Targeting Tumor Progression and Bone Metastasis with CSF-1R Inhibitor PLX3397 in Mouse Models

Tumor-associated macrophages play a crucial role in cancer progression, making them a potential therapeutic target. PLX3397 is an orally available, selective small molecule inhibitor of the colony stimulating factor-1 receptor (CSF-1R) kinase, a key player in macrophage recruitment to tumors and osteoclast differentiation in bone metastasis. The compound has demonstrated efficacy in multiple animal cancer models and is currently in Phase I clinical trials. Additionally, PLX3397 inhibits the kinase Kit, but the observed effects are believed to be primarily due to CSF-1R inhibition.

In a study using female nude mice with SK-N-SH human neuroblastoma xenografts, PLX3397 significantly inhibited tumor growth after 18 days of oral dosing, contrasting its minimal impact on in vitro SK-N-SH cell growth. This suggests that the inhibitory effect on tumor growth in vivo is likely due to targeting the microenvironment rather than direct effects on tumor cells.

The MMTV-PyMT transgenic mouse breast cancer model revealed that PLX3397 significantly reduced circulating tumor cells (CTCs) by 90%, as measured by FACS analysis. The compound also decreased the ability of macrophages to induce invasive acini in breast cancer cells cultured as spheroids.

Furthermore, PLX3397 was tested in a bone metastasis model using MDA-MB-468 human breast tumor cells in female SCID mice. The compound prevented the increase in osteoclasts and bone loss associated with tumor-induced bone destruction, indicating its potential to inhibit CSF-1R in vivo and suggesting a possible benefit for cancer patients with bone metastasis.