In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 907-907
Abstract:
Small molecule inhibitors of Janus kinase 2 (JAK2) such as Ruxolitinib and SAR302503 have demonstrated efficacy in clinical trials for treatment of myeloproliferative disorders. Activated JAK2 signaling has been reported in some acute myeloid leukemia (AML) samples even though JAK2 mutations are relatively rare in AML. Whether JAK2 inhibitors are effective in AML, particularly against the disease-sustaining leukemia stem cells (LSC), is not clear. We report that SAR302503 (Sanofi, Cambridge MA), an orally administered small molecule JAK2 inhibitor, shows efficacy in a xenograft model of human AML established by intrafemoral injection of primary AML cells into sublethally irradiated NOD.SCID mice. The AML samples tested were of multiple subtypes with heterogeneous cytogenetic and molecular abnormalities. Starting 2 weeks post transplantation to permit establishment of an AML graft, mice received twice daily oral gavage with 60 mg/kg SAR302503 or vehicle alone (0.5% methylcellulose) for 14 consecutive days. In 17 of 34 AML samples, SAR302503 treatment reduced leukemic engraftment in the injected femur (56-94% relative reduction, RR, compared to controls; p & lt;0.05) as well as non-injected bones (30-95% RR; p & lt;0.05). 5 additional samples exhibited a partial response ( & lt;50% RR in injected femur and 31-64% RR in non-injected bones, p & lt;0.05). In preliminary serial transplantation studies, AML cells harvested from SAR302503-treated primary mice showed reduced ability to generate a leukemic graft in untreated secondary mice compared to controls, suggesting that JAK2 inhibition reduces LSC function and/or survival. Given the heterogeneous response to SAR302503 treatment observed in vivo, we carried out phosphoflow cytometric analysis of patient samples to identify biomarkers that could predict drug response. AML samples that were sensitive to JAK2 inhibition in xenotransplantation assays exhibited high basal levels of pSTAT5, often in only a small subset of cells, that were rapidly decreased by SAR302503 treatment in vitro, whereas non-responding samples showed low levels of pSTAT5, suggesting that pSTAT5 is a useful drug response biomarker. Our results demonstrate the potential of SAR302503 to target AML cells including LSCs in a broad cross section of AML patients, and warrant further studies to identify responders and non-responders and better characterize proteomic biomarkers of drug response. The approach we have taken, which focuses on large-scale analysis of primary samples using state-of-the-art xenograft assays, offers a new paradigm for preclinical drug development to identify both novel agents that effectively target LSCs and the patients most likely to benefit from targeted treatment. Citation Format: Weihsu C. Chen, Andreea C. Popescu, Yan Xing, Gitte Gerhard, Julie Yuan, Mark Minden, Cynthia Guidos, Donna E. Hogge, John E. Dick, Jean CY Wang. Efficacy of SAR302503, a JAK2 inhibitor, in primary human acute myeloid leukemia xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 907. doi:10.1158/1538-7445.AM2013-907
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-907
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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