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

References

• Oriol A, Vives S, Hernández-Rivas J-M, et al. Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA study group. Haematologica. 2010;95(4):589–596.
   PubMed Web of Science ®Google Scholar
• Surapaneni UR, Cortes JE, Thomas D, et al. Central nervous system relapse in adults with acute lymphoblastic leukemia. Cancer. 2002;94(3):773–779.
   PubMed Web of Science ®Google Scholar
• Larson RA. Managing CNS disease in adults with acute lymphoblastic leukemia. Leuk Lymphoma. 2018;59(1):3–13. Jan
   PubMed Web of Science ®Google Scholar
• Yao H, Price TT, Cantelli G, et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature. 2018;560(7716):55–60.
   PubMed Web of Science ®Google Scholar
• Coustan-Smith E, Song G, Clark C, et al. New markers for minimal residual disease detection in acute lymphoblastic leukemia. Blood. 2011;117(2):6267–6276.
   PubMedGoogle Scholar
• DiGiuseppe JA, Fuller SG, Borowitz MJ. Overexpression of CD49f in precursor B-cell acute lymphoblastic leukemia: potential usefulness in minimal residual disease detection. Cytometry B Clin Cytom. 2009;76(2):150–155.
   PubMedGoogle Scholar
• Gang EJ, Kim HN, Hsieh YT, et al. Integrin α6 mediates drug resistance of acute lymphoblastic B-cell leukemia. Blood. 2020;136:210–223.
   PubMed Web of Science ®Google Scholar
• Reif K, Okkenhaug K, Sasaki T, et al. Cutting edge: differential roles for phosphoinositide 3-kinases, p110γ and p110δ, in lymphocyte chemotaxis and homing. J Immunol. 2004;173(4):2236.
   PubMed Web of Science ®Google Scholar
• Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15(1):7–24.
   PubMed Web of Science ®Google Scholar
• Franke TF, Hornik CP, Segev L, et al. PI3K/Akt and apoptosis: size matters. Oncogene. 2003;22(56):8983–8998.
   PubMed Web of Science ®Google Scholar
• Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, et al. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010 May;11(5):329–341.
   PubMed Web of Science ®Google Scholar
• Hanna S, El-Sibai M. Signaling networks of Rho GTPases in cell motility. Cell Signalling. 2013;25(10):1955–1961.
   PubMed Web of Science ®Google Scholar
• Parri M, Chiarugi P. Rac and Rho GTPases in cancer cell motility control. Cell Commun Signal. 2010;8(1):23.
   PubMedGoogle Scholar
• Reiske HR, Kao S-C, Cary LA, et al. Requirement of phosphatidylinositol 3-kinase in focal adhesion kinase-promoted cell migration. J Biol Chem. 1999;274(18):12361–12366.
   PubMed Web of Science ®Google Scholar
• Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606–619.
   PubMed Web of Science ®Google Scholar
• Katso R, Okkenhaug K, Ahmadi K, et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001;17:615–675.
   PubMed Web of Science ®Google Scholar
• Evangelisti C, Cappellini A, Oliveira M, et al. Phosphatidylinositol 3-kinase inhibition potentiates glucocorticoid response in B-cell acute lymphoblastic leukemia. J Cell Physiol. 2018;233(3):1796–1811.
   PubMed Web of Science ®Google Scholar
• Lannutti BJ, Meadows SA, Herman SEM, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591–594.
   PubMed Web of Science ®Google Scholar
• Patnaik A, Appleman LJ, Tolcher AW, et al. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas. Ann Oncol. 2016;27(10):1928–1940.
   PubMed Web of Science ®Google Scholar
• Smith LK, Cidlowski JA. Glucocorticoid-induced apoptosis of healthy and malignant lymphocytes. Prog Brain Res. 2010;182:1–30.
   PubMed Web of Science ®Google Scholar
• Hall CP, Reynolds CP, Kang MH. Modulation of glucocorticoid resistance in pediatric T-cell acute lymphoblastic leukemia by increasing BIM expression with the PI3K/mTOR inhibitor BEZ235. Clin Cancer Res. 2016;22(3):621.
   PubMed Web of Science ®Google Scholar
• Safaroghli-Azar A, Bashash D, Sadreazami P, et al. PI3K-δ inhibition using CAL-101 exerts apoptotic effects and increases doxorubicin-induced cell death in pre-B-acute lymphoblastic leukemia cells. Anti Cancer Drugs. 2017;28(4):436–445.
   PubMed Web of Science ®Google Scholar
• Silveira AB, Laranjeira ABA, Rodrigues GOL, et al. PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia. Oncotarget. 2015;6(15):13105–13118. Vol
   PubMedGoogle Scholar
• Xie M, Yang A, Ma J, et al. Akt2 mediates glucocorticoid resistance in lymphoid malignancies through FoxO3a/Bim axis and serves as a direct target for resistance reversal. Cell Death Dis. 2019;9(10):1013–1013.
   PubMedGoogle Scholar
• Krause G, Hassenrück F, Hallek M. Copanlisib for treatment of B-cell malignancies: the development of a PI3K inhibitor with considerable differences to idelalisib. Drug Des Devel Ther. 2018;12:2577–2590.
   PubMed Web of Science ®Google Scholar
• Liu N, Rowley BR, Bull CO, et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110 alpha and p110delta activities in tumor cell lines and xenograft models. Mol Cancer Ther. 2013;12(11):2319–2330.
   PubMed Web of Science ®Google Scholar
• Gökbuget N, Kneba M, Raff T, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120(9):1868–1876.
   PubMed Web of Science ®Google Scholar
• Jabbour E, Short NJ, Jorgensen JL, et al. Differential impact of minimal residual disease negativity according to the salvage status in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Cancer. 2017;123(2):294–302. (
   PubMed Web of Science ®Google Scholar
• Jabbour E, Gökbuget N, Advani A, et al. Impact of minimal residual disease status in patients with relapsed/refractory acute lymphoblastic leukemia treated with inotuzumab ozogamicin in the phase III INO-VATE trial. Leuk Res. 2020;88:106283–105835.
   PubMed Web of Science ®Google Scholar
• Short NJ, Jabbour E. Minimal residual disease in acute lymphoblastic leukemia: how to recognize and treat it. Curr Oncol Rep. 2017;19(1):1534–6269. (
   Web of Science ®Google Scholar
• Pui C-H, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol. 2008;9(3):257–268.
   PubMed Web of Science ®Google Scholar
• Miller BW, Przepiorka D, de Claro RA, et al. FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin Cancer Res. 2015;21(7):1525–1529. Apr 1
   PubMed Web of Science ®Google Scholar
• Liu P, Cheng H, Roberts TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627–644.
   PubMed Web of Science ®Google Scholar
• Lonetti A, Cappellini A, Spartà AM, et al. PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors. Oncotarget. 2015;6(12):10399–10414.
   PubMedGoogle Scholar
• Sklarz LM, Gladbach YS, Ernst M, et al. Combination of the PI3K inhibitor Idelalisib with the conventional cytostatics cytarabine and dexamethasone leads to changes in pathway activation that induce anti-proliferative effects in B lymphoblastic leukaemia cell lines. Cancer Cell Int. 2020;20(1):390.
   PubMed Web of Science ®Google Scholar
• Bashash D, Safaroghli-Azar A, Delshad M, et al. Inhibitor of pan class-I PI3K induces differentially apoptotic pathways in acute leukemia cells: shedding new light on NVP-BKM120 mechanism of action. Int J Biochem Cell Biol. 2016;79:308–317.
   PubMed Web of Science ®Google Scholar
• Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2017;35(35):3898–3905.
   PubMed Web of Science ®Google Scholar