The potential of pirtobrutinib in multiple B-cell malignancies

Bruton’s tyrosine kinase (BTK) is a critical downstream signaling element from the B-cell receptor (BCR) that has been effectively inhibited in B-cell cancers by irreversible, covalent inhibitors including ibrutinib and acalabrutinib. All FDA-approved covalent BTK inhibitors rely on binding to the cysteine 481 (C481) amino acid within the active site of BTK, thus rendering it inert. While covalent BTK inhibitors have been very successful in multiple B-cell malignancies, improving both overall survival and progression-free survival relative to chemoimmunotherapy in phase 3 trials, they can be limited by intolerance and disease progression. Pirtobrutinib is a novel, highly selective, and non-covalent BTK inhibitor that binds independently of C481, and in a recent, first-in-human phase 1/2 clinical trial was shown to be extremely well tolerated and lead to remissions in relapsed/refractory patients with multiple B-cell malignancies. Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies

Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia.

PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki. Peripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay. pan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively. Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders

Docosahexaenoic acid slows inflammation resolution and impairs the quality of healed skin tissue

There is no consensus on the effects of omega-3 (ω-3) fatty acids (FA) on cutaneous repair. To solve this problem, we used 2 different approaches: 1) FAT-1 transgenic mice, capable of producing endogenous ω-3 FA; 2) wild-type (WT) mice orally supplemented with DHA-enriched fish oil. FAT-1 mice had higher systemic (serum) and local (skin tissue) ω-3 FA levels, mainly docosahexaenoic acid (DHA), in comparison to WT mice. FAT-1 mice had increased myeloperoxidase (MPO) activity and content of CXCL-1 and CXCL-2, and reduced IL-10 in the skin wound tissue three days after the wound induction. Inflammation was maintained by an elevated TNF-α concentration and presence of inflammatory cells and edema. Neutrophils and macrophages isolated from FAT-1 mice, also produced increased TNF-α and reduced IL-10 levels. In these mice, the wound closure was delayed, with a wound area 6-fold bigger in relation with WT group, on the last day of analysis (14 days post-wounding). This was associated with poor orientation of collagen fibers and structural aspects in repaired tissue. Similarly, DHA group had a delay during late inflammatory phase. This group had increased TNF-α content and CD45+F4/80+ cells at the 3rd day after skin wounding and increased concentrations of important metabolites derived from ω-3, like 18-HEPE and reduced concentrations of those from ω-6 FA. In conclusion, elevated DHA content, achieved in both FAT-1 and DHA groups, slowed inflammation resolution and impaired the quality of healed skin tissue

Docosahexaenoic acid slows inflammation resolution and impairs the quality of healed skin tissue

Abstract There is no consensus on the effects of omega-3 (ω-3) fatty acids (FA) on cutaneous repair. To solve this problem, we used 2 different approaches: (1) FAT-1 transgenic mice, capable of producing endogenous ω-3 FA; (2) wild-type (WT) mice orally supplemented with DHA-enriched fish oil. FAT-1 mice had higher systemic (serum) and local (skin tissue) ω-3 FA levels, mainly docosahexaenoic acid (DHA), in comparison with WT mice. FAT-1 mice had increased myeloperoxidase (MPO) activity and content of CXCL-1 and CXCL-2, and reduced IL-10 in the skin wound tissue three days after the wound induction. Inflammation was maintained by an elevated TNF-α concentration and presence of inflammatory cells and edema. Neutrophils and macrophages, isolated from FAT-1 mice, also produced increased TNF-α and reduced IL-10 levels. In these mice, the wound closure was delayed, with a wound area 6-fold bigger in relation with WT group, on the last day of analysis (14 days post-wounding). This was associated with poor orientation of collagen fibers and structural aspects in repaired tissue. Similarly, DHA group had a delay during late inflammatory phase. This group had increased TNF-α content and CD45+F4/80+ cells at the third day after skin wounding and increased concentrations of important metabolites derived from ω-3, like 18-HEPE, and reduced concentrations of those from ω-6 FA. In conclusion, elevated DHA content, achieved in both FAT-1 and DHA groups, slowed inflammation resolution and impaired the quality of healed skin tissue.</jats:p