Editors' ChoiceCancer

A two-step program preventing bone metastatic relapse

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Science Translational Medicine  27 Nov 2019:
Vol. 11, Issue 520, eaaz9759
DOI: 10.1126/scitranslmed.aaz9759

Abstract

Treating bone metastatic prostate cancer with docetaxel nanoparticles and denosumab averts tumor regrowth.

Bone metastases are incurable and associated with decreased patient survival rates. For a majority of patients with prostate cancer, bone metastases occur after the failure of initial androgen deprivation therapy. Taxane chemotherapy is the primary second line of treatment for these patients, although bone metastatic relapse is common. Many prostate cancer bone lesions are osteolytic or mixed, indicating increased bone-resorbing osteoclast activation. In patients with breast cancer, aromatase inhibitor–induced bone loss is targeted with denosumab to block osteoclast function. Neither therapy prevents tumor progression or relapse in the bone microenvironment.

Labhasetwar and colleagues recently developed biodegradable, taxane-loaded nanoparticles that preferentially localize to prostate cancer bone metastases. The authors injected docetaxel nanoparticles intravenously in immunocompromised mice after the establishment of intratibial-injected PC3 human prostate cancer cells. Microcomputed tomography measured alterations in bone structure, bioluminescence assessed tumor burden, and changes in body weight indicated toxicity. Treatment with the docetaxel nanoparticles every 4 weeks blocked tumor regrowth between treatments. With this repeated single-agent dosing regimen, almost complete regression occurred at 21 weeks, with relapse at 42 weeks. To improve outcomes, the authors co-injected docetaxel nanoparticles and denosumab every 4 weeks for 4 total treatments. Mice under the combined treatment did not experience tumor regrowth. Conversely, denosumab alone resulted in tumor relapse at 36 weeks. Thus, the combination of docetaxel nanoparticles and denosumab prevented the relapse of bone metastatic prostate cancer.

Ongoing clinical trials are assessing the effect of denosumab in patients with established bone metastases. Currently, denosumab is only U.S. Food and Drug Administration–approved for use in patients without metastatic disease and in prostate cancer patients receiving androgen deprivation therapy. Docetaxel is approved for patients with metastatic prostate cancer who fail androgen deprivation therapy but is primarily administered as an unbound drug in a polysorbate 80 solution, and additional testing may be required for approval of the nanoparticle-bound form. Additional studies will also be needed to assess the effects of the combination treatment in the presence of a functional immune system as denosumab can induce immunosuppression, which is masked in immunocompromised mice. Combination therapy with denosumab and docetaxel nanoparticles represents a potential method to prevent metastatic relapse and improve metastatic cancer survival rates.

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