Targeting Brain Tumors With Plx3397, An Inhibitor Of The Csf-1 Receptor Kinase

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Cancer growth in the brain incites a neuroinflammatory response that becomes a defining feature of the brain tumor microenvironment. Microglia and macrophages provide important functions that support the invasiveness of glioblastoma. Other cancer types that become metastatic to brain also rely on the microenvironment to support angiogenesis. PLX3397 is a potent inhibitor of the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). The CSF-1R is required for the differentiation and activation of microglia and macrophages. Oral administration of PLX3397 to mice at 20 mg/kg qd significantly reduces the microglia/macrophage marker, Iba1, as determined by western blotting. PLX3397 penetrates the blood-brain barrier, as determined through pharmacokinetic analysis, with brain levels reaching substantial fractions of the concurrent plasma levels. PLX3397 is highly bound to plasma albumin, and therefore the levels attained in the brain likely affect Iba1 levels through a local inhibition of brain microglia and macrophages, although a peripheral effect may also contribute. Culture of glioblastoma cell lines including U87, and treatment with chemotherapeutic agents or radiation, was found to cause a 4-fold elevation of the two CSF-1R ligands, CSF-1 and IL-34, as quantified by QPCR. This indicates that glioma cells can recruit and stimulate microglia and macrophages, and that current standard therapies likely exacerbate this stimulation. Other cancer types that are known to form metastases to brain, including melanoma and breast cancer, show similar abilities to produce these cytokines in response to standard therapies. The rat 9L glioblastoma line forms an aggressive tumor when tested as an orthotopic model in syngeneic Fisher rats. Seven days after implantation, PLX3397 was administered via rodent chow for 14 days, reducing the tumor growth by 44% as determined by MRI. These results provide preclinical evidence that PLX3397 may show a clinical benefit in brain cancers, either as a single agent or in combination with standard chemo- or radiation therapies. PLX3397 is nearing completion of a successful Phase 1 dose-escalation safety trial in solid tumor cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 552. doi:10.1158/1538-7445.AM2011-552