Page 152 - Haematologica June

Ferrata Storti Foundation
Stem Cell Transplantation
A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support
Haematologica 2018 Volume 103(6):1054-1064
1Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; 2Department of Pathology, Ulsan University College of Medicine, Asan Medical Center, Seoul, Republic of Korea; 3Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA; 4University Hospitals Seidman Cancer Center, Cleveland, OH, USA; 5Department of Pathology, Case Western Reserve University, Cleveland, OH, USA; 6Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA and 7Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
Amar Desai,1 Yongyou Zhang,1 Youngsoo Park,1,2 Dawn M. Dawson,3 Gretchen A. Larusch,1 Lakshmi Kasturi,1 David Wald,3,4,5 Joseph M. Ready,6,7 Stanton L. Gerson1,3,* and Sanford D. Markowitz1,3,4*
*SLG and SDM contributed equally to this work.
ABSTRACT
Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplantation and marrow recovery exposes recipi- ents to risks of fatal infection, a significant source of transplant-associated morbidity and mortality. We have previously described the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH, increases bone marrow prostaglandin E2, and accelerates hematopoietic recovery following murine transplant. Here we describe the efficacy of (+)- SW209415, a second-generation 15- PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 is 10,000-fold more soluble, providing the potential for intravenous delivery, while maintaining potency in inhibit- ing 15-PGDH, increasing in vivo prostaglandin E2, and accelerating hematopoietic regeneration following transplantation. In additional mod- els, (+)-SW209415: (i) demonstrated synergy with granulocyte colony- stimulating factor, the current standard of care; (ii) maintained efficacy as transplant cell dose was escalated; (iii) maintained efficacy when trans- plant donors and recipients were aged; and (iv) potentiated homing in xenotransplants using human hematopoietic stem cells. (+)-SW209415 showed no adverse effects, no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high-dose adminis- tration, no toxicity as assessed by weight, blood counts and serum chem- istry. These studies provide independent chemical confirmation of the activity of 15-PGDH inhibitors in potentiating hematopoietic recovery, extend the range of models in which inhibiting 15-PGDH demonstrates activity, allay concerns regarding potential for adverse effects from increasing prostaglandin E2, and thereby, advance 15-PGDH as a thera- peutic target for potentiating hematopoietic stem cell transplantation.
Correspondence:
sxm10@case.edu
Received: August 9, 2017. Accepted: February 20, 2018. Pre-published: February 22, 2018.
doi:10.3324/haematol.2017.178376
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/1054
©2018 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1054
haematologica | 2018; 103(6)
ARTICLE