Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster II
We have previously demonstrated that PU-H71, a novel purine scaffold HSP90 inhibitor with selectivity for a tumor-specific HSP90 and currently translating into Phase 2 clinical evaluation, is capable of ablating malignant blasts, progenitor and stem cells in AML patient samples using in vitro studies. We found that leukemia cell lines (n=18) and primary AML patient samples (n=26) with greater numbers of simultaneously activated signaling networks, including PI3K-AKT and JAK-STAT, were the most sensitive to HSP90 inhibition. Using different genetic models, our studies revealed that diverse oncogenic transformations that converge upon simultaneous hyperactivation of PI3K-AKT and JAK-STAT promote sensitivity to PU-H71.
To validate the efficacy of PU-H71 in vivo, we generated AML-GFP-luciferase xenograft models using cell lines with hyperactive signalosome. Xenotransplanted mice were treated with PU-H71 one week post-engraftment. In vivo imaging indicated that MOLM-13 xenografted leukemia was rapidly and significantly reduced by PU-H71 treatment. Six doses of PU-H71 produced robust anti-leukemic activity as indicated by in vivo imaging and flow cytometric analysis of post-treatment bone marrow (no disease detected). In addition, we generated 7 AML patient-derived xenografts (PDX) cohorts with samples that displayed varied levels of activation of PI3K-AKT and JAK-STAT signaling pathways. After initial validation that status of the PI3K-AKT and JAK-STAT signaling pathways were preserved in the PDX, we initiated treatment with PU-H71 and found that, as predicted, the AML-PDX with the most hyperactive signalosome were the most sensitive to in vivo treatment to PU-H71. Importantly, samples with hyperactive PI3K-AKT and JAK-STAT signaling also demonstrated a significant reduction in LSC using secondary transplants.
Taken together, we found that a hyperactive signalosome results in increased sensitivity to the HSP90 inhibitor PU-H71 in vitro and in vivo. Our study suggests that evaluation of PI3K-AKT and JAK-STAT signaling pathways may provide a means to select patients who are most likely to benefit from HSP90 inhibitory therapy.
Disclosures: No relevant conflicts of interest to declare.
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