A small molecule antagonist of the α_vβ₃integrin suppresses MDA-MB-435 skeletal metastasis

Abstract

IC50 for S247 adhesion to alpha(v)beta3 or alpha(IIB)beta3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 microM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25-50% of vehicle-only-treated mice; P = 0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the alpha(v)beta3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that alpha(v)beta3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.

αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer

“…To this regard, we reported that specific a v b 3 antagonists decreased the viability and growth of MCF-7 cells forced to overexpress CYR61, an angiogenic regulator that is differentially expressed in invasive human breast cancer cells (Tsai et al, 2000;Menendez et al, 2004). Recently, we demonstrated that these antagonists can revert CYR61-induced Taxol In vivo, S-247 displays favorable pharmacokinetic properties and inhibits the formation of breast cancer metastasis to bone and lungs in mice bearing wild-type MDA-MB-435 or a GFP-expressing counterpart (435/HAL) xenografts (Harms et al, 2004;Shannon et al, 2004). Remarkably, serum concentration of the drug reached 20 mM after administration of 100 mg/kg/day without signs of overt toxicity.…”

“…Different classes of a v b 3 antagonists inhibit angiogenesis, primary tumor growth, tumor-induced hypercalcemia and colon cancer metastasis in vivo (Carron et al, 1998;Reinmuth et al, 2003). Recent studies demonstrate that small RGD-based peptidomimetic agents, such as S-247, inhibit migration of endothelial and breast cancer cells (Harms et al, 2004;Shannon et al, 2004).…”

Molecular alterations that drive breast cancer metastasis to bone

“…The interaction between tumour cell a5b1 and host stromal cell fibronectin appears to contribute to the survival of growth-arrested breast cancer cells, a potential mechanism through which tumour cells can become sequestered and dormant within the bone marrow cavity and may later begin to proliferate and establish skeletal metastases. 74 Additional molecules associated with bone homing In addition to chemokines and intergrins, a multitude of other molecules have been shown to have important roles in chemotaxis of breast cancer cells to bone (see Figure 3): increased expression of MMP-1, interleukin 11 (IL-11) and connective tissue factor has been identified in bone-homing clones of MDA-MB-231 breast cancer cells compared with parental cells in vivo. 2 Using a similar approach in which bone-homing clones of MDA-MB-231 cells were compared with parental cells, we and others have found that bone homing is associated with decreased cellcell adhesion and migration, coupled with significantly reduced levels of the cell adhesion molecule fibronectin and calcium signal binding protein S100A4.…”

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

“…Thus changes in both the expression and clustering of integrins, as well as integrin-mediated signaling pathways induced by the rigid mineralized bone matrix, can activate SFKs, which might be essential for the ability of the cell to sense the rigidity of the matrix [96]. Specific inhibitors to Src tyrosine kinases, which are required to regulate integrin-cytoskeleton interactions, have shown promise in preclinical studies, reducing both tumor burden and incidence in bone [97,98] as well as metastasis to bone [99]. After activation, SFKs promote coupling of the cytoskeleton to integrins through talin [100][101][102], which enables mechanical forces on the integrins to engage the integrin/matrix catch bond [50].…”