Britta Will, PhD | Aplastic Anemia and MDS International Foundation

Britta Will, PhD

Therapeutic targeting of aberrant stem cells in MDS
Original Research Center: 
Albert Einstein College of Medicine
Pubmed Author Name: 
Will B

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.

2015
First Year Report: 

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).

Final Report: 

Final Report:

Lifelong regeneration and maintenance of healthy blood formation (hematopoiesis) critically depends on the correct regulation of gene activation and silencing. We and others have reported aging-associated acquired genetic and epigenetic alterations, some of which have been linked to MDS pathobiology, in the past.

This study evaluated a new therapeutic approach of targeting of aberrant gene activation in immature blood cells to eradicate leukemic (stem) cells in patients with myelodysplastic syndrome (MDS). Owing to the generous support of AA & MDS International Foundation we could establish critical preclinical rationales for the use of a novel and highly specific inhibitor of signal transducer and activator of transcription-3 (STAT3), a signaling-induced gene-regulatory protein, for the treatment of MDS.

We carried out a comprehensive gene expression analysis of purified hematopoietic stem cells (HSCs) from patients with MDS and MDS-to-AML, and found that disease-initiating hematopoietic stem and progenitor cells harbor significant STAT3 over-expression. Importantly, abnormal STAT3 message levels also correlated with decreased overall survival and worsened clinical parameters, indicating functional relevance in MDS pathology (AIM 1).

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), for the targeting of aberrant stem cells in MDS and AML (AIM 2 & 3). Specifically, our collected data show that AZD9150 specifically impairs STAT3-dependent gene activation, sparing other STAT family members, which has been the main obstacle in targeting STAT3 using small molecule inhibitors in the past. Our data further demonstrate that AZD9150 is readily taken up 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. Importantly, we found that ASO-mediated STAT3 inhibition selectively induced cell death and reduced the growth of leukemic cells ex vivo and upon transplantation into mice, while exerting no detectable molecular or functional changes in healthy immature blood cells. We are currently finalizing our study with a series of experiments evaluating in detail the efficacy of this novel therapeutic intervention for the successful targeting and impairment of aberrant HSCs, which we hope to complete and report by the end of this year. Together, our study provides a strong preclinical rationale for introducing AZD9150 as a new treatment option for patients with MDS. AZD9150 is currently under investigation in clinical phase I trials for advanced lymphoma or solid tumors (NCT01839604 (completed), NCT02417753) and could thus be implemented in the treatment of MDS in a timely fashion.