Tue, Apr 9, 8:00 AM - 12:00 PM
2432/2 - The bruton’s tyrosine kinase inhibitor ibrutinib synergized with the proteasome inhibitor carfilzomib and overcame immunoproteasome-mediated carfilzomib resistance in mantle cell lymphoma Abstract Number: 2432
Presentation Title: The bruton’s tyrosine kinase inhibitor ibrutinib synergized with the proteasome inhibitor carfilzomib and overcame immunoproteasome-mediated carfilzomib resistance in mantle cell lymphoma
Presentation Time: Tuesday, Apr 09, 2013, 8:00 AM -12:00 PM
Location: Hall A-C, Poster Section 4
Poster Board Number: 2
Author Block: Zhishuo Ou1, Liang Zhang1, Kate Newberry1, Luhong Sun1, Kirk J. Christopher2, Alex Rollo1, Archito Tamayo1, John Lee1, Richard J. Ford1, Michael Wang1, Lan V. Pham1. 1MD Anderson Cancer Center, Houston, TX; 2Onyx Pharmaceuticals, South San Francisco, CA
Abstract Body: Introduction: Mantle cell lymphoma (MCL) is not curable and novel therapeutic agents and their rational combinations are needed. The ubiquitin-proteasome pathway is an attractive target for antitumor therapy, as its persistent activity is associated with tumor formation, growth, metastasis, and drug resistance in many cancer types, including B-cell non-Hodgkin lymphoma. 20S proteasome activity is regulated by the catalytic subunits β1, β2, and β5 or in the case of the immunoproteasome (i20S) by the inducible catalytic subunits LMP2 (β1i), MECL-1(β2i), and LMP7 (β5i). Carfilzomib (CFZ), a proteasome inhibitor, inhibits the proteasome by binding specifically and irreversibly to the catalytic subunit β5/β5i.
Materials and Methods: CFZ was supplied by Onyx Pharmaceuticals (South San Francisco, CA). The Btk inhibitor ibrutinib (PCI-32765) was provided by Pharmacyclics (Sunnyvale, CA). Human MCL cell lines (Mino, Jeko-1, Z138, and Rec-1) were either created by our laboratory or obtained from American Type Culture Collection. Primary cells were obtained from newly diagnosed MCL patients with informed consent. Cell viability was assessed by an MTT assay, apoptosis by Annexin V binding assays, and proteasome expression by Western blotting.
Results: We found that MCL cells had different responses to CFZ. For the CFZ-sensitive MCL cell lines Mino and Z138 and freshly isolated MCL cells from 6 patients, CFZ significantly induced the growth inhibition and apoptosis at a low dose (IC50 2-6 nM). In contrast, for the CFZ-resistant MCL cell line (Rec-1) and fresh primary MCL cells from patients with clinical resistance, CFZ did not induce cell death (IC50 not reached at 100 nM). Next, Western blot analysis showed that the CFZ-resistant cells lacked expression of the i20S subunits LMP2, LMP7, and MECL-1. By contrast, the CFZ-sensitive cells showed high levels of LMP2, LMP7, and MECL-1. These results suggest that an intact immunoproteasome is necessary for CFZ-induced anti-MCL activity. In an attempt to overcome the CFZ resistance, we studied the effect of ibrutinib in CFZ-resistant MCL cells. Ibrutinib alone was toxic to both CFZ-sensitive and CFZ-resistant MCL cells with IC50 values ranging from 3 to 12.5 μM. Furthermore, we found that ibrutinib synergized with CFZ in CFZ-sensitive cell lines, and primary MCL cells. The Chou-Talay combination index was
Market conditions probably aren't where they need to be to get retail investors buying at this price (still a pretty high entry point), so bears are having an easy time of it. Also, all three breakthrough indications are for small patient populations (the most recent--17q del--happens in perhaps 10% of CLL, depending on whose data you look at). And the phase 2 data released recently don't represent anything really new.
This stock has risen dramatically and fallen dramatically several times in the past, and not always based on any particular news. It might resume its previous pattern of slowly gathering momentum to another new high. Or not.