Exploring polyamine biosynthesis as a therapeutic vulnerability in medulloblastoma

Medulloblastoma is the most common pediatric brain cancer and accounts for 20% of all pediatric brain tumors. Upon diagnosis, patients undergo tumor-resection surgery followed by intense chemotherapy and cerebrospinal irradiation (CSI) regimens. CSI therapy is highly toxic and poorly tolerated in pediatric patients and is known to cause long-term neurocognitive, endocrine, and developmental deficits that often diminish the quality of life for medulloblastoma patients. The development of targeted therapies is necessary for both increasing the chance of survival and reducing treatment-related morbidities. A potential therapeutic target of interest in medulloblastoma is the polyamine biosynthesis pathway. Polyamines are metabolites present in every living organism and are essential for cellular processes such as growth, survival, and differentiation. Recent studies have shown that polyamine production is dysregulated in several cancers, including brain cancers, and have highlighted polyamine biosynthesis as a potential cancer growth dependency. Dysregulated polyamine metabolism has also been linked to several oncogenic drivers, including the WNT, SHH, and MYC signaling pathways that characterize genetically distinct medulloblastoma subgroups. One way to target polyamine biosynthesis is through the inhibition of the rate-limiting enzyme ornithine decarboxylase with difluoromethylornithine (DFMO), an analog of the polyamine precursor ornithine. DFMO is well-tolerated in pediatric populations and exerts minimal toxicities, as shown through neuroblastoma clinical trials, and is a therapy of interest for medulloblastoma. While DFMO has been tested clinically in multiple cancers, few in vitro studies have been performed to understand the exact mechanisms of anti-proliferation and cytotoxicity. Our study screened two immortalized medulloblastoma cell lines, DAOY (SHH) and D283 (non-WNT/non-SHH), and three patient-derived medulloblastoma cell lines, SL00024 (SHH), SL00668 (non-WNT/non-SHH), SL00870 (Unknown subgroup), for DFMO sensitivity and profiled the immortalized medulloblastoma cell line metabolome to understand the interactions between inhibition of polyamine metabolism with other essential metabolic processes and tumor cell growth. We found that medulloblastoma cell lines are sensitive to DFMO and the adaptive response to DFMO in medulloblastoma may be caused by increased oxidative stress and free radical scavenging. Our study hopes to inform the use of DFMO as an anti-cancer therapy in medulloblastoma by understanding the drug’s single-agent anti-proliferative mechanisms.