Combination differentiation therapy and recurrence prevention of AML

ABSTRACT IN LAY TERMS Title: The Nrf2 and VDR signaling pathways in vitamin D-based combination differentiation therapy and recurrence prevention of AML Application number: 2017112 Principal Investigators: Prof. Michael Danilenko1, Prof. George P. Studzinski2, Dr. Xuening Wang2.

1 Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

2 Department of Pathology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.

Acute myeloid leukemia (AML) is a blood malignancy with a very high death rate. This project addresses one of the most pressing issues in AML treatment - the unmet need for tolerated therapies for patients who are unfit for aggressive chemotherapy. The hormonal form of vitamin D (calcitriol) produced in our body can potentially treat AML by inducing maturation and growth arrest of leukemic cells. However, this action requires pharmacological doses of calcitriol which may cause serious side effects by increasing blood calcium levels. We have previously shown that plant polyphenolic antioxidants (PAOx) can sensitize leukemic cells to low, non-toxic doses of calcitriol or synthetic vitamin D analogs (VDAs) by activating the regulatory protein Nrf2. While Nrf2, the “master regulator” of cell defense, is frequently overactive in AML cells, causing resistance to standard chemotherapy, this project is designed to provide proof of concept that patients with overactive Nrf2 can benefit from treatment with our proposed combinations of low-calcemic VDAs and PAOx. Based on our previous results, we also hypothesize that such combinations applied following mild chemotherapy may prevent leukemia recurrence following chemotherapy. These hypotheses will be tested in mice bearing AML cells with either high or low Nrf2 levels. Clinical significance of this project will be strengthened by determining the modes of Nrf2-mediated activation of the vitamin D receptor signaling pathways which are critical for the induction of maturation and growth arrest of AML cells. Positive outcome of these studies will lead to the development of mild but effective combination strategies for the treatment and/or recurrence prevention of AML, particularly, in the elderly who comprise the majority of patients with leukemia.