Targeting Aberrant Replication and DNA Repair Events for Treating Breast Cancers
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE161911 | GEO | 2022/06/01
REPOSITORIES: GEO
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Project description:The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.
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Project description:Targeting Aberrant Replication and DNA Repair Events for Treating Breast Cancers
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Project description:Amplification and expression of the MYC oncogene in tumor cells, including ovarian cancer cells correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. We have discovered that ovarian cancer cells overexpressing glutaminase (GLS), a MYC target and a key enzyme in glutaminolysis, are intrinsically resistant to platinum chemotherapy, and are enriched in the intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh 10 cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. Our findings suggest that applying a combined therapy of GLS inhibitor and PARP inhibitor could effectively treat chemoresistant ovarian cancers, especially those with high GLS expression.
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Project description:BackgroundCancer is a broad group of genetic diseases which account for millions of deaths worldwide each year. Cancers are classified by various clinical, pathological and molecular methods, but even within a well-characterized disease, there is a significant inter-patient variability in survival, response to treatment, and other parameters. Especially in molecular level, tumours of the same category can appear significantly dissimilar due to complex combinations of genetic aberrations leading to a similar malignancy. We extended the current classification methods by studying tumour heterogeneity at pathway level.MethodsWe computed the rate of alterations in 1994 pathways and 2210 tumours consisting of eight different cancers. Using gene set enrichment analysis, each sample was computed a pathway aberration profile that reflected its molecular state. The profiles were analysed together to infer the characteristic aberration rates for each pathway within each cancer. Subgroups of tumours defined by similar pathway aberrations were identified using clustering analyses. The pathway aberration and gene expression profiles of the subgroups were consecutively compared across all eight cancer types to search for similar tumours crossing the standard classification.ResultsWe identified pathways and processes that were common to all cancers as well as traits that are unique to a cancer type or closely related cancers. Studying the gene expression patterns within the pathway context suggested potential alteration mechanisms. Clustering analysis revealed five clinically relevant subgroups of tumours in four cancers that exhibited significant differences in survival compared to others. The cross-cancer analysis of the subgroups resulted in the identification of tumours that shared potentially significant alterations.ConclusionsThis study represents the first effort to extend the molecular characterizations towards pathway level descriptions across the family of cancers. In addition to providing a proof-of-concept for single sample pathway aberration analysis in this context, we present a comprehensive pathway aberration dataset that can be used to study pathway aberration patterns within or across cancers. Significant similarities between subgroups of different cancers on pathway and gene expression levels provide interesting hypotheses for understanding variable drug response, or transferring treatments across diseases by identifying common druggable pathways or genes, for example.
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Project description:Bacillus licheniformis (B. licheniformis) is a microorganism with a wide range of probiotic properties and applications. Isolation and identification of novel strains is a major aspect of microbial research. Besides, the role of different carbon sources affects B. licheniformis in regulating micro-environment and the mechanisms need to be further investigated. In this study, we first isolated and identified a new strain of B. licheniformis from bovine rumen fluid. Microcrystalline cellulose (MC) and cellobiose (CB) as the certain carbon sources to treat strain. Further, a combination of transcriptome and proteome analyses was used to different carbon sources effects. The results showed that B. licheniformis ABC transporter proteins, antibiotic synthesis, flagellar assembly, cellulase-related pathways and proteins were significantly up-regulated in the MC treatment compared to the CB treatment, and lactate metabolism was inhibited. In addition, MC was used as a certain carbon source to improve bacterial inhibition of B. licheniformis, its own disease resistance and to regulate the rumen micro-environment. In conclusion, our research provides a potential new probiotic for feed research and a theoretical basis for investigating the mechanisms by which bacteria respond to different carbon sources.
2024-01-26 | PXD042310 | Pride
Project description:Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, ARID1A is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that ARID1A mutation creates a dependence on glutamine metabolism. SWI/SNF represses glutaminase I (GLS1) and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of ARID1A mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents a novel therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as ARID1A mutations.
2020-10-21 | MSV000086347 | MassIVE
Project description:BackgroundBreast cancer is a highly heterogeneous pathology, exhibiting a number of subtypes commonly associated with a poor outcome. Due to their high stability, microRNAs are often regarded as non-invasive cancer biomarkers, having an expression pattern specific for their 'cell of origin'.MethodTriple negative breast cancer (TNBC: ER-, PR-, Her-2-) and double positive breast cancer (DPBC: ER+, PR+, Her-2) miRNA expression patterns were obtained by analysis of the TCGA (The Cancer Genome Atlas) data, followed by PCR-array analysis on plasma samples from 20 TNBC patients, 14 DPBC patients and 11 controls.ResultsThree downregulated and nine upregulated miRNAs were obtained from the TNBC analysis. Five overexpressed miRNAs were identified in the DPBC group. Four of the dysregulated miRNAs (miR-10a, miR-125b, miR-210 and miR-489) were common for both groups. The cluster miR-17-92 (miR-17, miR-20a, miR-20b, and miR-93), along with miR-130, miR-22 and miR-29a/c, were found to differentiate between TNBC and DPBC. A panel of five transcripts (miR-10a, miR-125, miR-193b, miR-200b and miR-489) was validated in a new set of plasma samples. The overlapping of TCGA and plasma profiling data revealed miR-200b, miR-200c, miR-210 and miR-29c as common signature. MiR-200b was validated on additional normal and tumor tissue samples. The expression level of this transcript from the TCGA data was correlated with lung and bone metastatic genes.ConclusionThe miR-200b presents a great potential for the future advancements in the diagnostic/prognostic and therapeutic approach of TNBC, along with other coding or non-coding transcripts. However, this needs to be further integrated in a regulatory network that acts in conjunction with other markers that affect the patients' prognosis or response to therapy.
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