Monday, July 25, 2011
The signaling background to CAL-101
Time to remind you of the diagram. If you follow the middle passage of Lyn and Syk activation, the PI-3K δ isoform, which is restricted to hematopoietic cells, plays a key role in B cell receptor signalling. BCR engagement activates PI-3Kδ, which adds an additional phosphate group to PIP2, generating phosphatidylinositol 3,4,5- trisphosphate (PIP3).
The Akt protein kinase and phosphoinositide-dependent protein kinase 1 (Pdk1) contain pleckstrin homology domains that mediate their binding to membrane-localized PIP3. The resulting juxtaposition of the two kinases allows activation of AKT by Pdk1-mediated phosphorylation. Activated Akt blocks apoptosis by multiple pathways.
Since we can identify activating mutations of PI-3k genes this pathway is very important in cancer. We also know that the PI-3k/Akt pathway is downregulated by the action of the phospholipase and tensin homolog (Pten), which dephosphorylates PIP3 to PIP2, thus terminating the ability of PIP3 to activate Akt. PTEN is therefore a tumour suppressor gene, whose loss results in aberrant activation of the PI-3k/Akt pathway in malignant cells.
Constitutive PI-3k activity is significantly greater in CLL cells than in normal B cells. Inhibition of PI-3k by LY294002 results in apoptosis of CLL cells. LY294002 lacks isoform specificity and is likely to cause unacceptable toxicities, especially due to hypoglycaemia resulting from broad inhibition of PI-3k isoforms. Isoform-selective inhibitors of both PI-3k and Akt are in clinical trials in solid tumors. The PI-3Kδ isoform is relatively selective for hematopoietic cells and is elevated approximately three-fold in CLL cells compared to normal B cells. PI-3kδ inhibition by the isoform-selective inhibitor CAL-101 induces apoptosis of CLL cells and is in quite advanced clinical trials. PI-103, an inhibitor that targets both PI-3k and its downstream target mTorc1, blocks the increase of Akt phosphorylation induced by CXCL12 and enhanced apoptosis induction by fludarabine.
I'm sure that those who have read the CAL-101 article will find this all too familiar, but here it is in the raw.