FLI-1 is a transcription factor of the ETS family that is involved inFLI-1 (Friend leukemia integration-i) is an ETS (E26 transformationspecific) transcription factor that plays an essential role in the megakaryocytic, granulocytic, and erythrocytic lineages and in endothelial cell development (1-4). FLI-1 shares, with other ETS family members, a conserved ETS domain responsible for nuclear targeting and specific binding to DNA elements containing a consensus GGA(A/T) core (ETS-binding site (EBS) 4 ) (for review, see Ref. 5). FLI-1 also possesses a pointed/SAM domain embedded in its major N-terminal activation domain and a C-terminal domain that also contributes to its transcriptional activation properties (for review, see Ref. 5). Consistent with its biochemical and biological functions, a number of genes specific to the megakaryocytic, granulocytic, and erythrocytic lineages have been found to be down-regulated in FLI-1-deficient bone marrow cells, with a subset of these genes being direct transcriptional targets of FLI-1 (Refs. 1, 3, and 4, and references therein). Remarkably, lineage-restricted expression of many megakaryocyte-specific genes relies on the cooperation between FLI-1 and GATA-1 on composite DNA elements present in their promoter/enhancer sequences (Ref. 6 and references therein). Depending on the cell and promoter contexts, FLI-1 can also repress EBS-driven transcription through ill characterized mechanisms (7,8). Finally, FLI-1 can interact in trans with other transcriptional regulators, including nuclear hormone receptors and erythroid-specific Krüppel-like factor, thereby modifying transcriptional output in pathways involving these factors (9, 10).Fli-1 was originally identified as a common proviral integration site in erythroleukemia induced in newborn mice by the Friend murine leukemia virus component of the Friend virus complex (for review, see Ref. 5). Consistent with its central role in Friend murine leukemia virus-induced erythroleukemia, enforced expression of FLI-1 in primary erythroblasts and erythroleukemic cell lines has been shown to strongly interfere with the normal, erythropoietin-induced differentiation of these cells (8, 11), an activity that requires its EBS-dependent transcriptional activation properties (12, 13). Other studies show that FLI-1 might also contribute to the transformed phenotype through interference with the expression of genes important to erythroblast differentiation (8,10,14). FLI-1 is rearranged in Ewing sarcoma (a childhood pediatric tumor of neuroectodermal origin) as a result of a t(11;22)(q24; q12) chromosomal translocation that fuses the 5Ј-end of the EWS gene to the 3Ј-end of FLI-1 and the expression of a chimeric EWS-FLI-1 protein endowed with abnormal transcriptional regulatory properties and transforming activity (for review, see Ref. 15).PIAS1 (protein inhibitor of activated STAT proteins) and PIAS3 have been identified as inhibitors of the cytokine receptor/JAK (Janus kinase)-induced activation of STAT1-and STAT3-DNA binding, respectively. In ...
1087 Background: OlympiAD (NCT02000622) demonstrated the benefit of olaparib over standard of care in patients (pts) with HER2-negative (HER2-) metastatic breast cancer (MBC) and germline BRCA mutations (gBRCAm). LUCY (NCT03286842) aimed to provide additional data on the real-world effectiveness and safety of olaparib monotherapy in this setting. Methods: This Phase IIIb, open-label, single-arm study of olaparib 300 mg twice-daily, enrolled pts with HER2- gBRCAm MBC who had received a taxane and/or anthracycline in the (neo)adjuvant/metastatic setting, and ≤2 lines of chemotherapy for MBC. Hormone receptor-positive (HR+) pts had progressed on prior endocrine therapy (ET), and further ET was considered unsuitable. Primary endpoint: investigator-defined progression-free survival (PFS). Secondary endpoints: overall survival, time to first subsequent therapy or death (TFST), and investigator-assessed clinical response rate (CRR). The interim analysis was planned after 160 PFS events. Results: From Oct 2018-Sept 2019, 252 pts were enrolled (160 sites, 15 countries; mean age 46.2 [range 22-75] years; 73.4% ECOG PS 0). Median total treatment duration: 7.9 months (mo; range 0.2-20.0). Median PFS: 8.1 mo (95% confidence interval [CI] 6.9, 8.7; 166 events [65.9%]). Clinical trial information: NCT03286842 . Median TFST: 9.7 mo (95% CI 8.7, 11.1). CRR: 48.6% (95% CI 42.2, 55.0). Adverse events (AEs) in >20% of pts (all grades): nausea, anemia, asthenia, vomiting, and fatigue. 24.6% of pts reported a grade ≥3 AE, including anemia (n=33 [13.1%]). 4.4% of pts had an AE leading to treatment discontinuation. Conclusions: Interim results in this real-world population of pts with HER2- gBRCAm MBC were consistent with the OlympiAD study, and support olaparib as a chemotherapy-free alternative treatment for pts with gBRCAm advanced BC. [Table: see text]
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