, and mutations in CDH1, CHEK2, PALB2, ATM and BRIP can increases over than 20% this risk. We analyzed 157 individuals from Northeastern region of Brazil with personal and/or familial breast cancer history. Gen...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Timoteo, A. R. d. S., Souza, J. E. S. d., Lajus, T. B. P. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B43: RECQ1, a breast cancer susceptibility gene, is upregulated by cancer therapeutics in a p53-dependent manner
Sensitivity of cancer cells to DNA-damaging chemotherapeutics is determined by DNA repair processes. Consequently, cancer cells may upregulate expression of certain DNA repair genes as a mechanism to promote chemoresistance. Here, we report identification of RECQ1, a breast cancer susceptibility gene that encodes the most abundant RecQ helicase in humans, as a p53-regulated target potentially acting as a defense against DNA-damaging agents. Quantitative RT-PCR analysis in a variety of cancer cell lines revealed RECQ1 to be upregulated following DNA damage, which was confirmed by Western blot experiments. Significant increa...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lu, X., Parvathaneni, S., Sharma, S. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A43: TFG-TEC oncogene modulates beta-enolase expression via both promoter activation and epigenetic modification
Recurrent chromosome translocations are the hallmark of many human cancers. A proportion of human extraskeletal myxoid chondrosarcomas (EMCs) are associated with the characteristic chromosomal translocation t(3;9)(q11-12;q22), which results in the formation of a chimeric protein in which the N-terminal domain of the TRK-fused gene (TFG) is fused to the translocated in extraskeletal chondrosarcoma (TEC; also called CHN, CSMF, MINOR, NOR1, and NR4A3) gene. The oncogenic effect of this translocation may be due to the higher transactivation ability of the TFG-TEC chimeric protein; however, downstream target genes of TFG-TEC ha...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Kim, A.-y., Lim, B., Choi, J., Kim, J. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A42: Identification of glutamate and aspartate ADP-ribosylation sites onto histones by mass mass spectrometry
Chromatin structure and function is regulated by histone post-translational modifications. Histone proteins are subject to a variety of post-translational modifications that can work combinatorially to alter the transcriptional state or the repair of DNA damage. The landscape of histone modifications includes mono- and poly(ADP-ribosylation), which can directly alter nucleosome structure and DNA accessibility. ADP-ribosylation occuring on glutamate and aspartate residues was the most intensively studied histone ADP-ribosylation modification in the past, primarily because these carboxylester-type ADP-ribose–protein bo...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Gagne, J.-P., Roux-Dalvai, F., Defoy, D., Droit, A., Michael, H. J., Poirier, G. G. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B41: REV7 is a possible prognostic predictor and a potential therapeutic target in human malignancy
Human REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene transcription and carcinogenesis, and is a key protein in translesion DNA synthesis. Here, we present our study to evaluate the significance of REV7 expression in human malignancy and its possibility to be a molecular target for cancer therapy. REV7 expression was assessed in epithelial ovarian cancer (EOC) and diffuse large B-cell lymphoma (DLBCL) by immunohistochemical staining. REV7 expression was detected in the majority of EOCs (92.0%) with especially high levels of expression frequently observed in ovarian clear cell ca...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Murakumo, Y., Niimi, K., Okina, S. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research
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 Res 2017;15(4_Suppl...
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
