LDHA as a potential therapeutic target for medulloblastoma

Abstract

Medulloblastomas are the most common solid malignant childhood brain tumour. Integrated genomic data has identified four distinct medulloblastoma sub-groups (Wnt, Shh, Group 3 and Group 4), which have different characteristic genetic abnormalities, and result in different clinical outcomes. Group 3 has the poorest prognosis, is the most frequently metastatic and characteristically over-expresses c-Myc. Lactate dehydrogenase A, known for its key role in metabolic functions, is a downstream target of c-Myc and HIF1α. I hypothesised LDHA inhibition would result in a decrease in lactate concentrations and a change from a glycolytic to an oxidative phosphorylation metabolic phenotype, leading to decreased medulloblastoma viability, proliferation and motility. I found that LDHA expression was significantly elevated in Group 3 medulloblastomas. Furthermore I showed that oxamate (a structural analogue of pyruvate) significantly inhibited medulloblastoma cell line LDHA activity, lactate production, aerobic glycolysis, proliferation and motility under normoxic and hypoxic conditions (1% O2) and also upregulated oxidative phosphorylation under normoxic conditions. Additionally, at low concentrations, oxamate inhibited LDHA activity and lactate production in the non-neoplastic paediatric astrocyte cell line CC2565 but it had no significant effects on the amount of viable, metabolically active cells or their motility under normoxic or hypoxic conditions. Despite showing 80% LDHA knockdown, our LDHA siRNA transfections did not have any significant downstream effects on MB cell line metabolism, growth or motility. Unfortunately our studies are inconclusive as to whether LDHA alone is a suitable therapeutic target for medulloblastoma. Oxamate may inhibit multiple LDH family members or >80% LDHA knockdown may be required. The results of further investigations will be critical as LDHA may prove to be an inadequate target for MB and a broader LDH family inhibitor or lactate inhibitor may be more appropriate. However these studies, combined with extensive research into the literature, support the concept and provide proof of principle that targeting aerobic glycolysis and lactate production in medulloblastoma is worthwhile therapeutic avenue worth pursuing further.

Date of Award	Feb 2016
Original language	English
Awarding Institution	University of Portsmouth
Supervisor	Geoff Pilkington (Supervisor), Laura Donovan (Supervisor) & Helen Fillmore (Supervisor)