Editors' ChoiceCancer

Protecting the Fortress: Preventing Metastasis by Neutralizing Niche Homing

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Science Translational Medicine  08 Oct 2014:
Vol. 6, Issue 257, pp. 257ec172
DOI: 10.1126/scitranslmed.3010421

Metastasis is a critical step in tumor malignancy, yet therapies generally are not designed to target this process. The bone marrow is a target organ to which metastatic tumor cells are attracted by a variety of signals, including stromal-cell–derived factor 1 (SDF-1). Roccaro and colleagues have now developed a high-affinity PEGylated Spiegelmer (artificial l-oligonucleotide) that targets SDF-1 and attenuates cancer cell homing and metastasis to the bone marrow in a multiple myeloma mouse model.

The bone marrow provides a niche with factors that are necessary for normal hematopoiesis. It often serves as a metastatic site as well because the bone marrow niche is permissive for tumor cell expansion. On the basis of known mechanisms that regulate tumor cells’ homing to this niche, the authors evaluated the bone marrow of patients with a variety of cancers, including multiple myeloma, and found an increased expression of the chemoattractant SDF-1. The authors also observed that bone marrow mesenchymal cells of patients with multiple myeloma produced more SDF-1 than those of controls. To develop a targeting strategy, the researchers identified L-RNA sequences that bound to SDF-1 and modified these oligonucleotides by conjugating them to polyethylene glycol (PEG) to increase their molecular weight and reduce in vivo clearance. When these oligonucleotides were injected into mouse models of multiple myeloma, they potently inhibited the cancer’s growth and increased the animals’ survival by inhibiting tumor cell colonization of the bone marrow. The authors then combined this treatment strategy with bortezomib, a chemotherapy drug used in multiple myeloma, and found that the combination was more effective in reducing in vivo tumor growth and inhibiting signaling through the extracellular signal–regulated kinase (ERK), Akt, and Src pathways.

Although strategies for targeting the SDF-1 receptor have been previously evaluated as anticancer therapies, these results demonstrate that SDF-1 can be neutralized to inhibit metastasis. These findings lay the foundation for the translation of this strategy for treating multiple myeloma. Moreover, it should be possible to expand this approach to target other advanced cancers by preventing tumor cell homing to the bone marrow niche.

A. M. Roccaro et al., SDF-1 inhibition targets the bone marrow niche for cancer therapy. Cell Rep. 10.1016/j.celrep.2014.08.042 (2014). [Abstract]

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