Pre-clinical Studies of Therapy for Myelodysplastic Syndrome

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Our initial studies used the DNA-methyltransferase inhibitor 5-azacytidine; some of these results have been published (Genome Res. 4:580-91, 2014).However, since our initial studies used transgenic mice, effective treatment with 5-azacytidine could not replace the MDS bone marrow with completely normal (ie, wildtype or WT) bone marrow, since all of the bone marrow was transgenic. Therefore, in order to distinguish improvement in peripheral blood cytopenia due to differentiation of the MDS clone from elimination of the MDS clone, we have repeated the experiments using chimeric mice, that have both WT and NHD13 bone marrow. Drs. Difillipantonio, Doroshow, and colleagues from the Division of Cancer Treatment and Diagnosis (DCTD) have developed two novel DNMT1 inhibitors, both of which are in phase I clinical trials. In collaboration with Dr. Difillipantonio and colleagues, we are now treating chimeric NHD13/WT mice with these compounds to assess efficacy in treatment of MDS. In addition, we have refined our model to enable transplant of NHD13 MDS hematopoietic cells without using ionizing radiation as a conditioning agent. We have successfully engrafted WT mice with NHD13 BM by pre-treating the recipient mice with the Cdc42 inhibitor CASIN, which leads to egress of the WT hematopoietic stem cells. A manuscript describing these studies, as well as an unexpected finding that one of the two novel DNMT1 inhibitors was associated with specific CG transversions, has recently been submitted. In addition to the experiments outlined above, we have transferred NHD13 mice to colleagues at many academic institutions, and have licensed NHD13 mice to industry for pre-clinical studies. These colleagues have treated NHD13 mice with a variety of agents, including histone deacetylase inhibitors, apoptosis inhibitors, and angiogenesis inhibitors. One of these compounds (ACE-536 or luspatercept) was recently approved for treatment of anemic MDS patients by the FDA. We previously executed a CRADA with Tolero Pharmaceuticals, who have provided us with funding to study the effects of alvocidib (a Cdk9/Mcl1 inhibitor) and DNMTi on NHD13 mice and cell lines. A manuscript describing the in vitro and in vivo results of these studies is now in preparation.