SmurfVA's Random Picks

[Ned Serious]

IDRA is presenting at the AACR (amer assoc cancer research) on Monday afternoon (after the close I believe as its 1-5pm San Diego time). My hopes are that they are releasing additional data points or any other info to backup their recent positive study.

I'm not planning to average down at the moment and am still believing in it's ability to bounce back. I don't have too much available to avg down as I'll be needing to remove some money from the account.

IDRA Presentation at AACR : April 7th 1PM-5PM (San Diego - PST)

TITLE:
IMO-8400, a selective antagonist of TLRs 7, 8 and 9, inhibits MYD88 L265P mutation-driven signaling and cell survival: A potential novel approach for treatment of B-cell lymphomas harboring MYD88 L265P mutation

In studies of B-cell lymphoma, Staudt and colleagues have identified oncogenic mutations in the signaling pathways associated with the B-cell receptor (BCR) and, more recently, the MYD88 L265P mutation (Ngo et al, Nature 2011, 470:115). MYD88 is a key adaptor protein in the Toll-like Receptor (TLR) signaling pathway. It has been shown that the MYD88 L265P mutation leads to the over activation of the TLRs 7 and 9 signaling pathway, whereas blocking of this pathway decreased cell survival, providing a rationale for targeting TLRs 7 and 9 signaling as a therapeutic approach (Lim et al, AACR 2013, #2332). The MYD88 L265P mutation is reported to be present in over 90% of Waldenström’s macroglobulinemia (WM) patients, 29% of patients with activated B-cell-like (ABC) diffuse large B cell lymphoma (DLBCL), and in other B-cell lymphomas. We evaluated IMO-8400, an antagonist for TLRs 7, 8 and 9, in preclinical studies employing three cell lines with the MYD88 L265P mutation (OCI-Ly3, OCI-Ly10 and TMD8), primary bone marrow cells from a WM patient with the mutation, and a control GCB-DLBCL cell line SU-DHL-6 with wild-type MYD88. The presence of MYD88 L265P mutation was confirmed by allele-specific PCR and Sanger sequencing. All cell lines expressed TLRs 7 and 9. Treatment of mutation-positive cell lines with IMO-8400 resulted in dose- and duration-dependent decreases in multiple parameters of cell activation, including cell survival (EC50: 0.95 µM and ~5 µM, with and without use of lipid, respectively), phosphorylation of BTK, IRAK1, IRAK4, NF-?B, STAT3 and p38 (assayed by Western blot), and secretion of cytokines including IL-10, MIG and IL-2R. Gene array analysis indicated that IMO-8400 inhibited the expression of several genes in the NF-?B and JAK/STAT pathways, including NFKB1, TNFSF10, STAT3 and IL2RA. IMO-8400 also inhibited cell survival and cytokine secretion in cells from the WM patient. In a murine model of disseminated OCI-LY10, IMO-8400 as a single treatment agent showed potent anti-tumor activity in vivo, with dose-dependent increase in animal survival. Treatment was well-tolerated at all dose levels. In a subcutaneous tumor model, growth of even well-established tumor nodules (approximately 500 mm³) was significantly inhibited by IMO-8400 treatment, and this effect correlated with decreased I?Ba phosphorylation and IL-10 expression (gene and protein) in tumor cells as well as decreased human IL-10 in the serum of the mice. In contrast, IMO-8400 treatment had no effects on control SU-DHL-6 cells in vitro or in vivo. Our studies show that IMO-8400 inhibits oncogenic MYD88 L265P-mediated cell survival and provides a novel approach for treatment of patients with this mutation. A Phase 1/2 trial of IMO-8400 in patients with WM is now open for enrollment.

link: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3404&sKey=de3e8036-5855-4dba-93cf-0df382ff49e5&cKey=c3dbcd4b-7d20-4332-b345-5c44a08d67e3&mKey=6ffe1446-a164-476a-92e7-c26446874d93