The hematopoietic transcription factor GATA-1 is essential for development of the erythroid and megakaryocytic lineages. Using the conserved zinc finger DNA-binding domain of GATA-1 in the yeast two-hybrid system, we have identified a novel, multitype zinc finger protein, Friend of GATA-1 (FOG), which binds GATA-1 but not a functionally inactive mutant lacking the amino (N) finger. FOG is coexpressed with GATA-1 during embryonic development and in erythroid and megakaryocytic cells. Furthermore, FOG and GATA-1 synergistically activate transcription from a hematopoietic-specific regulatory region and cooperate during both erythroid and megakaryocytic cell differentiation. These findings indicate that FOG acts as a cofactor for GATA-1 and provide a paradigm for the regulation of cell type-specific gene expression by GATA transcription factors.
Background gpNMB is an internalizable transmembrane protein overexpressed in ˜40% of TNBC, and associated with a worse prognosis. Preclinical data implicates gpNMB in tumor invasion and metastasis. GV is a novel ADC designed to deliver monomethyl auristatin E (MMAE) to gpNMB-overexpressing cells. Prior phase 1/2 studies suggested promising activity of GV in gpNMB-overexpressing TNBC. Methods In the METRIC trial (NCT#01997333), patients (pts) with mTNBC were randomized 2:1 to GV (1.88 mg/kg IV q21 days) or capecitabine (2,500 mg/m2 PO daily d1-14 q21 days) until disease progression or intolerance. Key eligibility criteria included: gpNMB over-expression (>25% tumor cells positive by central immunohistochemistry of archival tissue); estrogen and progesterone receptor expression <10% and HER2 negative; ECOG 0-1; prior taxane; prior anthracycline exposure (if indicated); <2 chemotherapy regimens for advanced BC. The primary endpoint was progression-free survival (PFS) per independent, blinded central review using RECIST 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), safety, and pharmacokinetics. The trial had 85% power to detect a PFS hazard ratio of 0.64 with two-sided α = 0.05. Results From Feb 2014 to Aug 2017, 327 women were randomized at 120 institutions to GV (n=218) or capecitabine (n=109). Pretreatment characteristics were well balanced between arms: median age of 55 years; 77% visceral disease; 2.4 years median duration of disease at study entry; 1 median prior anticancer regimen for metastatic disease. At the cut-off for final data analysis (Nov 30, 2017), 21 pts remained on treatment and 98 pts were alive. For GV vs. capecitabine based on independent central review, median PFS was 2.9 (95% CI: 2.8, 3.5) vs. 2.8 (95% CI: 1.6, 3.2) months (HR=0.95; p=0.76); median OS was 8.9 (95% CI: 7.9, 10.5) vs. 8.7 (95% CI: 6.9, 10.8) months (HR=1.06; p=0.73); ORR was 16% (95% CI: 11.1, 22.4) vs. 15% (95% CI: 8.6, 23.5); and median DOR was 5.6 (95% CI: 3.0, 7.8) vs. 4.2 (95% CI: 3.0, 12.2) months. A post-hoc subgroup analysis suggested the greatest benefit from GV was in potentially taxane-sensitive disease (i.e., not previously rechallenged or >6 months progression-free interval following last taxane). The incidence of grade ≥ 3 treatment-related adverse events (TRAEs) was 58% in the GV arm and 37% in the capecitabine arm. The most common grade ≥ 3 TRAEs were neutropenia (27%), rash (15%), and leukopenia (9%) in the GV arm, and diarrhea (14%) and palmar-plantar erythryodysesthesia (8%) in the capecitabine arm. There was 1 fatal TRAE of neutropenic sepsis in the GV arm and none in the capecitabine arm. Conclusion The METRIC study evaluating GV in mTNBC did not meet the primary efficacy endpoint of improved PFS over capecitabine. While anticancer activity was seen with GV, it was comparable to capecitabine with no therapeutic advantage of GV in terms of ORR, PFS, or OS. The safety profile of GV was consistent with prior experience with no new safety signals identified. Citation Format: Vahdat LT, Forero-Torres A, Schmid P, Blackwell K, Telli ML, Melisko M, Holgado E, Moebus V, Cortes J, Fehrenbacher L, Montero AJ, Ma C, Nanda R, Wright GS, He Y, Bagley RG, Halim A, Turner CD, Yardley DA. METRIC: A randomized international phase 2b study of the antibody-drug conjugate (ADC) glembatumumab vedotin (GV) in gpNMB-overexpressing, metastatic, triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-01.
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