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CCBIO seminar: Klas G. Wiman

Targeting missense and nonsense mutant p53 in cancer – from molecular biology to the clinic

Klas G. Wiman
Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden

The TP53 tumor suppressor gene is frequently mutated in human tumors. The p53 protein responds to cellular stress and regulates cell cycle progression and cell death through transactivation of downstream target genes, e.g. p21 and Puma. p53 can also regulate processes such as metabolism, differentiation and fertility. A large fraction of human tumors carry missense mutant p53. We have earlier identified the mutant p53-targeting compound APR-246 (PRIMA-1Met). APR-246 is converted to MQ, a Michael acceptor that binds to cysteines in the p53 core domain. APR-246 shows striking synergy with chemotherapeutic drugs, e.g. cisplatin and doxorubicin. APR-246 can also target components of the cellular redox system, including thioredoxin reductase (TrxR1) and glutathione (GSH), which probably contributes to the anti-tumor effect. APR-246 has been tested in a first-in-man phase I clinical trial in patients with hematological malignancies or prostate cancer. Clinical effects were observed. A phase II proof-of-concept clinical study in high-grade serous (HGS) ovarian cancer is currently being conducted by Aprea Therapeutics AB. A subset of TP53 mutations are nonsense mutations that give rise to truncated and unstable p53 protein. Aminoglycoside antibiotics at high concentrations have been shown to induce translational readthrough of nonsense mutant TP53 and expression of full length p53. Tumor suppressor genes like APC, PTEN, RB1 and BRCA1 carry nonsense mutations at even higher frequency than TP53. We are now screening for novel and less toxic compounds with higher readthrough-inducing potency. Pharmacological induction of translational readthrough of premature stop codons in tumor suppressor genes is a promising strategy for efficient treatment of cancer in the future.
 

Chairperson: Bjørn Tore Gjertsen <bjorn.gjertsen@uib.no>, CCBIO