The smac mimetic LCL161 targets established pulmonary osteosarcoma metastases in mice.

Autor: Harris MA; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia., Shekhar TM; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia., Miles MA; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia., Cerra C; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia., Hawkins CJ; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia. c.hawkins@latrobe.edu.au.
Jazyk: angličtina
Zdroj: Clinical & experimental metastasis [Clin Exp Metastasis] 2021 Oct; Vol. 38 (5), pp. 441-449. Date of Electronic Publication: 2021 Aug 16.
DOI: 10.1007/s10585-021-10116-9
Abstrakt: Osteosarcoma is the most common form of primary bone cancer and frequently metastasizes to the lungs. Current therapies fail to successfully treat over two thirds of patients with metastatic osteosarcoma, so there is an urgent imperative to develop therapies that effectively target established metastases. Smac mimetics are drugs that work by inhibiting the pro-survival activity of IAP proteins such as cIAP1 and cIAP2, which can be overexpressed in osteosarcomas. In vitro, osteosarcoma cells are sensitive to a range of Smac mimetics in combination with TNFα. This sensitivity has also been demonstrated in vivo using the Smac mimetic LCL161, which inhibited the growth of subcutaneous and intramuscular osteosarcomas. Here, we evaluated the efficacy of LCL161 using mice bearing osteosarcoma metastases without the presence of a primary tumor, modeling the scenario in which a patient's primary tumor had been surgically removed. We demonstrated the ability of LCL161 as a single agent and in combination with doxorubicin to inhibit the growth of, and in some cases eliminate, established pulmonary osteosarcoma metastases in vivo. Resected lung metastases from treated and untreated mice remained sensitive to LCL161 in combination with TNFα ex vivo. This suggested that there was little to no acquired resistance to LCL161 treatment in surviving osteosarcoma cells and implied that tumor microenvironmental factors underlie the observed variation in responses to LCL161.
(© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)
Databáze: MEDLINE
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