Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study

Butowski, Nicholas; Colman, Howard; Groot, John F. de; Omuro, Antonio; Nayak, Lakshmi; Wen, Patrick Y.; Cloughesy, Timothy F.; Marimuthu, A.; Haidar, Sam; Perry, Arie; Huse, Jason T.; Phillips, Joanna J.; West, Brian L.; Nolop, K. B.; Hsu, Henry H.; Ligon, Keith L.; Molinaro, Annette M.; Prados, Michael D.

doi:10.1093/neuonc/nov245

Cited by 467 publications

(372 citation statements)

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“…PLX5622 is a more specific (i.e., the compound does not inhibit c‐Kit) sister molecule of the clinically utilized CSF1R inhibitor PLX3397 (Butowski et al, 2016; Tap et al, 2015). This treatment eliminated ~85% of microglia throughout the CNS (Supporting Information Figure S1a–c).…”

Section: Resultsmentioning

confidence: 99%

“…While the long‐term elimination of microglia in humans is not currently feasible (e.g., the implications of microglial absence in the face of CNS infection or injury remain unclear), data from a clinical trial indicate that microglia are effectively eliminated from humans with short‐term administration of a CSF1R inhibitor (Butowski et al, 2016), and moreover, CSF1R inhibitor‐dependent microglial elimination and repopulation are observed in nonhuman primates (Hillmer et al, 2017). Thus, short‐term CSF1R inhibitor administration, followed by drug withdrawal, appears feasible in humans using existing compounds, allowing the possibility of microglial replacement in humans.…”

Section: Discussionmentioning

confidence: 99%

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Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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“…Importantly, CSF1R inhibitors are already in clinical trials for chronic diseases ranging from cancer to inflammatory arthritis (43)(44)(45). Perioperative CSF1R inhibition would be focused and short-lived by comparison, thus minimizing patient risk.…”

Section: Discussionmentioning

confidence: 99%

Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice

Feng¹,

Valdearcos²,

Uchida³

et al. 2017

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“…96 In recurrent glioblastoma, only a trend toward a decrease in the number of Iba-1+ microglia/macrophages and a lower number of CD14 dim , CD16+ monocytes in the glioma tissues were observed. 97 …”

Section: Inhibition Of Tumor-related Hematopoiesis and Blocking Of Acmentioning

confidence: 99%

The contribution of tumor-associated macrophages in glioma neo-angiogenesis and implications for anti-angiogenic strategies

et al. 2017

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"Tumor-associated macrophages" (TAMs) form a significant cell population in malignant tumors and contribute to tumor growth, metastasis, and neovascularization. Gliomas are characterized by extensive neo-angiogenesis, and knowledge of the role of TAMs in neovascularization is important for future anti-angiogenic therapies. The phenotypes and functions of TAMs are heterogeneous and more complex than a classification into M1 and M2 inflammation response types would suggest. In this review, we provide an update on the current knowledge of the ontogeny of TAMs, focusing on diffuse gliomas. The role of TAMs in the regulation of the different processes in tumor angiogenesis is highlighted and the most recently discovered mechanisms by which TAMs mediate resistance against current antivascular therapies are mentioned. Novel compounds tested in clinical trials are discussed and brought in relation to different TAM-related angiogenesis pathways. In addition, potential therapeutic targets used to intervene in TAM-regulated tumor angiogenesis are summarized.

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Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study

Abstract: PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.

Cited by 467 publications

References 20 publications

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice

The contribution of tumor-associated macrophages in glioma neo-angiogenesis and implications for anti-angiogenic strategies

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