Abstract 39: XPO1 inhibitor, KPT-8602, is well tolerated and highly active against AML blasts and LICs
Bibliographic record
Abstract
Abstract Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. An attractive target for AML therapy is nuclear exporter exportin 1 (XPO1), which mediates continuous nuclear export of a subset of proteins and RNAs. The orally bioavailable XPO1 inhibitor of the Selective Inhibitor of Nuclear Export (SINE) class of compounds, selinexor (KPT-330), is currently in phase 1 and 2 clinical trials in adult patients with AML and in phase 1 trials for relapsed childhood ALL and AML. The results of these trials are encouraging, as they have demonstrated that selinexor is active in inducing remission in patients with relapsed or refractory disease. Here we report the antileukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the CNS-mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two- or three-times-weekly regimen of selinexor. To define the antileukemia activity of KPT-8602 against primary AML blasts and LICs in a relevant preclinical setting, we established patient-derived xenograft (PDX) models, in which leukemic blasts from AML patients with poor-prognosis disease (cytogenetically normal AML with FLT3-ITD (AML-CN), AML with complex karyotype (AML-CK), and MDS-derived AML (MDS/AML) are transplanted into immunodeficient NOD-SCID-IL2Rcgnull (NSG) mice. Mice engrafted with leukemic blasts are treated with vehicle, selinexor (20 mg/kg three times per week), or KPT-8602 (15 mg/kg daily for 4 weeks). KPT-8602 exhibits superior antileukemic activity and better tolerability in the AML PDX models tested, with nearly complete elimination of human AML cells in AML-CN model. To determine the frequency of LICs in the vehicle control, selinexor or KPT-8602, we used a limiting dilution transplantation assay. Although both selinexor and KPT-8602 effectively targeted LICs, KPT-8602 is more potent in eliminating LICs, as evidenced by a more profound reduction of LIC frequency in the AML-CK and AML-CN PDX models (507-fold vs. 0.9-fold reduction in AML-CK, P<0.0001; and 437-fold vs. 111-fold reduction in AML-CN by KPT-8602 vs. selinexor, P=0.79). The impact on normal human hematopoietic stem and progenitor cell (HSPC) fractions by CD34/CD38 flow analysis and limiting dilution transplantation assays (performed by the same methodology as described for PDX models of AML) demonstrates that, in contrast to its profound effects against AML LIC, KPT-8602 does not preferentially kill normal HSPC, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. KPT-8602 has entered a phase 1/2 trial in patients with relapsed/refractory multiple myeloma. Our preclinical results indicate that KPT-8602 should be tested in clinical trials to determine its toxicity and efficacy in patients with relapsed or refractory AML, with the hope that it can eventually be integrated into upfront combination chemotherapy regimens. To delineate the pathways that mediate the apoptotic signaling in response to the SINE compounds, we are conducting the RNA-seq, ChIP-seq and ATAC-seq studies on AML cell lines treated in vitro as well as AML cells isolated from PDX mice. The preliminary results of these studies will be presented at the meeting. Citation Format: Julia Etchin, Alla Berezovskaya, Amy S. Conway, Ilene A. Galinsky, Richard M. Stone, Erkan Baloglu, William Senapedis, Yosef Landesman, Michael Kauffman, Sharon Shacham, Jean CY Wang, A Thomas Look. XPO1 inhibitor, KPT-8602, is well tolerated and highly active against AML blasts and LICs [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 39.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".