KPT-8602 IS A SECOND-GENERATION XPO1 INHIBITOR WITH IMPROVED IN VIVO TOLERABILITY AND POTENT IN VIVO ACTIVITY AGAINST ACUTE LYMPHOBLASTIC LEUKEMIA
Author(s): ,
Jolien De Bie
Affiliations:
Center for human genetics,KU Leuven - VIB,Leuven,Belgium
,
Jasper Neggers
Affiliations:
Rega Institute for Medical Research,KU Leuven,Leuven,Belgium
,
Antonis Dagklis
Affiliations:
Center for human genetics,KU Leuven - VIB,Leuven,Belgium
,
Thomas Vercruysse
Affiliations:
Rega Institute for Medical Research,KU Leuven,Leuven,Belgium
,
Olga Gielen
Affiliations:
Center for human genetics,KU Leuven - VIB,Leuven,Belgium
,
Erkan Baloglu
Affiliations:
Karyopharm Therapeutics,Newton MA,United States
,
William Senapedis
Affiliations:
Karyopharm Therapeutics,Newton MA,United States
,
Sharon Shacham
Affiliations:
Karyopharm Therapeutics,Newton MA,United States
,
Yosef Landesman
Affiliations:
Karyopharm Therapeutics,Newton MA,United States
,
Anne Uyttebroeck
Affiliations:
Pediatric Haematology and Oncology,University Hospitals Leuven,Leuven,Belgium
,
Nancy Boeckx
Affiliations:
Laboratory Medicine,University Hospitals Leuven,Leuven,Belgium
,
Jan Cools
Affiliations:
Center for human genetics,KU Leuven - VIB,Leuven,Belgium
Dirk Daelemans
Affiliations:
Rega Institute for Medical Research,KU Leuven,Leuven,Belgium
(Abstract release date: 05/19/16) EHA Library. De Bie J. 06/09/16; 132406; E857
Ms. Jolien De Bie
Ms. Jolien De Bie
Contributions
Abstract
Abstract: E857

Type: Eposter Presentation

Background
Human exportin-1 (XPO1) is a transport protein that exports a wide variety of different cargo proteins from the nucleus to the cytoplasm. Selective Inhibitor of Nuclear Export (SINETM) compounds block the formation of the XPO1-cargo complex leading to accumulation of tumor suppressors in the nucleus and show potent anti-cancer activity. Selinexor (KPT-330) is currently in Phase-II/IIb clinical trials for treatment of both hematologic and solid tumors, while KPT-8602 is in Phase 1/2 clinical trials for treatment of relapsed refractory multiple myeloma. 

Aims
We investigated the in vitro and in vivo activity of KPT-8602, a second-generation clinical stage XPO1 inhibitor with improved tolerability, against acute lymphoblastic leukemia (ALL).

Methods
We performed co-localization experiments and a phenotypic reporter assay to evaluate the anti-XPO1 activity of KPT-8602. We cultured 5 T-ALL and 3 B-ALL cell lines with different concentrations of the drug and assessed cell viability after 72h exposure.  CRISPR/Cas genome editing was used to mutate XPO1 in ALL cell lines. For the in vivo experiments, NSG mice were injected with a T-ALL patient derived xenograft (PDX) sample, and animals were treated with KPT-8602 10mg/kg or placebo once a day by oral gavage for 3 weeks.  Mice were bled weekly to measure the total white blood cell count and number of human leukemic cells. 

Results
KPT-8602 strongly inhibited XPO1-cargo interaction as well as XPO1-dependent nuclear export at nanomolar concentrations and induced potent cytotoxicity on T-ALL and B-ALL cell lines in vitro (EC50 values ranging from 25 to 140 nM). To determine the drug-target specificity, we used CRISPR/Cas mediated genome editing to introduce XPO1 mutations that prevented KPT-8602 binding and resulted in loss of inhibitory activity, indicating that the inhibitory effects of KPT-8602 are completely dependent on XPO1 inhibition. Daily oral treatment with KPT-8602 could block leukemic expansion in mice engrafted with a JAK3 mutant T-ALL at an early stage of disease development.  Also when KPT-8602 treatment was initiated at day 28 after injection (when more than 5% of human leukemic cells were detected in the blood), we observed a significant reduction of leukemia cell numbers, without affecting normal erythropoiesis. KPT-8602 treatment during 3 weeks led to prolonged survival of the animals, compared to placebo treated animals (p = 0.0041).

Conclusion
KPT-8602 is a highly specific second-generation XPO1 inhibitor with potent anti-ALL activity both in vitro and in vivo. It displays better tolerability compared to selinexor, which allows for daily dosing and warrants further evaluation of this new drug in patients.

Session topic: E-poster
Abstract: E857

Type: Eposter Presentation

Background
Human exportin-1 (XPO1) is a transport protein that exports a wide variety of different cargo proteins from the nucleus to the cytoplasm. Selective Inhibitor of Nuclear Export (SINETM) compounds block the formation of the XPO1-cargo complex leading to accumulation of tumor suppressors in the nucleus and show potent anti-cancer activity. Selinexor (KPT-330) is currently in Phase-II/IIb clinical trials for treatment of both hematologic and solid tumors, while KPT-8602 is in Phase 1/2 clinical trials for treatment of relapsed refractory multiple myeloma. 

Aims
We investigated the in vitro and in vivo activity of KPT-8602, a second-generation clinical stage XPO1 inhibitor with improved tolerability, against acute lymphoblastic leukemia (ALL).

Methods
We performed co-localization experiments and a phenotypic reporter assay to evaluate the anti-XPO1 activity of KPT-8602. We cultured 5 T-ALL and 3 B-ALL cell lines with different concentrations of the drug and assessed cell viability after 72h exposure.  CRISPR/Cas genome editing was used to mutate XPO1 in ALL cell lines. For the in vivo experiments, NSG mice were injected with a T-ALL patient derived xenograft (PDX) sample, and animals were treated with KPT-8602 10mg/kg or placebo once a day by oral gavage for 3 weeks.  Mice were bled weekly to measure the total white blood cell count and number of human leukemic cells. 

Results
KPT-8602 strongly inhibited XPO1-cargo interaction as well as XPO1-dependent nuclear export at nanomolar concentrations and induced potent cytotoxicity on T-ALL and B-ALL cell lines in vitro (EC50 values ranging from 25 to 140 nM). To determine the drug-target specificity, we used CRISPR/Cas mediated genome editing to introduce XPO1 mutations that prevented KPT-8602 binding and resulted in loss of inhibitory activity, indicating that the inhibitory effects of KPT-8602 are completely dependent on XPO1 inhibition. Daily oral treatment with KPT-8602 could block leukemic expansion in mice engrafted with a JAK3 mutant T-ALL at an early stage of disease development.  Also when KPT-8602 treatment was initiated at day 28 after injection (when more than 5% of human leukemic cells were detected in the blood), we observed a significant reduction of leukemia cell numbers, without affecting normal erythropoiesis. KPT-8602 treatment during 3 weeks led to prolonged survival of the animals, compared to placebo treated animals (p = 0.0041).

Conclusion
KPT-8602 is a highly specific second-generation XPO1 inhibitor with potent anti-ALL activity both in vitro and in vivo. It displays better tolerability compared to selinexor, which allows for daily dosing and warrants further evaluation of this new drug in patients.

Session topic: E-poster

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