Reactivation of tumor suppressor gene TP53 for novel efficient cancer therapy

The TP53 tumor suppressor gene is frequently mutated in cancer. Reactivation of mutant TP53 is an attractive strategy for novel cancer therapy.

We have previously identified the missense mutant p53-targeting compound APR-246 which is converted to the Michael acceptor MQ that binds to p53 cysteines. A phase III clinical study with APR-246 in TP53 mutant MDS is ongoing, sponsored by Aprea Therapeutics.

To achieve higher therapeutic efficacy, we will develop combination treatment with APR-246 and agents that inhibit glucose metabolism, induce genotoxic stress or modulate immune responses.

We shall also explore the use of APR-246 for cancer prevention in a mouse model for the cancer-prone Li-Fraumeni syndrome (LFS). 10% of TP53 mutations are nonsense mutations that cause premature termination and expression of truncated inactive p53 protein.

We have found that the 5-fluorouracil (5-FU) metabolite 5-fluorouridine (5-FUr) can induce expression levels of full length p53 in cells with R213X nonsense mutant TP53. We have also identified novel compounds with similar effect.

We shall characterize these candidate readthrough-inducing compounds further to confirm and optimize readthrough of nonsense mutant TP53 and test their ability to suppress tumor growth in mouse models, including our new R210X nonsense mutant Trp53 knock-in mice.

Our aim is to initiate clinical studies with the most promising compounds and/or combination strategies during the 5-year funding period.