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Multiple Myeloma, Gammopathies

A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells

Leukemia volume 31, pages 2652–2660 (2017)Cite this article

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Abstract

Novel therapies for multiple myeloma (MM) can target mechanism(s) in the host-MM bone marrow (BM) microenvironment mediating MM progression and chemoresistance. Our studies showed increased numbers of tumor-promoting, immunosuppressive and drug-resistant plasmacytoid dendritic cells (pDCs) in the MM BM microenvironment. pDC-MM cell interactions upregulate interleukin-3 (IL-3), which stimulates both pDC survival and MM cell growth. Since IL-3 R is highly expressed on pDCs in the MM BM milieu, we here targeted pDCs using a novel IL-3 R-targeted therapeutic SL-401. In both in vitro and in vivo models of MM in its BM milieu, SL-401 decreases viability of pDCs, blocks pDC-induced MM cell growth, and synergistically enhances anti-MM activity of bortezomib and pomalidomide. Besides promoting pDC survival and MM cell growth, IL-3 also mediates progression of osteolytic bone disease in MM. Osteoclast (OCL) progenitor cells express IL-3 R, and we show that SL-401 abrogates monocyte-derived OCL formation and bone resorption. Finally, we show that SL-401 also decreases the viability of IL-3 R-expressing cancer stem-like cells in MM. Overall, our study provides the preclinical basis for clinical trials of SL-401 to block pDC-induced MM cell growth, inhibit osteoclastogenesis and target MM stem-like cell subpopulations to improve patient outcome in MM.

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Acknowledgements

The grant support for this investigation was provided by National Institutes of Health Specialized Programs of Research Excellence (SPORE) grant P50100707, R01CA207237, and RO1 CA050947. KCA is an American Cancer Society Clinical Research Professor.

Author contributions

DC designed the research, analyzed the data and wrote the manuscript; AR performed the experiments and analyzed the data; CLB and VM provided SL-401 and reviewed the manuscript; DSD helped in in vivo SCID-hu mouse study and flow cytometry; YS helped in generation of Oct4 cells and flow cytometry; PR provided clinical samples; and KCA analyzed the data and wrote the manuscript.

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  1. D Chauhan and K C Anderson: Joint Senior authors.

Authors and Affiliations

  1. Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    A Ray, D S Das, Y Song, P Richardson, D Chauhan & K C Anderson

  2. Stemline Therapeutics, New York, NY, USA

    V Macri & C L Brooks

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Correspondence to D Chauhan or K C Anderson.

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Competing interests

KCA is on Advisory board of Celgene, Millenium, Gilead and Bristol Myers Squibb, and is a Scientific Founder of Acetylon, Oncopep, and C4 Therapeutics. DC is consultant to Stemline Therapeutic, Inc. The remaining authors declare no conflict of interest.

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Ray, A., Das, D., Song, Y. et al. A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells. Leukemia 31, 2652–2660 (2017). https://doi.org/10.1038/leu.2017.135

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