From the Guidelines
Targeted therapies for tumors with TP53 mutation are available, including APR-246 (eprenetapopt), which has shown promise in clinical trials for myelodysplastic syndrome and acute myeloid leukemia, particularly when combined with azacitidine 1. These therapies aim to restore wild-type p53 function in mutated cells, and their effectiveness depends on the specific p53 mutation type and cancer context. Some key points to consider when evaluating these therapies include:
- The heterogeneity of TP53 variants and their impact on tumor behavior and response to treatment 1
- The importance of molecular profiling to determine the specific p53 mutation type and cancer context before considering targeted therapies 1
- The potential for combination therapies, such as APR-246 with azacitidine, to enhance treatment efficacy 1
- The existence of other targeted therapies, such as MDM2 inhibitors and CRISPR-based gene editing, which may offer alternative treatment options for patients with TP53 mutations 1 In terms of specific treatment recommendations, patients with TP53 deletion/mutation may be treated with ibrutinib in the front line, or with a BCL2 inhibitor such as venetoclax if they are unsuitable for BCR inhibitor therapy 1. Overall, while targeted therapies for TP53 mutations are still an active area of research, they offer promising treatment options for patients with these mutations, and molecular profiling and careful consideration of the specific cancer context are crucial to determining the most effective treatment approach 1.
From the Research
Targeted Therapies for Tumors with TP53 Mutation
- Several studies have investigated targeted therapies for tumors with TP53 mutation, including:
- Combination therapy strategy using deoxyuridine analogues and PARP inhibitors, which has shown promise in preclinical animal studies 2
- Targeting secondary genes or pathways that are critical for survival in p53-mutant cells, such as the Base-Excision Repair (BER) pathway 2, 3
- Restoring tumor suppressor function with compounds that act in a generic manner or are selective for specific p53 mutations 4, 5
- Depleting mutant p53 or targeting vulnerabilities created by mutant p53 expression 4, 6
- These therapies aim to exploit the specific dependencies of p53-mutant cells, such as their reliance on certain DNA repair pathways or their vulnerability to synthetic lethal interactions 3, 6
- Some studies have also explored the use of noncoding RNAs as synthetic lethal targets for mutant p53, which may provide additional therapeutic benefits 6
Specific Therapies
- PRIMA-1 and PRIMA-1MET are compounds that can restore wild-type properties to mutant p53, and are potentially useful in cancers with a high prevalence of p53 mutations 5
- Nutlins are compounds that prevent the binding of MDM2/MDM4 to WT p53, thereby blocking its degradation, and may be efficacious in malignancies where MDM2 or MDM4 is overexpressed 5
- MDM2 inhibitors and mutant p53-restoring compounds are currently under development and have shown promise in clinical trials 4