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haematologica | 2018; 103(6)
15-PGDH inhibition in multiple models of murine BMT
mechanism of action of (+)-SW209415 is distinct from approaches that have examined acute ex vivo exposure of donor cells to PGE2 analogs prior to graft administration.14- 17 These findings, across multiple different models, are consistent with and extend our prior observations with SW033291, a first-generation 15-PGDH inhibitor, that demonstrated inhibiting 15-PGDH increased bone mar- row stem cells as assessed by both cell surface markers and by marrow colony-forming assays.20
These demonstrations of efficacy are further buttressed by findings supporting the safety of (+)-SW209415, both when tested for evidence of hypothesized or potential on- target toxicities and when tested for off-target effects. We have previously shown that administering a 15-PGDH inhibitor to mice receiving a bone marrow transplant had no adverse effects, as assayed by ability to serially trans- plant the regenerated bone marrow, and also did not show any evidence of tumor induction during 7 months follow- ing whole body irradiation.20 These new studies also pro- duce no evidence that inhibiting tissue 15-PGDH has any effect on in vivo growth of either human MM cells or human AML cells. Although studies in additional human tumor models remain warranted, the absence of any effect of increased PGE2 on the in vivo growth of these cancer cells allays, at least, in part the hypothetical concern of this as a potential on-target toxicity of therapies employing 15- PGDH inhibitors.26 This observed lack of effect of PGE2 modulation on growth of established human cancer cells is consistent with clinical observations of a lack of effects
of non-steroidal anti-inflammatory drugs, which lower tissue PGE2, in clinical trials testing these drugs as thera- peutic agents for treating established cancers,34-37 and is consistent with prior hypotheses that oncogene activation may render tumor stem cells independent of PGE2 signal- ing.38 Furthermore, we found no evidence of off-target tox- icity associated with (+)-SW209415 when chronically administered at doses 10-fold above the dose that is ther- apeutically effective in potentiating BMT recovery, thus demonstrating a substantial therapeutic index for this chemical scaffold.
In conclusion, our results identify (+)-SW209415 as a promising second-generation 15-PGDH inhibitor that val- idates the efficacy and safety of targeting 15-PGDH in multiple murine models and thereby advances 15-PGDH as a therapeutic target for potentiating HSCT.
Funding
This work was funded by NIH grants R35 CA197442, R01 216863, and U54 HL119810, by a Harrington Discovery Institute Scholar Innovator Award, by an award from the Case Western Reserve University Council to Advance Human Health, by the Welch Foundation (I-1612), and by a sponsored research agreement to Case Western Reserve University from Rodeo Therapeutics. This research was also supported by the Radiation Resources Core Facility (P30CA043703), the Hematopoietic Biorepository and Cellular Therapy Core Facility (P30CA043703), and the Cytometry & Imaging Microscopy Core Facility of Case Comprehensive Cancer Center (P30CA043703).
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Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood. 2009;113(22):5444-5455.
16. Goessling W, Allen RS, Guan X, et al. Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models. Cell Stem Cell. 2011;8(4):445-458.
17. Cutler C, Multani P, Robbins D, et al.
24. Kim MJ, Kim MH, Kim SA, Chang JS. Age- related deterioration of hematopoietic stem cells. Int J Stem Cells. 2008;1(1):55-63.
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26. FitzGerald GA. Biomedicine. Bringing PGE(2) in from the cold. Science. 2015;348 (6240):1208-1209.
27. Bergmann C, Wobser M, Morbach H, et al.
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