Pan-PI3Ki targets multiple B-ALL microenvironment interactions that fuel systemic and CNS relapse
| Autor: | Andrew E. Whiteley, Andrew S. Murray, Trevor T. Price, Prioty Islam, Brennan G. Simon, Maegan L. Brockman, Hisayuki Yao, Dorothy A. Sipkins, Sarah M. Ridge |
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| Rok vydání: | 2021 |
| Předmět: |
Gene isoform
Cancer Research Systemic disease medicine.medical_treatment Central nervous system Article Metastasis Central Nervous System Neoplasms Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Recurrence Chemosensitization Tumor Microenvironment medicine Animals Humans PI3K/AKT/mTOR pathway Copanlisib Chemotherapy business.industry Hematology Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease medicine.anatomical_structure Oncology chemistry Cancer research business Signal Transduction |
| Zdroj: | Leuk Lymphoma |
| ISSN: | 1029-2403 1042-8194 |
| DOI: | 10.1080/10428194.2021.1929963 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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