Publications by authors named "Suzy Brown"
Mutant BRAF is one of the most common oncogenic drivers in metastatic melanoma. While first generation BRAF inhibitors are capable of controlling tumors systemically, they are unable to adequately treat tumors that have metastasized to the brain due to insufficient penetration across the blood-brain barrier (BBB). Through a combination of structure-based drug design (SBDD) and the optimization of physiochemical properties to enhance BBB penetration, we herein report the discovery of the brain-penetrant BRAF inhibitor () In mice studies, proved to be highly brain-penetrant and was able to drive regressions of A375 BRAF tumors implanted both subcutaneously and intracranially.
View Article and Find Full Text PDFArticle Synopsis
- RAF inhibitors have improved treatment for BRAFV600-mutant cancers, but challenges like ERK signaling adaptation and poor brain penetration limit their effectiveness.
- PF-07799933 is a new, brain-penetrant, selective pan-mutant BRAF inhibitor that shows promising results in preclinical trials by inhibiting dimer signaling and maintaining wild-type ERK signaling.
- A clinical trial for PF-07799933 demonstrated it was well-tolerated and led to multiple positive responses in patients with treatment-resistant BRAF-mutant tumors, highlighting its potential as an effective therapy combined with MEK inhibitors.
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles.
View Article and Find Full Text PDFPurpose: To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer.
Patients And Methods: In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters.