Myelodysplastic syndromes (MDS) are the most common hematologic malignancies in the elderly, presenting as bone marrow failure and characterized by disorderly growth and differentiation of aberrant hematopoietic stem and progenitor cells. Bone marrow transplantation is currently the only curative option for MDS. Even though 5-azacitidine (5-aza) has resulted in clinical responses and improvements in overall survival, relapse and refractory disease continue to occur in some patients.
Recent findings show that cancer-initiating cells (CIC) can exist as pools of relatively quiescent cells that do not respond well to common cell-toxic agents and contribute to treatment failure. In fact, we and others have shown that karyotypically abnormal hematopoietic stem cells (HSCs) can survive during 5-aza induced remissions and expand before relapses. As a consequence, future treatments must be directed against those CIC-containing compartments, especially long-lived HSC populations, to develop a lasting cure for the disease.
Our study will generate further evidence that the characterization of molecular alterations in aberrant HSCs will uncover potent new therapeutic options for future stem cell-directed therapies. Most importantly, our work will inspire further studies that monitor the successful eradication of aberrant and pre-leukemic HSCs during therapy. Ultimately, this will enable us to eradicate functionally altered HSCs suppressing normal blood production in other bone marrow failure syndromes, such as aplastic anemia, or leukemia.
Over the last year we have made substantial progress towards evaluating the use of antisense-mediated targeting of aberrant STAT3 expression and activation in leukemic (stem) cells from patients with MDS. Specifically, the comprehensive gene expression analysis of purified hematopoietic stem cells (HSCs) from 100 patients with MDS and MDS-to-AML has been initiated and is currently ongoing (AIM 1). We are collecting further patient material which is processed for global gene expression analysis by RNA-sequencing. We have further generated very exciting and strongly encouraging proof of concept data for using STAT3-ISIS-Rx / AZD9150, a therapeutic Generation 2.5 antisense oligonucleotide (ASO), in the therapeutic targeting of aberrant stem cells in MDS and AML (AIMs 2 & 3).
Specifically, our current data shows that AZD9150 specifically reduces STAT3 networks without compromising other STAT, family members which have been the main obstacle in targeting STAT3 using small molecule inhibitors in the past. Moreover, we found that STAT3 inhibition induced cell death and reduced the growth of leukemic cells, both ex vivo and upon transplantation into mice. We have now also data demonstrating that the AZD9150 is well incorporated into primary patient-derived hematopoietic cells which provides a critical proof of concept to utilize ASO-mediated interference as a novel therapeutic strategy in MDS. Our upcoming liens of experiments will evaluate in detail the efficacy of this novel therapeutic intervention using primary patient-derived stem cells. If we find successful targeting and impairment of aberrant HSCs by AZD9150, this strategy could be implemented in clinical practice in a very short period of time, as it is currently under investigation in clinical phase I trials for advanced lymphoma or solid tumors (NCT01839604 (completed), NCT02417753).