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The use of NSC12, a novel small molecule that specifically halts the FGF/FGFR axis in Waldenstrom macroglobulinemia (WM), was associated with anti-WM activity, with researchers suggesting this activity may be partially driven by inhibition of the MYD88 gene. Mutations in the MYD88 are highly prevalent in WM.
Results from this study were presented at the 62nd American Society of Hematology Annual Meeting &amp; Exposition by Antonio Sacco, RN, of the ASST Spedali Civili di Brescia in Italy.
The researchers of this study examined the role of FGF/FGFR system blockade in patients with WM with the use of NSC12.
There was significant enrichment of FGF/FGFR-driven signaling cascades in patients’ CD19-positive cells derived from the bone marrow. In WM cells, there was also a higher expression of FGFs compared with their normal cellular counterpart. Additionally, FGFRs were also overexpressed in WM.
Transcriptome profiling of NSC12-treated WM cells confirmed the blockade of the FGFR-signaling blockade, the researchers noted. They also observed effective silencing of MYD88 and MYD88-downstream target HCK in WM cells.
The NSC12-dependent inhibition of MYD88 also led to silencing of the MAPK-ERK signaling cascade. Ultimately, this led to NSC12-induced Myc-silencing in WM cells. The investigators also confirmed the efficacy of NSC12 in silencing stromal cell-induced FGFR3 phosphorylation in bone marrow. There was also no cytotoxicity associated with NSC12 on CD19+ cells derived from peripheral blood mononuclear cells in healthy donors.
In NSC12-treated mice, there was also a significant inhibition of WM tumor growth. And in harvested femurs of mice, there was also an NSC12-dependent reduction of WM tumor cell infiltration in bone marrow compared with vehicle-treated mice. There was also a significant reduction of MYD88 and MYD88-downstream target HCK in mice treated with NSC12 (P&lt;0.05).

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Novel Small Molecule Effectively Silences MYD88, Gene Frequently Mutated in Waldenstrom Macroglobulinemia

ASH Annual Meeting 2020

The use of NSC12, a novel small molecule that specifically halts the FGF/FGFR axis in Waldenstrom macroglobulinemia (WM), was associated with anti-WM activity, with ...

Novel Small Molecule Effectively Silences MYD88, Gene Frequently Mutated in Waldenstrom

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