Figure provided by Dr. Dudakov
Exposure to high dose radiation, whether accidental or therapeutic, results in serious toxicities due to the depletion of hematopoietic stem cells (HSC), the cells giving rise to the blood cells. Previous studies investigating ways to improve recovery of stem cell function showed that inhibition of sex hormones stimulates hematopoiesis. Degarelix, an FDA-approved antagonist of luteinizing hormone (LH), has been successfully used for the treatment of prostate cancer but never been evaluated in the context of hematopoiesis. In a recent study published in the journal Nature medicine, Dr. Jarrod Dudakov (Clinical Research Division) in collaboration with Drs. Enrico Velardi and Marcel van den Brink (Memorial Sloan Kettering Cancer Center) and Dr. Hans-Peter Kiem (Fred Hutch), demonstrated that Degarelix also improves hematopoietic stem cells recovery following radiation injury. As explained by Dr. Dudakov, “Degarelix could be adapted to improve transplant outcomes, and in particular improving immune reconstitution, which can influence all of the major complications after allogeneic transplant - infection, relapse and graft-versus-host-disease. In fact, a trial looking at this very question is currently under way at Memorial Sloan Kettering Cancer Center. However, it gets especially complicated when you consider that Degarelix (and other similar drugs) does not just block LH but also its downstream sex steroids, which we know can have profound effects on both HSC function and immunity in general.”
The study, performed in immunocompetent mice, demonstrated that survival of mice treated with Degarelix one day after receiving an otherwise lethal dose of irradiation survived significantly (p<0.0001) better than the control mice treated with the vehicle alone, with a more pronounced effect in males than in females. The Degarelix treatment was still efficient, albeit less, when administered two days after irradiation. Untreated mice could be rescued by bone marrow transplant, confirming bone marrow failure as a cause of death in this group, while bone marrow cells from the treated mice started recovering after 10 days. Additionally, secondary transplants using cells isolated from the bone marrow or spleen, a gold standard to demonstrate the phenotype and function integrity of the transplanted cells, demonstrated significantly improved hematopoietic engraftment in the Degarelix-treated mice relative to the untreated mice during the seven month follow-up period.
While LH stimulates HSC proliferation in ex vivo experiments, Degarelix maintain long-term repopulating HSCs in a quiescent state following radiation. Indeed, a lower proportion of Ki67-expressing cells, a marker of cell proliferation, were detected in the bone marrow of Degarelix-treated mice relative to the mock-treated mice. Degarelix protects the HSCs from an excessive cell proliferation following radiation that would otherwise results in HSC exhaustion and myelosuppression (decreased bone marrow activity resulting in decreased presence of white and red blood cells in the peripheral blood). In agreement, reactivation of the HSCs proliferation by the immunostimulant polyinosinic-polycytidylic acid resulted in higher cell viability when pre-treated with Degarelix. Additionally, expression of anti-apoptotic (Bcl2 or Mcl1) and quiescence (Hes1, Cdkn1a) genes was more elevated in the Degarelix-treated mice after irradiation.
Interestingly, expression of the LH receptor was restricted to the most primitive and long-term repopulating HSC. Constitutive stimulation of this receptor abrogated Degarelix protective effect, demonstrating that the antagonist exerts its function through LH signaling.
These data establish for the first time the role of luteinizing hormone signaling in HSC reconstitution following radiation injury and identifies a new purpose for the already FDA-approved drug Degarelix; to protect HSCs from excessive cell proliferation and exhaustion. “We are excited about several avenues that this work has opened up”, explained Dr. Dudakov, “First and foremost is to translate this into an effective therapy as a radiation countermeasure. To achieve that we need to first investigate why there are such differences in responses between male and female mice. We hypothesize that this is because of the differential effects of downstream sex hormones - estrogen has a largely positive effect on HSC function while androgens have largely negative effect. We are also very enthusiastic about exploiting the restricted expression of the LH receptor on HSCs so that we can develop an effective means of isolating the most primitive HSCs based on only one marker. We are currently working with the Antibody Technology Facility to generate a monoclonal antibody against LH receptor for that purpose.”
Financial support for this study was provided by the National Institutes of Health, The Lymphoma Foundation, The Susan and Peter Solomon Divisional Genomics Program, MSKCC Cycle for Survival, the European Union’s Seventh Framework Programme for Research, Technological Development and Demonstration, the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, the Italian Foundation for Cancer Research, the Italian Society of Pharmacology, and an American Society of Bone Marrow Transplantation, the Australian National Health and Medical Research Council, the American Society of Hematology, the DKMS Foundation for Giving Life, the Sloan Kettering Institute and Boehringer Ingelheim Fonds.
Velardi E, Tsai JJ, Radtke S, Cooper K, Argyropoulos KV, Jae-Hung S, Young LF, Lazrak A, Smith OM, Lieberman S, Kreines F, Shono Y, Wertheimer T, Jenq RR, Hanash AM, Narayan P, Lei Z, Moore MA, Kiem HP, van den Brink MRM, Dudakov JA. 2018. Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nature medicine. 24, pages 239–246.