IntroductionMantle cell lymphoma (MCL) is a well-defined lymphoid neoplasm genetically characterized by the t(11;14)(q13;q32) translocation leading to a constitutive overexpression of cyclin D1. 1 In addition to classical MCL, a blastoid variant of this disease has been described, characterized by high proliferation and associated with INK4a/ARF deletions, p53 mutations, and complex karyotypes. [2][3][4] The clinical behavior is aggressive, and few patients reach long survival or can be considered cured with current therapies. Recent results from clinical trials using the proteasome inhibitor bortezomib have shown promising results in the management of patients with MCL. [5][6][7][8] Bcl-2 family proteins are key regulators of apoptosis, determining cellular fate in response to numerous stress. 9,10 In mammalian cells, the prosurvival members (Bcl-2, Bcl-X L , Mcl-1, Bcl-w, and A1) oppose 2 proapoptotic groups: the multidomain proteins (Bax, Bak, and Bok) and the BH-3-only proteins (Bim, Puma, Noxa, Bad, Bid, Bmf, Bik, and Hrk). A balance between prosurvival and prodeath Bcl-2 members dictates the outcome of many deathinitiating signaling pathways. The BH3-only members function as sensors of cellular well-being, and when activated by cytotoxic signals, selectively engage the prosurvival members by inserting its BH3 domain into a hydrophobic groove on the antiapoptotic member surfaces. 11 This event allows Bax and Bak displacement from antiapoptotic members, their oligomerization and permeabilization of the mitochondrion, provoking the release of proapoptotic factors, caspase activation and finally cell death. 12,13 There is growing evidence that the Bcl-2 pathway is deregulated in most neoplasms. Several studies have described high levels of Bcl-2 in MCL cells. 14,15 Bcl-X L overexpression has also been described in MCL cells, linked to constitutive activation of the NF-B pathway. 16 Moreover, Mcl-1 overexpression has been correlated with high-grade MCL. 17 In addition, we have recently shown that bortezomib induces both the accumulation of the antiapoptotic protein Mcl-1 and the activation of the proapoptotic BH3-only protein Noxa, which counteracts, at least partially, the effect of its antiapoptotic partner. 18 It is conceivable that Mcl-1 accumulation may delay bortezomib-induced apoptosis. In this context, the emergence of small-molecule inhibitors that modulate Bcl-2 pathway represents a rational approach for the treatment of this neoplasm and may synergize with bortezomib activity. GX15-070 (GeminX Biotechnologies, Montreal, QC, Canada) is a small-molecule pan-Bcl-2 inhibitor that belongs to the polypirrole class of molecules, which binds to Bcl-2, Bcl-w, Bcl-X L , and Mcl-1 with a K d in the range of 0.5 M. 19 This compound has been designed to mimic proapoptotic BH3-only proteins in its binding to the antiapoptotic Bcl-2 family members, and appears to fall into the class of BH3 "sensitizers." 20 GX15-070 is currently in phase 1 clinical trials for the treatment of refractory solid tumors, and in phases...
