Antisense inhibition of STAT3 as a therapeutic strategy against leukemic stem cells
Aditi Shastri
MDAlbert Einstein College of Medicine
Project Term: July 1, 2019 - June 30, 2022
STAT3 is over-expressed in highly purified leukemic stem & progenitor cells and its expression is associated with a worse prognosis. Inhibition of STAT3 by an anitsense oligonucleotide AZD9150 leads to decreased viability of leukemic stem cells in in vitro & in vivo models. In the proposed studies, we will comprehensively examine the role of STAT3 in AML stem cell dynamics, identify the mechanisms of its actions and determine the efficacy of clinically available STAT3 inhibitors.
Acute myeloid leukemia(AML) is a hematologic malignancy that can arise from a small population of cancer-initiating stem cells that are not eliminated by conventional chemotherapies. An improved understanding of the molecular pathways that regulate these diseases is required for the development of future targeted therapies that will prevent disease relapses. My mentor’s lab (Dr.Amit Verma's lab) has demonstrated that a pool of disease-initiating stem cells exist in AML that contains and progressively acquires genetic and epigenetic alterations that lead to the development of low blood counts or cytopenias which are the hallmarks of this disease. My mentor and others have also demonstrated that STAT3 is up regulated in AML hematopoietic stem cells (HSC’s) and is a marker of poor prognosis. To therapeutically target AML HSC’s, we propose a translational study to determine the preclinical efficacy of a specific antisense oligonucleotide (AZD9150) against STAT3 to develop it for future clinical trials for patients with MDS. AZD9150 is a next-generation drug in a class of drugs known as antisense oligonucleotides. This drug has already shown promise in clinical trials for patients with advanced cancers & lymphomas. The success of our study will allow this novel antisense drug to progress rapidly to the late clinical trial phase and provide treatment options for patients with AML, an area of oncology with a limited therapeutic arsenal. Beyond direct clinical-translational relevance to AML, this study also has important implications in the field of other hematologic malignancies. STAT3 is a therapeutic target in many other hematologic malignancies such as CLL, DLBCL and others. Our findings with STAT3 inhibitors will be translatable to these malignancies.