Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children. While aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the Sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated MBs do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated MB. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPCs). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent MB. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2/M phases of the cell cycle. Here, we show that CD15+ cells progress more rapidly through the cell cycle than CD15- cells and contain an increased proportion of cells in G2/M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora and Polo-like kinases, key regulators of G2/M, induces cell cycle arrest, apoptosis and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived MB xenografts are also sensitive to Aurora and Polo-like kinase inhibitors. Our findings suggest that targeting G2/M regulators may represent a novel approach for treatment of human MB.

Molecular mechanisms and therapeutic targets in pediatric brain tumors

“…Examples of second-site SMOis include the antifungal agent itraconazole and the cyclopamine derivative IPI-926 (saridegib), both of which have shown promise in preclinical studies (65,66). Inhibitors of downstream components of the SHH pathway include arsenic trioxide, which can promote GLI2 degradation (65); bromodomain inhibitors, which not only reduce expression and transcriptional activity of the SHH target MYCN (67) but also impair the function of GLI1 and GLI2 (68); and Aurora kinase A inhibitors, some of which can impair cell cycle progression as well as destabilize MYCN (69)(70)(71). The observation of increased PI3K pathway activity in tumors that develop resistance to SMOis (63,64), along with reports of recurrent mutations affecting this pathway (12,42), has suggested that PI3K inhibition may be an important strategy for preventing or overcoming resistance of SHH-MB.…”

“…The observation of increased PI3K pathway activity in tumors that develop resistance to SMOis (63,64), along with reports of recurrent mutations affecting this pathway (12,42), has suggested that PI3K inhibition may be an important strategy for preventing or overcoming resistance of SHH-MB. Finally, preclinical studies have suggested that Polo-like kinase inhibitors may be particularly effective in SHH-MB (71,72). The heterogeneity of driver mutations and resistance mechanisms even within the SHH-MB subgroup suggests that careful patient selection and a diversity of therapeutic approaches will be necessary to effectively target this disease.…”

Slug inhibition increases radiosensitivity of nasopharyngeal carcinoma cell line C666‑1

“…Due to radiation resistance, radiotherapy is sometimes ineffective, resulting in worse side effects (18). Therefore, it is necessary to understand the radiosensitive tumor targets and mechanisms underlying the development of radioresistance.…”

Inhibition of Plk1 represses androgen signaling pathway in castration-resistant prostate cancer

“…[11][12][13][14] BI2536 is an ATP-competitive Plk1 kinase inhibitor and has been used in phase II clinical studies in breast cancer, endometrial cancer, head and neck cancer, melanoma, ovarian cancer and sarcoma. 15 In prostate cancer, Plk1 knockdown by RNAi causes induction of mitotic catastrophe, 16 suggesting that Plk1 might be a target and BI2536 might be a potential drug of PCa treatment.…”