A phase Ib study of sapacitabine and olaparib in patients with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer
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PROVIDER: PRJNA1276162 | ENA |
REPOSITORIES: ENA
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Project description:A phase Ib study of sapacitabine and olaparib in patients with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer
| PRJNA1276163 | ENA
Project description:BRCA1 pathogenic variant may have the negative impact on ovarian function. Poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitor, olaparib exploit the principle of synthetic lethality to selectively kill the cells that have a deficiency in homologous recombination repair. To evaluate the effect to olaparib on ovaries, we performed the study of subcutaneous olaparib injections for 2 weeks in wild-type and BRCA1+/- rats. We compared the microarray gene expression profiles of rat ovary tissues from the study.
2025-02-15 | GSE249187 | GEO
Project description:Purpose: As estrogen receptor (ER)-positive breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER negative BRCA1 mutated breast cancer, it has been suggested that these tumors are ?sporadic? and not BRCA1-driven. With the introduction of targeted treatments specific for tumors with a non-functioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor, is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER+ tumors. Experimental design: Genomic profiling, BRCA1 promoter methylation assessment, and loss of heterozygosity analysis were done on 16 BRCA1-mutated ER+ tumors. Results were compared with 57 BRCA1-mutated ER- tumors, 36 BRCA2-mutated ER+ associated tumors, and 182 sporadic ER+ tumors [GSE9021, GSE9114, GSE16511, GSE50407] Results: The genomic profile of BRCA1-mutated ER+ tumors was different from BRCA1-mutated ER- breast tumors, but highly similar to BRCA2-mutated ER+ tumors. In 83% of the BRCA1-mutated ER+ tumors, loss of the wildtype BRCA1 allele was observed. In addition, clinico-pathological variables in BRCA1-mutated ER+ cancer were also more similar to BRCA2-mutated ER+ and sporadic ER+ breast cancer than to BRCA1 mutated ER- cancers. Conclusions: As BRCA1-mutated ER+ tumors show a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in BRCA1-mutated ER+ tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the BRCA1 gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER-positive breast cancer.
2016-10-01 | GSE77603 | GEO
Project description:Purpose: As estrogen receptor (ER)-positive breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER negative BRCA1 mutated breast cancer, it has been suggested that these tumors are ?sporadic? and not BRCA1-driven. With the introduction of targeted treatments specific for tumors with a non-functioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor, is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER+ tumors. Experimental design: Genomic profiling, BRCA1 promoter methylation assessment, and loss of heterozygosity analysis were done on 16 BRCA1-mutated ER+ tumors. Results were compared with 57 BRCA1-mutated ER- tumors, 36 BRCA2-mutated ER+ associated tumors, and 182 sporadic ER+ tumors [GSE9021, GSE9114, GSE16511, GSE50407]. Results: The genomic profile of BRCA1-mutated ER+ tumors was different from BRCA1-mutated ER- breast tumors, but highly similar to BRCA2-mutated ER+ tumors. In 83% of the BRCA1-mutated ER+ tumors, loss of the wildtype BRCA1 allele was observed. In addition, clinico-pathological variables in BRCA1-mutated ER+ cancer were also more similar to BRCA2-mutated ER+ and sporadic ER+ breast cancer than to BRCA1 mutated ER- cancers. Conclusions: As BRCA1-mutated ER+ tumors show a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in BRCA1-mutated ER+ tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the BRCA1 gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER-positive breast cancer.
2016-10-01 | GSE77604 | GEO
Project description:PARP inhibitor and platinum based drugs such as cisplatin are promising therapies for triple negative breast cancer and exploit the deficiencies in BRCA1 or BRCA2, or homologous recombination repair defects. However, PARP inhibitor resistance is proven to be a major clinical problem. Acquired PARP inhibitor resistance has been linked with co-resistance to platinum-based drugs. To determine how acquired olaparib resistance affects cisplatin response and whether this is influenced by their BRCA1 status, we performed RNAseq transcriptome analysis of isogenic triple negative breast cancer models of olaparib resistance with normal and mutant BRCA1.
2021-07-22 | GSE165914 | GEO
Project description:Despite numerous therapeutic advances over the years, ovarian cancer, especially high grade serous ovarian carcinoma remains the deadliest gynecological malignancy. Although PARP inhibition has been shown to be an effective (maintenance) therapy for homologous recombination repair deficient or BRCA1 mutated ovarian cancer, there may be further potential for combination therapy with other drugs such as immune checkpoint inhibitors. BRCA1 mutation as well as PARP inhibitor (Olaparib) treatment influenced the activation of immune response pathways such as cGAS-STING signaling and Interferon-alpha response in ovarian cancer cell lines. Bioinformatics functional analyses uncovered further immune related cellular responses and signaling pathways such as JAK-STAT signaling.
2023-08-01 | GSE237361 | GEO
Project description:Sequencing of olaparib-resistant PEO1 derivatives (C4, C5, C10 and C18) and parental PEO1 (P1 and P2) cells was performed in order to determine mechanisms of acquired resistance in the resistant cell lines. PEO1 parental cell lines were authenticated prior to sequencing. PEO1 parental were confirmed to be BRCA2-mutated (5139C>G). Olaparib PEO1 resistant cells were generated through a step-wise escalation of olaparib (10nM to 8uM olaparib). In olaparib resistant lines an increase canonical Wnt signaling and loss of of non-canonical Wnt signaling was observed.
2018-07-28 | GSE117765 | GEO
Project description:To examine the immune responses that occur in Brca1-deficent tumors upon olaparib treatment, we performed gene expression analysis of a panel of 4604 cancer and immune-related genes in tumor tissues harvested from Brca1-deficient ovarian tumor-bearing mice after treatment with olaparib or vehicle. Transcriptome analysis showed that the expression of genes associated with immune response, T-cell activation and interferon-gamma(IFNgamma) response were markedly upregulated in tumors treated with olaparib as compared to vehicle. Our data reveal the antitumor immune response of PARP inhibition and demonstrate that it contributes to therapeutic efficacy of PARP inhibition in Brca1-deficient tumors.
2019-02-13 | GSE120500 | GEO
Project description:While new defects in BRCA1 are still being found, it is unclear whether current breast cancer diagnostics misses many BRCA1-associated cases. A reliable test that is able to indicate the involvement of BRCA1 deficiency in cancer genesis could support decision making in genetic counselling and clinical management. To find BRCA1-specific markers and explore the effectiveness of the current diagnostic strategy, we designed a classification method, validated it and examined whether we could find BRCA1-like breast tumours in a group of patients initially diagnosed as non-BRCA1/2 mutation carriers. A classifier was built based on array-CGH profiles of 18 BRCA1-related and 32 control breast tumours, and validated on independent sets of 16 BRCA1-related and 16 control breast carcinomas. Subsequently, we applied the classifier to 48 breast tumours of patients from Hereditary Breast and Ovarian Cancer (HBOC) families in whom no germ line BRCA1/BRCA2 mutations were identified. The classifier showed an accuracy of 91% when applied to the validation sets. In 48 non-BRCA1/2 patients, only two breast tumours presented a BRCA1-like CGH profile. Additional evidence for BRCA1 dysfunction was found in one of these tumours. We here describe the specific chromosomal aberrations in BRCA1-related breast carcinomas. We developed a predictive genetic test for BRCA1-association and show that BRCA1-related tumours can still be identified in HBOC families after routine DNA diagnostics.
2010-12-02 | GSE9021 | GEO