The multifunctional nonclassical antifolates were well tolerated when administered either by intraperitoneal (IP) injection or oral gavage (per os; PO) and were effective at inhibiting tumor progression and extending survival in mouse pancreatic cancer xenograft tumor models as well as our potentially novel hTS/Ink4a/Arf null genetically engineered mouse model (GEMM). Here, CDKN2A is linked to neoplasm.