Pan-PI3Ki targets multiple B-ALL microenvironment interactions that fuel systemic and CNS relapse

The majority of adult patients with acute lymphoblastic leukemia (ALL) suffer relapse, and in patients with central nervous system (CNS) metastasis, prognosis is particularly poor. We recently demonstrated a novel route of ALL CNS metastasis dependent on PI3K delta regulation of the laminin receptor integrin alpha 6. B-ALL cells did not, however, rely on PI3K delta signaling for growth. Here we show that broad targeting of PI3K isoforms can induce growth arrest in B-ALL, reducing systemic disease burden in mice treated with a single agent pan-PI3Ki, copanlisib. Moreover, we show that cellular stress activates PI3K/Akt-dependent survival pathways in B-ALL, exposing their vulnerability to PI3K delta and pan-PI3Ki. The addition of a brief course of copanlisib to chemotherapy delivered the combined benefits of increased survival, decreased systemic disease, and reduced CNS metastasis. These data suggest the promising, multifaceted potential of pan-PI3Ki for B-ALL CNS prophylaxis, systemic disease control, and chemosensitization.