Pemetrexed and Gemcitabine May Be Effective in Group 3 Medulloblastoma

Although medulloblastoma can be classified into four subtypes based on genetic and clinical features, the majority of patients are uniformly treated. Group 3 tumors, which often express high levels of MYC, are frequently metastatic and have a poor prognosis. To identify potential Group 3–specific therapeutic agents, Morfouace and colleagues screened over 7,000 bioactive compounds for those that preferentially inhibited proliferation of neurospheres derived from a Group 3 medulloblastoma mouse model in which Trp53^−/−; Cdkn2c^−/− cerebellar granule neuronal progenitors (GNP) were retrovirally transformed with MYC. Prioritization of drug candidates based on previous FDA approval, potency, selectivity, and mechanism of action identified pemetrexed, gemcitabine, and decitabine. Compared with murine sonic hedgehog (SHH) group medulloblastomas and normal GNPs, Group 3 medulloblastomas expressed higher levels of enzymes targeted by pemetrexed and gemcitabine, including those involved in folate biosynthesis and nucleotide metabolism, and Group 3 medulloblastomas are known to have high levels of histone H3 lysine 27 trimethylation, which is targeted by decitabine. Based on published preclinical pharmacokinetic data, decitabine was not predicted to achieve effective brain concentrations and was not studied further, but pemetrexed and gemcitabine were found to cross the blood–brain barrier in mice. Pemetrexed or gemcitabine treatment alone extended the life span of mice bearing murine or patient-derived Group 3 medulloblastomas compared with vehicle, and combined pemetrexed and gemcitabine treatment extended survival even further without noticeable toxicity. Of note, the combination of pemetrexed and gemcitabine with cisplatin and cyclophosphamide, components of current Group 3 medulloblastoma treatment regimens, synergistically extended the life span of mice harboring Group 3 but not SHH medulloblastomas, further pointing to selective effects of pemetrexed and gemcitabine in Group 3 tumors. Together, these results provide a rationale for the clinical evaluation of pemetrexed and gemcitabine in Group 3 medulloblastomas, particularly those that express high levels of MYC.

Morfouace M, Shelat A, Jacus M, Freeman BB 3rd, Turner D, Robinson S, et al. Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma. Cancer Cell 2014 Mar 27 [Epub ahead of print].