Targeting p110δ with CAL-101: A Novel Therapeutic Approach for Chronic Lymphocytic Leukemia

The PI3K/Akt signaling pathway is crucial for the growth and survival of cells, particularly in cancers like CLL. Among the eight PI3K isoforms, class IA PI3Ks, specifically p110α, p110β, and p110δ, are key in activating Akt and causing cell transformation. While p110α and p110β are found in various adult tissues, p110δ is mainly present in blood-forming cells and is essential for B-cell reactions. Studies have shown that the absence of p110δ leads to a halt in B-cell antigen receptor-induced Akt phosphorylation and cell cycle progression, and also compromises the survival supported by CD40-ligand. Our hypothesis was that inhibiting p110δ could be detrimental to B-CLL cells.

We analyzed the p110δ protein in CD19+ B cells from CLL patients and found that all 24 samples overexpressed this isoform, whereas p110α and p110β were less consistently present. Using CAL-101, a specific p110δ inhibitor, we observed significant cell death in CLL cells at concentrations ranging from 0.1 to 10μM, with 5μM leading to a median of 59.6% viable cells across 18 patient samples. The cytotoxic effect of CAL-101 was marked by the cleavage of PARP and caspase 3.

Previous studies have indicated that CD40-ligand signaling can activate CLL cells and protect them from apoptosis. We found that CAL-101 treatment reduced the CD40 and CD86 activation markers induced by CD40L. Additionally, CAL-101 reversed the increase in cell viability caused by CD40L. However, IL-4 did not show a similar effect on apoptosis reduction.

We also evaluated the impact of CAL-101 on normal immune cells, such as NK and T cells, from healthy individuals. In vitro treatment did not affect the viability of these cells. This was further confirmed in a phase I trial with healthy volunteers, where CAL-101 treatment for seven days reached peak plasma levels of 5μM without altering general hematology or NK and T cell subpopulations.

Our findings suggest that the p110δ isoform could be a promising therapeutic target for CLL, as it selectively targets cancer cells without affecting normal immune cells and disrupts the crucial CD40-CD40L survival pathway. The in vitro and in vivo data support the ongoing Phase 1 clinical trial aimed at treating patients with CLL and related malignancies.