The smac mimetic LCL161 targets established pulmonary osteosarcoma metastases in mice
Michael A Harris1, Tanmay M Shekhar1, Mark A Miles1
1Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
Abstract:
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.
Insights
Smac mimetics like LCL161 show promise in treating osteosarcoma lung metastases. This study found LCL161, alone or with doxorubicin, inhibited or eliminated established metastases in mice, suggesting a potential new therapy for bone cancer spread.
Area of Science:
- Oncology
- Pharmacology
- Cancer Metastasis Research
Background:
- Osteosarcoma, the most common primary bone cancer, often metastasizes to the lungs, with current therapies failing over two-thirds of patients.
- Targeting established metastases is critical, necessitating novel therapeutic strategies.
- Smac mimetics inhibit inhibitor of apoptosis (IAP) proteins, which are overexpressed in osteosarcomas and promote cancer cell survival.
Purpose of the Study:
- To evaluate the efficacy of the Smac mimetic LCL161 in treating established pulmonary osteosarcoma metastases.
- To model a clinical scenario where the primary tumor has been surgically removed, focusing solely on metastatic disease.
- To assess LCL161's effectiveness as a single agent and in combination with doxorubicin.
Main Methods:
- Utilized a mouse model with established pulmonary osteosarcoma metastases, simulating post-surgical metastatic disease.
- Administered LCL161 as a single agent and in combination with doxorubicin.
- Assessed treatment efficacy by measuring inhibition of metastasis growth and elimination in vivo; evaluated ex vivo sensitivity to LCL161 and TNFα.
Main Results:
- LCL161, both alone and combined with doxorubicin, demonstrated significant inhibition of established pulmonary osteosarcoma metastases in vivo.
- In some cases, LCL161 treatment led to the complete elimination of lung metastases.
- Ex vivo analysis showed resected metastases remained sensitive to LCL161 plus TNFα, indicating minimal acquired resistance.
Conclusions:
- Smac mimetic LCL161 is an effective therapeutic agent against established osteosarcoma lung metastases, even in the absence of a primary tumor.
- Combination therapy with doxorubicin enhances the efficacy of LCL161 in controlling metastatic osteosarcoma.
- The study suggests that tumor microenvironmental factors, rather than acquired resistance, may influence variable responses to LCL161 treatment.
