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Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia.
Blood 2017; 129(2):177-187Blood

Abstract

Philadelphia chromosome (Ph)-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or phosphatidylinositol 3-kinase (PI3K) signaling and poor clinical outcomes. PI3K pathway signaling inhibitors have been minimally investigated in Ph-like ALL. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or target of rapamycin complex 1/2 (TORC1/TORC2) would decrease leukemia proliferation and abrogate aberrant kinase signaling and that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy. We treated 10 childhood ALL patient-derived xenograft models harboring various Ph-like genomic alterations with 4 discrete PI3K pathway protein inhibitors and observed marked leukemia reduction and in vivo signaling inhibition in all models. Treatment with dual PI3K/mTOR inhibitor gedatolisib resulted in near eradication of ALL in cytokine receptor-like factor 2 (CRLF2)/JAK-mutant models with mean 92.2% (range, 86.0%-99.4%) reduction vs vehicle controls (P < .0001) and in prolonged animal survival. Gedatolisib also inhibited ALL proliferation in ABL/platelet-derived growth factor receptor (PDGFR)-mutant models with mean 66.9% (range, 42.0%-87.6%) reduction vs vehicle (P < .0001). Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more effectively inhibited ALL proliferation than either inhibitor alone (P < .001) and further enhanced survival. Similarly, superior efficacy of combined gedatolisib and dasatinib was observed in ABL/PDGFR-mutant models (P < .001). Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo; antileukemia activity was further enhanced with combination inhibitor therapy. Clinical trials testing combinations of kinase inhibitors in Ph-like ALL patients are indicated.

Authors+Show Affiliations

Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.Department of Pathology, University of New Mexico, Albuquerque, NM.Department of Pathology, University of New Mexico, Albuquerque, NM.Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.Department of Pathology, University of New Mexico, Albuquerque, NM.Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Division of Hematology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; and.Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.Division of Hematology/Oncology, University of California San Francisco Benioff Children's Hospital, and. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Division of Hematology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; and.Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27777238

Citation

Tasian, Sarah K., et al. "Potent Efficacy of Combined PI3K/mTOR and JAK or ABL Inhibition in Murine Xenograft Models of Ph-like Acute Lymphoblastic Leukemia." Blood, vol. 129, no. 2, 2017, pp. 177-187.
Tasian SK, Teachey DT, Li Y, et al. Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2017;129(2):177-187.
Tasian, S. K., Teachey, D. T., Li, Y., Shen, F., Harvey, R. C., Chen, I. M., ... Grupp, S. A. (2017). Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood, 129(2), pp. 177-187. doi:10.1182/blood-2016-05-707653.
Tasian SK, et al. Potent Efficacy of Combined PI3K/mTOR and JAK or ABL Inhibition in Murine Xenograft Models of Ph-like Acute Lymphoblastic Leukemia. Blood. 2017 01 12;129(2):177-187. PubMed PMID: 27777238.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. AU - Tasian,Sarah K, AU - Teachey,David T, AU - Li,Yong, AU - Shen,Feng, AU - Harvey,Richard C, AU - Chen,I-Ming, AU - Ryan,Theresa, AU - Vincent,Tiffaney L, AU - Willman,Cheryl L, AU - Perl,Alexander E, AU - Hunger,Stephen P, AU - Loh,Mignon L, AU - Carroll,Martin, AU - Grupp,Stephan A, Y1 - 2016/10/24/ PY - 2016/05/13/received PY - 2016/10/17/accepted PY - 2016/10/26/pubmed PY - 2017/8/8/medline PY - 2016/10/26/entrez SP - 177 EP - 187 JF - Blood JO - Blood VL - 129 IS - 2 N2 - Philadelphia chromosome (Ph)-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or phosphatidylinositol 3-kinase (PI3K) signaling and poor clinical outcomes. PI3K pathway signaling inhibitors have been minimally investigated in Ph-like ALL. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or target of rapamycin complex 1/2 (TORC1/TORC2) would decrease leukemia proliferation and abrogate aberrant kinase signaling and that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy. We treated 10 childhood ALL patient-derived xenograft models harboring various Ph-like genomic alterations with 4 discrete PI3K pathway protein inhibitors and observed marked leukemia reduction and in vivo signaling inhibition in all models. Treatment with dual PI3K/mTOR inhibitor gedatolisib resulted in near eradication of ALL in cytokine receptor-like factor 2 (CRLF2)/JAK-mutant models with mean 92.2% (range, 86.0%-99.4%) reduction vs vehicle controls (P < .0001) and in prolonged animal survival. Gedatolisib also inhibited ALL proliferation in ABL/platelet-derived growth factor receptor (PDGFR)-mutant models with mean 66.9% (range, 42.0%-87.6%) reduction vs vehicle (P < .0001). Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more effectively inhibited ALL proliferation than either inhibitor alone (P < .001) and further enhanced survival. Similarly, superior efficacy of combined gedatolisib and dasatinib was observed in ABL/PDGFR-mutant models (P < .001). Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo; antileukemia activity was further enhanced with combination inhibitor therapy. Clinical trials testing combinations of kinase inhibitors in Ph-like ALL patients are indicated. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/27777238/Potent_efficacy_of_combined_PI3K/mTOR_and_JAK_or_ABL_inhibition_in_murine_xenograft_models_of_Ph_like_acute_lymphoblastic_leukemia_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&amp;pmid=27777238 DB - PRIME DP - Unbound Medicine ER -