KPT-8602, A SECOND GENERATION CLINICAL STAGE SELECTIVE INHIBITOR OF NUCLEAR EXPORT (SINE) COMPOUND SHOWS ENHANCED ANTI-TUMOR ACTIVITY WHEN COMBINED WITH VENETOCLAX OR BENDAMUSTINE IN DLBCL
Author(s): ,
Erkan Baloglu
Affiliations:
Karyopharm Therapeutics,Newton, MA,United States
,
Hua Chang
Affiliations:
Karyopharm Therapeutics,Newton, MA,United States
,
William Senapedis
Affiliations:
Karyopharm Therapeutics,Newton, MA,United States
,
Trinayan Kashyap
Affiliations:
Karyopharm Therapeutics,Newton, MA,United States
,
Sivan Elloul
Affiliations:
Karyopharm Therapeutics,Newton, MA,United States
,
Sharon Shacham
Affiliations:
Karyopharm Therapeutics,Newton, MA,United States
Sharon Friedlander
Affiliations:
Karyopharm Therapeutics,Newton, MA,United States
(Abstract release date: 05/19/16) EHA Library. Baloglu E. 06/09/16; 132940; E1391
Dr. Erkan Baloglu
Dr. Erkan Baloglu
Contributions
Abstract
Abstract: E1391

Type: Eposter Presentation

Background
Selinexor, the first-in-class oral selective inhibitor of nuclear export (SINE) compound, is currently in Phase 1/2 clinical trials for the treatment of solid and hematological malignancies, including relapsed/refractory diffuse large B-cell lymphoma (DLBCL; NCT02227251). XPO1, the target of selinexor, has been shown to export >200 cargo proteins from the nucleus including major tumor suppressors (TSPs). SINE compounds prevent the nuclear export of many of TSPs facilitating suppressor reactivation. KPT-8602 is a second generation clinical stage oral SINE compound currently undergoing a Phase 1/2 open label study in patients with relapsed/refractory multiple myeloma (NCT02649790).

Aims
In preclinical studies KPT-8602 demonstrated improved tolerability over selinexor, possibly due to its reduced brain penetration. The goal of this study was to test whether single agent or combination of KPT-8602, with either venetoclax (selective BCL2 inhibitor) or bendamustine (DNA damaging agent) can further enhance the anti-tumor effect of KPT-8602 in DLBCL.

Methods
The effects of KPT-8602, bendamustine and venetoclax as single agents and KPT-8602 in combination with either bendamustine or venetoclax on cell viability were tested on a panel of DLBCL cell lines (i.e. RL, DB, SUDHL4, SUDHL10, Pfeiffer, U937, and Farage including the double hit lymphomas Toledo, DoHH2, and SUDHL6) using MTT assays. Total RNA and whole protein cell lysates from DLBCL cells were extracted and analyzed by qPCR and immunoblots. DoHH2 sub-cutaneous xenograft in mice were treated with KPT-8602, venetoclax or bendamustine alone or in combinations of KPT-8602-bendamustine or -venetoclax. Percent tumor growth inhibition (%TGI) and overall survival were determined for each treatment condition. Tumors were collected and analyzed using standard immunohistochemistry (IHC) methods.

Results
Combinations of KPT-8602 with bendamustine or venetoclax were highly effective both in vitro and in vivo. Using an MTT assay, we showed KPT-8602 was potent against a panel of DLBCL cells (median IC50: ~100 nM) and was synergistic/additive when combined with bendamustine or venetoclax. In the KPT-8602-bendamustine combination DoHH2 xenograft, treatment with each drug showed a %TGI of 52% (KPT-8602) and 76% (bendamustine) while the combination %TGI was 107%. Western and IHC analyses showed that KPT-8602 reduced the expression of key DNA Damage Response (DDR) proteins preventing treated cells from repairing the damage induced by bendamustine. In the KPT-8602-venetoclax in vivo study, the individual drugs had similar %TGI (52%; KPT-8602 and 56%; venetoclax). However, when the two drugs were combined, the treatment showed an additive effect (98%). Although, the anti-BCL2 proteins, Bax and Bim, were upregulated in KPT-8602 treated xenograft tumors, these pro-apoptotic pathway proteins were elevated to a greater extent in the combination-treated tumors suggesting the two drugs induced non-redundant mechanism of apoptosis activation.

Conclusion
KPT-8602 shows single agent activity as well as enhanced antitumor activity in combination with bendamustine or venetoclax through modulation of the DDR and BCL2 pathways in models of DLBCL (including double hits). These data provide rational support for the study of single agent KPT-8602 and in combinations with bendamustine or venetoclax in future DLBCL clinical trials.

Session topic: E-poster

Keyword(s): DLBCL, NHL
Abstract: E1391

Type: Eposter Presentation

Background
Selinexor, the first-in-class oral selective inhibitor of nuclear export (SINE) compound, is currently in Phase 1/2 clinical trials for the treatment of solid and hematological malignancies, including relapsed/refractory diffuse large B-cell lymphoma (DLBCL; NCT02227251). XPO1, the target of selinexor, has been shown to export >200 cargo proteins from the nucleus including major tumor suppressors (TSPs). SINE compounds prevent the nuclear export of many of TSPs facilitating suppressor reactivation. KPT-8602 is a second generation clinical stage oral SINE compound currently undergoing a Phase 1/2 open label study in patients with relapsed/refractory multiple myeloma (NCT02649790).

Aims
In preclinical studies KPT-8602 demonstrated improved tolerability over selinexor, possibly due to its reduced brain penetration. The goal of this study was to test whether single agent or combination of KPT-8602, with either venetoclax (selective BCL2 inhibitor) or bendamustine (DNA damaging agent) can further enhance the anti-tumor effect of KPT-8602 in DLBCL.

Methods
The effects of KPT-8602, bendamustine and venetoclax as single agents and KPT-8602 in combination with either bendamustine or venetoclax on cell viability were tested on a panel of DLBCL cell lines (i.e. RL, DB, SUDHL4, SUDHL10, Pfeiffer, U937, and Farage including the double hit lymphomas Toledo, DoHH2, and SUDHL6) using MTT assays. Total RNA and whole protein cell lysates from DLBCL cells were extracted and analyzed by qPCR and immunoblots. DoHH2 sub-cutaneous xenograft in mice were treated with KPT-8602, venetoclax or bendamustine alone or in combinations of KPT-8602-bendamustine or -venetoclax. Percent tumor growth inhibition (%TGI) and overall survival were determined for each treatment condition. Tumors were collected and analyzed using standard immunohistochemistry (IHC) methods.

Results
Combinations of KPT-8602 with bendamustine or venetoclax were highly effective both in vitro and in vivo. Using an MTT assay, we showed KPT-8602 was potent against a panel of DLBCL cells (median IC50: ~100 nM) and was synergistic/additive when combined with bendamustine or venetoclax. In the KPT-8602-bendamustine combination DoHH2 xenograft, treatment with each drug showed a %TGI of 52% (KPT-8602) and 76% (bendamustine) while the combination %TGI was 107%. Western and IHC analyses showed that KPT-8602 reduced the expression of key DNA Damage Response (DDR) proteins preventing treated cells from repairing the damage induced by bendamustine. In the KPT-8602-venetoclax in vivo study, the individual drugs had similar %TGI (52%; KPT-8602 and 56%; venetoclax). However, when the two drugs were combined, the treatment showed an additive effect (98%). Although, the anti-BCL2 proteins, Bax and Bim, were upregulated in KPT-8602 treated xenograft tumors, these pro-apoptotic pathway proteins were elevated to a greater extent in the combination-treated tumors suggesting the two drugs induced non-redundant mechanism of apoptosis activation.

Conclusion
KPT-8602 shows single agent activity as well as enhanced antitumor activity in combination with bendamustine or venetoclax through modulation of the DDR and BCL2 pathways in models of DLBCL (including double hits). These data provide rational support for the study of single agent KPT-8602 and in combinations with bendamustine or venetoclax in future DLBCL clinical trials.

Session topic: E-poster

Keyword(s): DLBCL, NHL

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