Global ETD Search
Search theses and dissertations gathered from participating repositories worldwide. Every result links back to the library that holds it. No account is needed.
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Showing 1 to 20 of 44 for “"Synthetic lethality"”.
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IDENTIFYING AND EXPLOITING SYNTHETIC LETHALITY FOR CANCER THERAPEUTICS
Synthetic Lethality (SL) is considered a promising approach for the development of personalized treatments. However, SL interactions in humans remain largely unknown and there is a need to discover more such pairs, especially those that are clinically actionable, and to develop tools that can …
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Mechanisms of Synthetic Lethality in Renal Cell Carcinoma
… of cells lacking functional pVHL. These reveal a synthetic lethal relationship between Core Binding Factor β (CBF-β) and pVHL. While CBF-β is critical for normal osteogenesis and haematopoiesis, little is known about its role in renal tissue. CBF-β classically stabilises the Runt related …
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Synthetic Lethality of Cdk Inhibition and Doxorubicin In Triple-Negative Breast Cancer Requires P53 Inactivation
… roscovitine prior to doxorubicin treatment is synthetic lethal explicitly in TNBC cells. Furthermore, this novel combination therapy is well tolerated and efficacious, significantly reducing tumor volume and increasing overall survival compared to single drug treatment arms in a pre-clinical …
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Utilizing the IN4MER CRISPR/CAS12A Multiplex Knockout Platform To Investigate Synthetic Lethality in the Human Genome
… to achieve in the clinic. The concept of synthetic lethality has gained traction as a promising opportunity to discover novel cancer-specific vulnerabilities and therapeutic targets. Unfortunately, initial technologies for combinatorial genetic perturbation in mammalian cells suffer from …
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Induction of Synthetic Lethality In Mutant Kras Cells For Non-Small Cell Lung Cancers Chemoprevention and Therapy
… of TRAIL and Smac mimetic induced the synthetic lethal reaction specifically in the mutant-KRAS cells but not in normal lung cells and wild-type <em>KRAS</em> lung cancer cells. Therefore, a synthetic lethal interaction among TRAIL, Smac mimetic and <em>KRAS</em> mutations could be used …
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DEFINING THE ROLE OF THE PCGF3-CONTAINING POLYCOMB REPRESSIVE COMPLEX 1 IN SYNOVIAL SARCOMA
… PCGF3, a key component of PRC1.3, as a robust synthetic lethality hit specific to SS. Employing cutting-edge techniques like CRISPR/Cas9 and the dTAG system, I meticulously investigated the molecular mechanisms underpinning PCGF3's synthetic lethality, focusing on its strong catalytic activity. …
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Predicting Genetic Interactions Using Functional Interaction Networks
… the context of cancer. Among these interactions, synthetic lethality, where simultaneous loss of two genes is lethal but loss of either alone is tolerated, offers a powerful framework for selectively targeting tumor-specific dependencies. In model organisms like S. cerevisiae, comprehensive …
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Rational identification of a dual inhibitor of PARP-1 and ATM kinase
… PARP inhibitors are used to exploit the synthetic lethality between pharmacological inhibition of PARP (poly-ADP ribose polymerase) and BRCA (breast cancer gene) defects leading to successful patient treatment in ovarian, breast and prostate cancers. However, their use is limited to …
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Yeast Mutants That Require the GPI Biosynthetic Gene GPI1 for Growth
… of t-s smp3, gaa1, and gpi2 strains using a synthetic lethality screen demonstrates that this is a valid approach to identify genes involved in GPI anchor biosynthesis. This suggests that many of the remaining S.L. mutants are also likely to harbor mutations in GPI and cell wall assembly. …
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Sexual Reproduction and Signal Transduction in the Candida Species Complex
… in <em>S. cerevisiae</em> had demonstrated a synthetic lethality between hom6 and fpr1, the gene encoding FKBP12 a prolyl-isomerase that is the binding target of the immunosuppressant FK506. Thiss synthetic lethality was due to the buildup of a toxic intermediate in the methionine and …
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Expanding cancer therapy options through genome-scale identification of synthetic lethal paralogs
Synthetic lethal therapies have the potential to expand cancer treatment options. Synthetic lethality is a form of context-dependent gene essentiality in which dual inactivation of a gene pair leads to cell death but single-gene inactivation does not affect viability. When one synthetic lethal gene …
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Machine Learning Methods for Learning Genetic Dependencies
Synthetic lethality refers to a genetic interaction where the simultaneous perturbation of gene pairs leads to cell death. Synthetically lethal gene pairs (SL pairs) provide a potential avenue for selectively targeting cancer cells based on genetic vulnerabilities. The rise of large-scale gene …
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Targeting tGLI1-positive Breast Cancer with Ketoconazole
… make tGLI1 an ideal therapeutic target. Using a synthetic lethality chemical screen approach, we found that ketoconazole, an FDA-approved azole antifungal, was able to kill tGLI1-expressing cancer cells with increased efficacy against the CSC subpopulation. Additionally, ketoconazole selectively …
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MODELING COHESIN-DEPENDENT ONCOGENESIS IN VITRO AND IN VIVO: POSSIBLE AMELIORATIVE EFFECTS OF PARP INHIBITION
… that their combined impairment might cause synthetic lethality, highlighting a new tumor vulnerability.
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Incomplete paralog compensation and splicing regulation by TRA2A and TRA2B in cancer
… also creates therapeutic opportunities through synthetic lethality, where co-disruption of both paralogs results in cell death. This dissertation explores the functional relationship between the splicing factor paralogs TRA2A and TRA2B, members of the serine/arginine-rich (SR) protein family. In …
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Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening
… The aim of this project is to identify novel synthetic lethal interactions within melanoma. Synthetic lethality describes a relationship between two genes, where loss of either of the pair is compatible with cellular viability, but simultaneous loss of both genes induces cell death. This …
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Selection of a Non-Phosphorylated Peptide Inhibitor of BRCA1’s (BRCT)2 Domain
… Inhibitors of BRCA1 would take advantage of this synthetic lethality and represent a significant advance in cancer treatment as well as an understanding of the biology of DNA repair. Despite significant study of BRCA1 protein and function, it is a large protein (220 KDa) that is still largely …
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Novel Functions of Cetuximab In Egfr-Targeted Therapy: Radiosensitization, Glycolysis Inhibition, and Cellular Redox Status Regulation
… with cetuximab, leads to a synergetic and synthetic lethality in cancer cells, which bypasses most currently known cetuximab resistant mechanisms. In summary, our findings provide novel mechanistic insights into cetuximab-mediated EGFR targeted therapy and suggest novel therapeutic …
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Consequences of telomerase inhibition and telomere dysfunction in BRCA1 mutant cancer cells
… with DNA-damaging drugs, suggesting potential synthetic lethality of the BRCA1 cancer subtype and telomerase inhibition In a related study to examine the roles of BRCA1/2 in telomere maintenance, DNA and RNA extracted from peripheral blood were used to investigate the age-adjusted telomere …
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Investigating the role of protein ubiquitylation in the maintenance of genome stability
… of a key hallmark of HR-deficient cells, namely synthetic lethality with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, as a means of screening for new HR factors. In this manner, I identify the E2 ubiquitin conjugating enzyme UBE2S as a novel factor required for olaparib resistance, …
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