Turalio (pexidartinib)

Microglia inhibition or depletion by treating organotypic cultures with minocycline or PLX3397 resulted in reduced levels of all the evaluated cytokines in the medium, confirming the role of microglia in the inflammatory microenvironment of glioblastoma. These findings provide valuable insights into how microglia interact with tumors and healthy cells in the tumor microenvironment, driving neuroinflammation and tumor cell dedifferentiation. This understanding could pave the way for the development of innovative therapies for glioblastoma.

Specific depletion of microglia in aged mice, achieved by drinking water supplemented with the colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 for seven consecutive days, resulted in a reduction of postoperative hippocampal neuroinflammation and a significant improvement in cognitive dysfunction. Similarly, perioperative inhibition of microglial activation with minocycline resulted in cognitive improvement...These findings suggest that the activation of hippocampal microglia and the associated neuroinflammatory response following surgery play a crucial role in PND. The underlying mechanism may be related to disturbed gamma oscillations and a reduction in the inhibitory function of PV interneurons.

P=N/A, N=30, Recruiting, Daiichi Sankyo | Trial completion date: Mar 2036 --> Jun 2036 | Trial primary completion date: Jun 2025 --> Jun 2036

These findings identify Gal-9 upregulation as a key mechanism mediating immune evasion and limiting EGFR-TKI efficacy, providing a promising combinational therapeutic strategy of EGFR-TKI and Gal-9 blockade for the treatment of EGFR-driven cancers.

P1, N=54, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2028 | Trial primary completion date: Dec 2025 --> Dec 2026

Inhibition of CYP1A1, 2C9, and 3A4/5 significantly increased pexidartinib-induced cytotoxicity in primary human hepatocytes. Collectively, these data suggest that pexidartinib induced apoptosis, ER stress, mitochondria dysfunction, and autophagy in hepatic cells, and CYPs-mediated metabolism played a protective role in reducing pexidartinib toxicity.

Blockade of CSF1R by the Food and Drug Administration-approved drug pexidartinib contrasts MD-TAMs accumulation observed in the IL34-enriched microenvironment and improves response to sunitinib or anti-PD1 treatment to reduce metastatic growth. Altogether, our data highlight the role of the IL34-CSF1R axis in regulating the tumor immune-vascular crosstalk in RCC and indicate pexidartinib as a therapeutic alternative in combination with current therapies.

We previously reported that gefitinib induces CD8⁺ T cell-related tumor immunity in a genetically engineered mouse model (GEMM)...Combining osimertinib with the colony-stimulating factor-1 receptor (CSF1R) inhibitor pexidartinib reduced CD206⁺ macrophages and enhanced the efficacy of osimertinib...M2-like macrophages may contribute to immune tolerance of persister cancer cells against EGFR-TKI-induced tumor immunity. A clinical trial evaluating combined osimertinib and CSF1R inhibitor therapy is warranted for Egfr-mutated lung cancer.

Additionally, we discuss the preclinical and clinical evidence surrounding key inhibitors, such as PLX3397, AMD3100, and Crizotinib, which have shown promise in reprogramming TAMs and improving treatment outcomes in GBM. While these strategies offer hope for overcoming some of the challenges of GBM therapy, the review also addresses the limitations and obstacles in clinical translation, emphasizing the need for further research and the development of combination therapies to achieve sustained therapeutic benefit.

It selectively inhibits cancer cell viability, induces necroptosis, and reduces cell migration. Its stronger binding to RIPK1 and VEGFR2 more than CSF1R.

P2, N=9, Active, not recruiting, Daiichi Sankyo Co., Ltd. | N=21 --> 9

This research is the first to illustrate that TREM2 activation mitigates WMI following ICH through a microglia-dependent mechanism involving the PI3K/Akt/GSK-3β pathway. TREM2 represents a potential therapeutic target for ICH.