Targeting PI3K Pathway with CAL-101: A Therapeutic Approach for Acute Lymphoblastic Leukemia and Other Hematological Malignancies

The class I PI3K enzymes, which are crucial for cell functions such as movement, metabolism, and survival, can become deregulated in various cancers, including blood-related malignancies. Targeting the PI3K pathway specifically in blood cancers may offer a more effective treatment with fewer side effects than general PI3K inhibitors. The p110d isoform of class IA PI3Ks is predominantly found in blood cells and is vital for lymphocyte signaling. A newly identified inhibitor, CAL-101, has been shown to specifically target p110d with high potency, exhibiting an IC50 of 1–10 nM for the purified subunit and 30–70 nM for cellular activity in whole blood. In clinical trials, CAL-101 maintained plasma concentrations well above the required levels for inhibition in a 7-day study with human volunteers, demonstrating safety and tolerability. It also showed a significant level of selectivity over other PI3K family members and related proteins. Screening various leukemia and lymphoma cell lines revealed that p110d is expressed in over 90% of them, often with active Akt phosphorylation. CAL-101 was effective in reducing p-Akt levels and inhibiting downstream signaling in different types of cancer cells, including those from acute myeloid leukemia, ALL, and diffuse large B-cell lymphoma. It has been particularly noted that CAL-101 can reduce cell proliferation and induce cell death in ALL cell lines, regardless of PTEN status, and it promotes apoptosis through the activation of caspase pathways. The findings from these studies are being applied to analyze primary patient samples, providing a foundation for the therapeutic use of CAL-101 in treating ALL. The compound has shown promising results in clinical trials, with high drug exposure and favorable pharmacokinetics, supporting its ongoing Phase 1 clinical trial for a variety of hematological cancers.