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Synthetic lethality

Bijan S Kheirabadi, Nahir Miranda, Irasema B Terrazas, Mary D Gonzales, Rose C Grimm, Michael A Dubick
INTRODUCTION: Prehospital, small-volume resuscitation of combat casualties with a synthetic colloid [6% hydroxyethyl starch (HES) 670/0.75] has been recommended when blood or blood components are unavailable. We studied hemostatic effects of a newer synthetic colloid (6% HES 130/0.4,) compared to either a natural colloid (albumin) or to crystalloids in an uncontrolled hemorrhage model. METHODS: Spontaneously breathing NZW rabbits (3.4±0.1 kg) were anesthetized, instrumented and subjected to a splenic injury with uncontrolled bleeding...
October 25, 2016: Journal of Trauma and Acute Care Surgery
Dai Horiuchi, Roman Camarda, Alicia Y Zhou, Christina Yau, Olga Momcilovic, Sanjeev Balakrishnan, Alexandra N Corella, Henok Eyob, Kai Kessenbrock, Devon A Lawson, Lindsey A Marsh, Brittany N Anderton, Julia Rohrberg, Ratika Kunder, Alexey V Bazarov, Paul Yaswen, Michael T McManus, Hope S Rugo, Zena Werb, Andrei Goga
Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors...
October 24, 2016: Nature Medicine
Yan Long, Wen-Bin Tsai, Jeffrey T Chang, Marcos Estecio, Medhi Wangpaichitr, Naramol Savaraj, Lynn G Feun, Helen H W Chen, Macus Tien Kuo
Many human tumors require extracellular arginine (Arg) for growth because the key enzyme for de novo biosynthesis of Arg, argininosuccinate synthetase 1 (ASS1), is silenced. These tumors are sensitive to Arg-starvation therapy using pegylated arginine deiminase (ADI-PEG20) which digests extracellular Arg. Many previous studies reported that ASS1 silencing is due to epigenetic inactivation of ASS1 expression by DNA methylation, and that the demethylation agent 5-aza-deoxycytidine (Aza-dC) can induce ASS1 expression...
September 28, 2016: Oncotarget
Songjia Lu, Chunhui Cai, Gonghong Yan, Zhuan Zhou, Yong Wan, Vicky Chen, Lujia Chen, Gregory F Cooper, Lina M Obeid, Yusuf A Hannun, Adrian V Lee, Xinghua Lu
Defining processes that are synthetic lethal with p53 mutations in cancer cells may reveal possible therapeutic strategies. In this study, we report the development of a signal-oriented computational framework for cancer pathway discovery in this context. We applied our bipartite-graph-based functional module discovery algorithm to identify transcriptomic modules abnormally expressed in multiple tumors, such that the genes in a module were likely regulated by a common, perturbed signal. For each transcriptomic module, we applied our weighted k-path merge algorithm to search for a set of somatic genome alterations (SGA) that likely perturbed the signal, i...
October 10, 2016: Cancer Research
Elena Castro, Joaquin Mateo, David Olmos, Johann S de Bono
Several genomic studies have identified DNA repair gene defects in prostate cancer in the last 5 years. The mechanisms by which these DNA repair defects promote carcinogenesis and tumor progression in the prostate have not been fully elucidated, but their presence in at least 20-25% of metastatic castration-resistant prostate cancers (CRPCs) provides an opportunity for a therapeutic strategy that turns a tumor strength into its weakness and may lead to arguably the first molecularly stratified treatment for this disease...
September 2016: Cancer Journal
Robert C A M van Waardenburg
Tyrosyl-DNA phosphodiesterase I (TDP1), like most DNA repair associated proteins, is not essential for cell viability. However, dysfunctioning TDP1 or ATM (ataxia telangiectasia mutated) results in autosomal recessive neuropathology with similar phenotypes, including cerebellar atrophy. Dual inactivation of TDP1 and ATM causes synthetic lethality. A TDP1H(493)R catalytic mutant is associated with spinocerebellar ataxia with axonal neuropathy (SCAN1), and stabilizes the TDP1 catalytic obligatory enzyme-DNA covalent complex...
2016: Journal of Neurology & Neuromedicine
Jimmy Hwang
Esophagogastric cancers (EGCa) are a leading cause of cancer related mortality worldwide. It has been recognized that they represent heterogenous diseases based on histology and anatomy. However, it is also increasingly evident that these are diverse malignancies based on genetic alterations, and this is increasingly making these diseases amenable to targeted therapies. While epidermal growth factor receptor (EGFR) and mTOR inhibitors have failed to prove effective in the treatment of advanced EGCa, vascular endothelial growth factor (VEGF) inihibitor have now been demonstrated to improve survival, at least in the 2nd line setting of adenocarcinomas...
October 2016: Journal of Gastrointestinal Oncology
Eziuche A Ugbogu, Ke Wang, Lilian M Schweizer, Michael Schweizer
Two of the five unlinked genes theoretically capable of encoding 5-phosphoribosyl-1(α)-pyrophosphate (PRPP) synthetase (Prs) in Saccharomyces cerevisiae, PRS1 and PRS5, contain in-frame insertions which separate the cation- and PRPP-binding sites, diagnostic of Prs polypeptides. The impairment of cell wall integrity (CWI) mitogen-activated protein kinase (MAPK) cascade in strains lacking PRS1 and the synthetic lethality associated with loss of PRS1 and PRS5 imply that these insertions are not gratuitous. Co-immunoprecipitation revealed that Prs1 interacts with the CWI MAPK pathway, only when Slt2 has been phosphorylated by Mkk1/2...
October 15, 2016: FEMS Yeast Research
David T Hoang, Kenneth A Iczkowski, Deepak Kilari, William See, Marja T Nevalainen
Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways...
October 10, 2016: Oncotarget
G E Konecny, R S Kristeleit
Poly(ADP-ribose) polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including BRCA-mutated tumours, by exploiting synthetic lethality. PARP inhibitors are being evaluated in late-stage clinical trials of ovarian cancer (OC). Recently, olaparib was the first PARP inhibitor approved in the European Union and United States for the treatment of advanced BRCA-mutated OC. This paper reviews the role of BRCA mutations for tumorigenesis and PARP inhibitor sensitivity, and summarises the clinical development of PARP inhibitors for the treatment of patients diagnosed with OC...
October 13, 2016: British Journal of Cancer
Gregory R Bean, Jeff C Kremer, Bethany C Prudner, Aaron D Schenone, Juo-Chin Yao, Matthew B Schultze, David Y Chen, Munir R Tanas, Douglas R Adkins, John Bomalaski, Brian P Rubin, Loren S Michel, Brian A Van Tine
Sarcomas comprise a large heterogeneous group of mesenchymal cancers with limited therapeutic options. When treated with standard cytotoxic chemotherapies, many sarcomas fail to respond completely and rapidly become treatment resistant. A major problem in the investigation and treatment of sarcomas is the fact that no single gene mutation or alteration has been identified among the diverse histologic subtypes. We searched for therapeutically druggable targets that are common to a wide range of histologies and hence could provide alternatives to the conventional chemotherapy...
October 13, 2016: Cell Death & Disease
Andrew G Matveenko, Polina B Drozdova, Mikhail V Belousov, Svetlana E Moskalenko, Stanislav A Bondarev, Yury A Barbitoff, Anton A Nizhnikov, Galina A Zhouravleva
[PSI(+) ] is the prion form of the translation termination factor Sup35 (eRF3); [PSI(+) ] strains display nonsense suppression. Another prion-like element, [ISP(+) ], is linked to antisuppression in a specific background. Transcriptional regulator Sfp1 was shown to be responsible for [ISP(+) ] propagation. In this work, we identified SFP1 as a multicopy inducer of [PSI(+) ]-dependent lethality. Sfp1 is likely to up-regulate transcription of genes encoding release factors; however, its overproduction increases Sup35, but not Sup45 protein level...
October 12, 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Prabhakar Bastola, Lisa Neums, Frank J Schoenen, Jeremy Chien
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis...
September 28, 2016: Molecular Oncology
Peter Haahr, Saskia Hoffmann, Maxim A X Tollenaere, Teresa Ho, Luis Ignacio Toledo, Matthias Mann, Simon Bekker-Jensen, Markus Räschle, Niels Mailand
Activation of the ATR kinase following perturbations to DNA replication relies on a complex mechanism involving ATR recruitment to RPA-coated single-stranded DNA via its binding partner ATRIP and stimulation of ATR kinase activity by TopBP1. Here, we discovered an independent ATR activation pathway in vertebrates, mediated by the uncharacterized protein ETAA1 (Ewing's tumour-associated antigen 1). Human ETAA1 accumulates at DNA damage sites via dual RPA-binding motifs and promotes replication fork progression and integrity, ATR signalling and cell survival after genotoxic insults...
October 10, 2016: Nature Cell Biology
G Jeanne, D Purper-Ouakil, H Rigole, N Franc
AIM: There have been significant changes in adolescent consumption habits over the past fifteen years. New molecules have been synthesized, new devices created and a number of products have increased in popularity; and as a result clinicians sometimes lack information. We chose to focus on this population because of its vulnerability, as adolescents show low sensitivity to long-term outcomes of their actions and may be easily influenced by peers as regards experimentation of new drugs...
October 6, 2016: L'Encéphale
Delphine Albrecht, Johanna Ceschin, Jim Dompierre, Florian Gueniot, Benoît Pinson, Bertrand Daignan-Fornier
Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach aimed at targeting cancer cells directly. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-Amino-4-Imidazole CarboxAmide Ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of several histone-modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4 methylation), greatly enhanced AICAR inhibition on growth via combined-effects of both the drug and the mutations on G1 cyclins...
October 5, 2016: Genetics
Luís Adriano Anholeto, Patrícia Rosa de Oliveira, Rodney Alexandre Ferreira Rodrigues, Caroline Dos Santos Spindola, Marcelo Bahia Labruna, Marcos Aparecido Pizano, Karina Neoob de Carvaldo Castro, Maria Izabel Camargo-Mathias
The use of synthetic acaricides is currently the main method to control ticks. However, the indiscriminate use of these chemicals can lead to the selection of resistant individuals and in the accumulation of chemical residues in the environment, contaminating the soil and water streams, consequently affecting the flora, fauna, and the human beings as well. In this sense, the objective of this study was to investigate the acaricidal effect of crude ethanolic extract of Acmella oleracea (L.) R.K. Jansen aerials parts at different concentrations on fed males and semi-engorged females of A...
September 30, 2016: Ticks and Tick-borne Diseases
Małgorzata Czyż, Monika Toma, Anna Gajos-Michniewicz, Kinga Majchrzak, Grazyna Hoser, Janusz Szemraj, Margaret Nieborowska-Skorska, Phil Cheng, Daniel Gritsyuk, Mitchell Levesque, Reinhard Dummer, Tomasz Sliwinski, Tomasz Skorski
Cancer including melanoma may be ''addicted" to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes...
September 27, 2016: Oncotarget
Remco Nagel, Ekaterina A Semenova, Anton Berns
Historically, cancers have been treated with chemotherapeutics aimed to have profound effects on tumor cells with only limited effects on normal tissue. This approach was followed by the development of small-molecule inhibitors that can target oncogenic pathways critical for the survival of tumor cells. The clinical targeting of these so-called oncogene addictions, however, is in many instances hampered by the outgrowth of resistant clones. More recently, the proper functioning of non-mutated genes has been shown to enhance the survival of many cancers, a phenomenon called non-oncogene addiction...
October 4, 2016: EMBO Reports
Ying Zhou, Jason Dang, Kung-Yen Chang, Edwin Yau, Pedro Aza-Blanc, Jorge Moscat, Tariq M Rana
Global miRNA functional screens can offer a strategy to identify synthetic lethal interactions in cancer cells that might be exploited therapeutically. In this study, we applied this strategy to identify novel gene interactions in KRAS-mutant cancer cells. In this manner, we discovered miR-1298, a novel miRNA that inhibited the growth of KRAS-driven cells both in vitro and in vivo Using miR-TRAP affinity purification technology, we identified the tyrosine kinase FAK and the laminin subunit LAMB3 as functional targets of miR-1298...
October 1, 2016: Cancer Research
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