Ganetespib synergizes with cyclophosphamide to improve survival of mice with autochthonous tumors in a mutant p53-dependent manner

摘要

The DNA-alkylating cytotoxic agent cyclophosphamide (CTX) is commonly used in the clinic to treat hematological malignancies like lymphomas and leukemias as well as solid tumors, but shows dose-dependent potentially life-threatening toxicities and can induce secondary malignancies. Thus, the clinical utility of CTX would be improved if a companion drug could be identified that allows lowering the CTX dose, while maintaining or even increasing its antineoplastic therapeutic efficacy. In mouse models, high-dose CTX (300?mg/kg) is effective in treating T-lymphomas, while low dose (defined here as 100?mg/kg) is ineffective. We previously showed that the HSP90 inhibitor ganetespib potently suppresses T-lymphoma initiation and progression and extends overall survival (OS) in hotspot knockin mice expressing the p53 gain-of-function mutants R175H and R248Q (mutp53) by 30–59%. Here we asked whether ganetespib could potentiate the effect of low-dose CTX (100?mg/kg) in the autochthonous T-lymphoma-bearing mutp53 R248Q mouse model. Indeed, combinatorial CTX/ganetespib synergistically suppresses growth of autochthonous T-lymphomas in R248Q (p53Q/?) but not p53?/? control mice by reducing mutp53 levels and triggering apoptosis. Combinatorial treatment extends progression-free (PFS) and OS in p53Q/? mice significantly longer than in p53?/? mice. Specifically, PFS of p53Q/? mice improves 8.9-fold over CTX alone versus 3.6-fold in p53?/? mice. Likewise, OS of R248Q/? mice improves 3.6-fold, but worsens in p53?/? mice (0.85-fold) over CTX alone. Moreover, half of the p53Q/? mice on combinatorial treatment lived over 60 days, and one animal reached 121 days. In contrast, p53Q/? mice on single-drug treatment and p53?/? mice on any treatment lived less than 24 days. In sum, ganetespib synergizes with a sub-effective dose of CTX in mutp53 T-lymphomas by suppressing tumor growth and extending survival. Our results provide a potential strategy to reduce the effective clinical dose of CTX in mutant p53-bearing malignancies and attenuate CTX toxicity.