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

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Adult acute lymphoblastic leukemia (ALL) frequently relapses, with central nervous system (CNS) metastasis indicating a poor prognosis.
• Previous research identified PI3Kδ-regulated integrin α6 as a route for ALL CNS metastasis, but B-ALL cells did not rely on PI3Kδ for growth.

Purpose of the Study:

• To investigate the efficacy of broad PI3K isoform targeting in B-ALL.
• To explore the vulnerability of B-ALL cells to PI3K inhibitors under cellular stress.
• To evaluate the potential of pan-PI3K inhibitors (pan-PI3Ki) for B-ALL treatment, including CNS prophylaxis and chemosensitization.

Main Methods:

• Treatment of B-ALL models with a pan-PI3K inhibitor, copanlisib.
• Assessment of B-ALL cell growth arrest and systemic disease burden in mice.
• Investigation of PI3K/Akt-dependent survival pathways activated by cellular stress in B-ALL.
• Evaluation of copanlisib combined with chemotherapy in reducing systemic disease and CNS metastasis.

Main Results:

• A single agent pan-PI3Ki, copanlisib, induced growth arrest in B-ALL and reduced systemic disease burden in mice.
• Cellular stress activates PI3K/Akt survival pathways in B-ALL, making them vulnerable to PI3Kδ and pan-PI3Ki.
• Combining copanlisib with chemotherapy improved survival, decreased systemic disease, and reduced CNS metastasis.

Conclusions:

• Broad targeting of PI3K isoforms can induce growth arrest in B-ALL.
• Pan-PI3Ki, such as copanlisib, demonstrate multifaceted potential for B-ALL CNS prophylaxis, systemic disease control, and chemosensitization.
• The combination of pan-PI3Ki with chemotherapy offers significant therapeutic benefits for B-ALL patients.