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

Leuk Lymphoma. 2021 Nov;62(11):2690-2702. doi: 10.1080/10428194.2021.1929963. Epub 2021 Aug 6.

Abstract

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 PI3Kδ regulation of the laminin receptor integrin α6. B-ALL cells did not, however, rely on PI3Kδ 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 PI3Kδ 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.

Keywords: CNS relapse; PI3K inhibition; acute lymphoblastic leukemia; chemosensitization; microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Central Nervous System Neoplasms* / drug therapy
  • Humans
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Recurrence
  • Signal Transduction
  • Tumor Microenvironment