Molecular Targeted Approaches in Mantle Cell Lymphoma

Abstract

Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by the translocation t(11;14) that leads to aberrant expression of cyclin D1. Response to first-line chemotherapy is good but most patients relapse resulting in a median survival of 5-7 years. The important PI3K/AKT/mTOR pathway can be targeted with small molecules. mTOR inhibitors have clinical activity and temsirolimus has been approved in Europe. Second generation mTOR inhibitors and the PI3K inhibitor CAL-101 offer additional means to target the pathway. Promising results with the BTK inhibitor PCI-32765 suggest that B-cell receptor signaling could play a role. For unknown reasons, MCL appears to be particularly sensitive to disruption of protein homeostasis. The proteasome inhibitor bortezomib achieves responses in up to 50% of relapsed patients. Much work has been done in elucidating the mechanism of its cytotoxicity, its incorporation into combination therapies, and the development of second generation proteasome inhibitors. Deacetylase and HSP90 inhibitors are also promising classes of drugs that can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients an immediate chance to benefit from these advances and is essential to maintain the momentum of progress.

Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

“…Our results suggest that mTOR activity is characteristic in most (but not all) non-germinal center-derived diffuse large B-cell lymphomas. Although the importance of mTOR activity in the production of survival factors is well demonstrated by mTOR-mediated cyclinD1 expression in mantle cell lymphoma, 20 we found no statistical correlation between mTOR activity and the expression of the examined pro-proliferative or anti-apoptotic factors (bcl-2 and bcl-6) (data not shown). However, significant correlation between germinal center/non-germinal center subtypes, and mTOR activity was detected in our 68 diffuse large B-cell lymphoma cases.…”

Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

“…7 Most recently, Btk inhibition in macrophages was shown to abolish Fc␥RIII-induced TNF-␣, IL-1␤, and IL-6 production as well as block B-cell receptor-dependent B-cell proliferation via NF-B activation, providing convincing evidence for Btk as a promising new therapeutic target in rheumatoid arthritis and B-cell lymphoma. [8][9][10][11][12][13][14] Encouragingly, the irreversible Btk inhibitor PCI-32765 (IC 50 ϭ 0.5nM) has demonstrated clinical activity against a variety of B-cell malignancies in ongoing phase 1 or 2 trials, including mantle cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B-cell lymphoma, with excellent tolerability.…”

Bruton tyrosine kinase (Btk) suppresses osteoblastic differentiation

“…Most recently, Btk inhibition in macrophages was shown to inhibit FccRIII-induced tumor necrosis factor (TNF) a, interleukin (IL)-1b, and IL-6 production as well as block BCR-dependent B cell proliferation by NF-jB activation, providing convincing evidence for Btk as a promising new therapeutic target for rheumatoid arthritis (RA) and B cell lymphoma [3][4][5][6][7][8][9].…”