TKI discontinuation studies demonstrate that a portion of
TKI discontinuation studies demonstrate that a portion of TKI-treated CML patients remain in remission for up to 3 years, although long-term risk assessment is still necessary (Bansal and Radich, 2016). The majority of CML patients depend on lifetime TKI treatment, and substantial efforts have been devoted to identifying LSC-targeting drugs for use together with TKIs, aiming for a deeper molecular response and improving the outcome after TKI discontinuation. Agonists of peroxisome proliferator-activated Furegrelate sodium salt γ (PPARγ), such as pioglitazone, erode CML LSCs, and the efficacy of TKI combination therapy has been demonstrated in phase II clinical trials (Prost et al., 2015). MEK inhibitors (such as trametinib), protein-phosphatase-2A-activating drugs (such as FTY720), and a blocking anti-CD27 monoclonal antibody (to interrupt CD27-CD70 interaction) reportedly target CML LSCs and help overcome TKI resistance (Ma et al., 2014, Neviani et al., 2013, Riether et al., 2015); the latter two approaches are indirectly linked to diminishing β-catenin activation. A proteomics screen found that p53 and c-Myc pathways act in concert to maintain CML, and dual targeting of p53 and c-Myc is proposed to be a TKI replacement, especially for TKI-refractory CML patients (Abraham et al., 2016). Although CML is considered an “easily treatable” leukemia, most patients are committed to lifelong TKI dependence, and the risks of progression to an advanced stage or blast crisis remain for TKI responders. In addition, the detailed molecular events underlying transformation to more ominous leukemia are still poorly understood. Because of heterogeneity in genetic background and responses to TKI therapy among the CML patients, identifying different pathways to target CML LSCs is, thus, a highly worthy effort to obtain complementary therapeutic options for CML at various stages. For new drugs, safety and specificity to LSCs remain top priorities. Our unbiased transcriptome-based approaches identified PGE1 (alprostadil) and its analog, misoprostol, as potent suppressors of LSCs. In the murine CML model, p210-transformed HSPCs give rise to rapidly developing, fatal myeloproliferative neoplasm-like disease—or, sometimes, acute lymphoblastic leukemia—without a preceding chronic phase. In spite of these caveats, PGE1 and misoprostol remained effective in greatly reducing LSCs and extended recipient survival with lasting effects. The efficacy of PGE1 on human CD34+ CML stem/progenitor cells was consistent for all CML patients at CP and was also evident for accelerated and blast crisis CMLs. Importantly, the safety of PGE1 and misoprostol in clinical use has been demonstrated. This study, thus, exemplifies a precision-medicine strategy for targeting a transcriptional program that specifically affects LSCs, minimizing risks of perturbing critical factors/pathways utilized by normal hematopoietic cells. The same principle is potentially applicable to other types of malignancies, including AMLs and solid tumors.
Acknowledgments We thank Matthew D. Breyer for permission to use EP4FL/FL mice and Richard M. Breyer (Vanderbilt University) and Pamela Harding (Henry Ford Health System) for sharing the EP4FL/FL mice. We thank I. Antoshechkin (Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech) for RNA-seq, the University of Iowa Flow Cytometry Core Facility (J. Fishbaugh, H. Vignes, and G. Rasmussen) for cell sorting, the Radiation Core Facility (A. Kalen) for mouse irradiation, the University of Iowa Tissue Procurement Core Facility (J. Galbraith and M. Knudson) for acquiring HSPC products, and Jessica C. Parrott (Iowa State University) for proofreading the manuscript. The Flow Cytometry Core Facility is supported by the Carver College of Medicine/Holden Comprehensive Cancer Center (the University of Iowa), the Iowa City Veterans Administration Medical Center, and the National Center for Research Resources of the NIH (1S10 OD016199). The Tissue Procurement Core Facility is supported by an NCI award (P30CA086862) and funding from the Carver College of Medicine (University of Iowa). This study is supported in part by grants from the NIH (AI112579, AI115149, AI119160, and AI121080 to H.-H.X.; HG006130 to K.T.; and P50 CA097274 to S.R.L.) and the Veteran Affairs BLR&D Merit Review Program (BX002903A to H.-H.X). H.-H.X. is the founder of Cure-it LifeSciences, but this organization had no role in the experimental design and data interpretation of this study.