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

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.

• Authors: A Ray, D S Das, Y Song, V Macri, P Richardson, C L Brooks, D Chauhan, K C Anderson
• Journal: Leukemia (Leukemia) Vol. 31 Issue 12 Pg. 2652-2660 (12 2017) ISSN: 1476-5551 [Electronic] England
• PMID: 28479592 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Proteasome Inhibitors
• Recombinant Fusion Proteins
• Thalidomide
• tagraxofusp
• pomalidomide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Bone Resorption (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dendritic Cells (drug effects, immunology, metabolism)
• Disease Models, Animal
• Drug Synergism
• Humans
• Mice
• Multiple Myeloma (drug therapy, immunology, metabolism, pathology)
• Neoplastic Stem Cells (drug effects, metabolism)
• Osteoblasts (cytology, metabolism)
• Osteoclasts (drug effects, metabolism)
• Proteasome Inhibitors (pharmacology)
• Recombinant Fusion Proteins (pharmacology)
• Thalidomide (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays