Targeting CAD or DHODH to inhibit pyrimidine synthesis for glioblastoma

INDICATION: Brain cancer

Blocking pyrimidine synthesis via inhibition of CAD or DHODH, an enzyme downstream CAD, could treat glioblastoma. In patients, high tumor expression of a pyrimidine metabolism gene signature was associated with poor overall survival. shRNAs against CAD or DHODH, which catalyze two rate-limiting steps in pyrimidine synthesis, reduced proliferation and self-renewal in human glioblastoma stem cells and improved survival in patient-derived xenograft (PDX) mouse models. In additional PDX models, the DHODH inhibitor Aubagio teriflunomide in combination with either Tykerb lapatinib or buparlisib -- two inhibitors of upstream signaling pathways -- decreased tumor volume and increased survival compared with any agent alone...