Thursday, July 28, 2011

Signaling in CLL: Inhibition of translation

The regulation of translational initiation

The Mek/Erk pathway regulates protein translation initiation via activation of the 90 kDa ribosomal S6 kinase p90RSK. The PI-3K/Akt pathway controls translation via a different pathway, involving the activation of a multi-subunit protein kinase complex, mTorc1. Both p90RSK and mTorc1 phosphorylate the ribosomal S6 protein, thereby altering the spectrum of mRNAs translated by the ribosome in a manner that may serve to block apoptosis. P90RSK may also block apoptosis via mechanisms distinct from translation control.

mTorc1 and p90RSK as potential therapeutic targets in CLL

The mTorc1 inhibitor rapamycin and its analogs temsirolimus, everolimus and deferolimus are in clinical trials against solid tumours. While constitutive activation of Akt in CLL remains controversial, mTorc1 can also be activated via the Erk pathway, which is also activated in CLL. Therefore, mTorc1 is a potential therapeutic target in this malignancy.

Rapamycin induces a G1 phase cell cycle arrest in CLL cells stimulated to proliferate by treatment with CpG-containing oligonucleotides and IL-2. The inhibitor also blocks phosphorylation of the mTorc1 target p70S6K. However, rapamycin fails to induce significant apoptosis of either cycling or quiescent cells. Rapamycin toxicity was similar in CLL cells and in normal peripheral blood mononuclear cells. The inhibitor induced synergistic killing when combined with chlorambucil or vincristine, but antagonized killing by fludarabine or cyclophosphamide.

Rapamycin inhibited S6 phosphorylation in vivo in the CLL-like malignant cells of Eμ-TCL1A transgenic mice, but their treatment with the inhibitor did not prolong survival.

Six of eight heavily pre-treated CLL patients achieved stable disease in a phase II single-agent trial of deferolimus. A trial of everolimus (RAD001) induced one partial remission and three cases of stable disease but it was terminated after the enrolment of only seven patients due to toxicity. Only four of 22 patients achieved partial remissions in a phase II study of oral everolimus in refractory CLL, but malignant cells were mobilized from bone marrow and lymph nodes and entered the peripheral circulation, with a consequent reduction of lymphadenopathy. Rapamycin analogs may therefore, have value in removing CLL cells from cytoprotective microenvironments.

In summary, in vitro data as well as clinical experience using rapamycin analogs is disappointing. These agents may be of value when used in carefully formulated combinations with conventional agents. Dual inhibitors targeting mTorc1 and PI-3k may be more effective than mTorc1 inhibitors alone, due to their ability to block the feedback activation of PI-3k resulting from mTor inhibition. The dual inhibitor NVP-BEZ235 strikingly inhibited growth of human lymphoma cells in vitro and in a mouse xenograft model. NVP-BEZ235 is in clinical trials for solid tumours and its actions on CLL cells should be evaluated.

A new generation of inhibitors that, unlike rapamycins, directly target the ATP-binding site of the mTorc1 protein kinase are currently entering clinical trials against solid tumours. These agents include OSI-027 and AZD8055 and Torin 1. Torin 1 was disappointingly only marginally toxic towards CLL cells, even at concentrations that effectively inhibited mTorc1. This may be because of increased autophagy with mTorc1 inhibition. In contrast, BI-D1870, a highly selective inhibitor of p90RSK, is substantially more toxic. Inhibition of the p90RSK arm of the translational control machinery may therefore be a better therapeutic approach in CLL than inhibition of mTorc1.

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