Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas

Abstract

Glioblastomas represent the most aggressive glioma grade and are associated with a poor patient prognosis. The current standard of care, consisting of surgery, radiation and chemotherapy, only results in a median survival of 14 months, underscoring the importance of developing effective new therapeutic strategies. Among the challenges in treating glioblastomas are primary resistance and the rapid emergence of recurrent disease, which can result from tumor cell-intrinsic mechanisms in addition to tumor microenvironment (TME)-mediated extrinsic resistance. Using a PDGF-B-driven proneural glioma mouse model, we assessed a panel of tyrosine kinase inhibitors with different selectivity profiles. We found that PLX3397, an inhibitor of colony stimulating factor-1 receptor (CSF-1R), blocks glioma progression, markedly suppresses tumor cell proliferation and reduces tumor grade. By contrast, the multi-targeted tyrosine kinase inhibitors dovitinib and vatalanib, which directly target tumor cells, exert minimal anti-tumoral effects in vivo, despite killing glioma cells in vitro, suggesting a TME-mediated resistance mechanism may be involved. Interestingly, PLX3397 interferes with tumor-mediated education of macrophages and consequently restores the sensitivity of glioma cells to tyrosine kinase inhibitors in vivo in preclinical combination trials. Our findings thus demonstrate that microenvironmental alteration by CSF-1R blockade renders tumor cells more susceptible to receptor tyrosine kinase inhibition in a preclinical glioblastoma model, which may have important translational relevance.

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…Many small molecules and antibodies were developed against CSF1R, and numerous clinical trials have been completed or are ongoing ( Table 3). PLX3397 is a small molecule targeting CSF1R, it reduced the number of TAMs in a preclinical GB model and showed an antitumor activity (Coniglio and Segall, 2013;Yan et al, 2017). In clinical studies, PLX3397 was also well tolerated and showed anti-tumor responses after treatment (Tap et al, 2015) (NCT01004861).…”

Nucleolar and spindle‐associated protein 1 is a tumor grade correlated prognosis marker for glioma patients

“…For example, patients with pilocytic astrocytoma (Grade I) had a five‐year survival rate of 94.4%, much higher than 4.7%, the five‐year survival rate of patients with glioblastoma multiforme (GBM, Grade IV) . Despite therapeutic advances in surgery, radiation, and pharmacotherapy, the median survival for GBM patients is only 14 months . With the identification of specific genetic mutations as “driver factors” of gliomagenesis, molecular parameters have been introduced to refine the diagnosis of gliomas such as IDH mutation, 1p/19q codeletion, and H3 K27M mutation, along with pathological parameters .…”

Astrocytes enhance glioblastoma growth

“…Several host cells have been shown to contribute to important features of cancer through several mechanisms. In GBMs, macrophages and microglia, astrocytes, and cells of the perivascular niche have been described to actively participate in the development of this disease through modulation of for example migration, invasion, angiogenesis, and therapeutic resistance (Calabrese et al, 2007;Charles, Holland, Gilbertson, Glass, & Kettenmann, 2012;Plate, Breier, Weich, & Risau, 1992;Pyonteck et al, 2013;Quail et al, 2016;Yan et al, 2017;Zhou et al, 2017).…”