Editors' ChoiceCancer

A trojan horse targeting bone metastasis

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Science Translational Medicine  02 Oct 2019:
Vol. 11, Issue 512, eaaz3715
DOI: 10.1126/scitranslmed.aaz3715


Nanoparticle delivery of a Gli2 inhibitor prevents tumor-induced bone degradation in mice.

Bone metastases are incurable, and current systemic treatment options inhibit the function of the bone-resorbing osteoclasts in all bones. Lack of specific targeting for the diseased bone results in pathological fractures and osteonecrosis of the jaw in many cancer patients. Thus, new therapeutics are needed to prevent tumor-induced bone remodeling while allowing normal bone turnover.

Prior data showed that the transcription factor Gli2, downstream of Hedgehog signaling, is overexpressed in bone metastases but not healthy adult bone, and that Gli2 stimulates the secretion of proteins controlling osteoclastogenesis. A recent study from Vanderburgh and colleagues used a Gli inhibitor, GANT58, to treat bone metastasis using triple-negative breast or squamous non–small cell lung cancer xenografts implanted in the murine bone microenvironment. Injection of carrier-free GANT58 resulted in injection site necrosis but did not reduce metastatic tumor growth or tumor-induced osteolysis. To improve targeting and release of the drug, GANT58 was encapsulated in polymeric micellar nanoparticles that degrade in the presence of reactive oxygen species. The nanoparticles preferentially accumulated in long bones where tumors were present and in clearance organs (liver and kidney). GANT58-containing nanocarriers reduced metastatic tumor growth and tumor-induced bone breakdown, inhibiting osteoclastogenesis without affecting osteoblast proliferation or activation. Most relevant to patient care, GANT58 release from nanoparticles had the greatest effect on tumor-induced bone resorption when delivery was delayed to allow intracardiac injected tumor cells to colonize the bone and establish micrometastases. Thus, treatment with GANT58 nanocarriers would likely be effective in patients with confirmed metastatic bone disease.

Further studies are needed to understand how GANT58 nanocarrier delivery would affect other types of bone metastases, particularly prostate cancer tumors, which are more likely to have an osteoblastic or mixed phenotype. Additionally, the use of immunocompromised mice prevented analysis of the immune system’s role in targeting and release of the drug. Because the nanoparticles described in this study are degraded by reactive oxygen species, targeting could be altered by aging or in comorbidities such as arthritis and obesity, which elevate basal reactive oxygen species. The findings from this study are promising, although human trials are necessary to confirm efficacy. If successful, targeted delivery of GANT58 nanoparticles would provide treatment options for patients with difficult to treat metastatic cancers.

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