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Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis
Jiabao Zhou1, Jennifer M Down1, Christopher N George1
1Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UK.
Abstract:
Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1β or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1β induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis.
Insights
Targeting the IL-1 pathway with specific inhibitors may offer a new strategy for treating breast cancer bone metastasis. Some inhibitors reduced metastasis without increasing primary tumor growth, suggesting therapeutic potential.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Breast cancer bone metastasis is a significant clinical challenge with limited treatment options.
- Interleukin-1 (IL-1) signaling is implicated in promoting breast cancer bone metastasis.
- Current IL-1 pathway inhibitors (Anakinra, Canakinumab) show efficacy against bone metastasis but can increase primary tumor growth.
Purpose of the Study:
- To investigate novel IL-1 pathway targets (Caspase-1, IL1β, IRAK1) for treating breast cancer bone metastasis.
- To evaluate therapeutic strategies that reduce bone metastasis without exacerbating primary tumor growth.
- To assess the efficacy of small molecule inhibitors of the IL-1 pathway in preclinical models.
Main Methods:
- In vitro assessment of IL-1 pathway inhibitors (MLX01, VX765, Pacritinib, Anakinra) on breast cancer cell viability, migration, and invasion.
- In vivo studies in mouse models to evaluate effects on primary tumor growth, spontaneous metastasis, and metastatic outgrowth in bone.
- Utilized E0771 and Py8119 mouse mammary cancer cell lines.
Main Results:
- MLX01 (IL1β secretion inhibitor), VX765 (Caspase-1 inhibitor), and Anakinra reduced cancer cell migration and invasion in vitro.
- VX765 and Anakinra significantly decreased spontaneous metastasis and bone metastatic outgrowth in vivo.
- MLX01 reduced both primary tumor growth and bone metastasis; Pacritinib showed no effect on metastasis.
Conclusions:
- Targeting IL-1 signaling, particularly via Caspase-1 inhibition (VX765) or IL-1 receptor antagonism (Anakinra), presents a promising therapeutic avenue for breast cancer bone metastasis.
- Small molecule inhibitors of the IL-1 pathway offer a potential strategy to manage bone metastasis without adverse effects on primary tumor burden.
- Further research into IL-1 pathway modulation is warranted for developing novel breast cancer treatments.
