Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

Nat Chem Biol. 2013 Dec;9(12):840-848. doi: 10.1038/nchembio.1367.

Kimberly A Hartwell ^# ¹ ² ³, Peter G Miller ^# ² ³, Siddhartha Mukherjee ⁴, Alissa R Kahn ⁵, Alison L Stewart ¹, David J Logan ¹, Joseph M Negri ¹, Mildred Duvet ¹ ⁴, Marcus Järås ², Rishi Puram ² ³, Vlado Dancik ¹, Fatima Al-Shahrour ¹ ², Thomas Kindler ², Zuzana Tothova ² ³, Shrikanta Chattopadhyay ¹ ⁶, Thomas Hasaka ¹, Rajiv Narayan ¹, Mingji Dai ¹ ⁷, Christina Huang ¹, Sebastian Shterental ², Lisa P Chu ², J Erika Haydu ², Jae Hung Shieh ⁵, David P Steensma ³ ⁸, Benito Munoz ¹, Joshua A Bittker ¹, Alykhan F Shamji ¹, Paul A Clemons ¹, Nicola J Tolliday ¹, Anne E Carpenter ¹, D Gary Gilliland ¹ ² ⁸ ⁹, Andrew M Stern ¹, Malcolm A S Moore ¹⁰, David T Scadden ¹ ⁴ ⁶, Stuart L Schreiber ¹ ⁹ ⁷, Benjamin L Ebert ¹ ² ³ ⁸, Todd R Golub ¹ ³ ⁹ ¹¹

Affiliations

1 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2 Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
3 Harvard Medical School, Boston, MA 02115, USA.
4 Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
5 Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
6 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
7 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
8 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
9 Howard Hughes Medical Institute, Harvard Medical School, Chevy Chase, MD 20815, USA.
10 Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
11 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
# Contributed equally.

PMID: 24161946 DOI: 10.1038/nchembio.1367

Abstract

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.

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HY-18714

BRD7116

99.73%, Bacterial Inhibitor

Bacterial

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