A step closer to drugging the p53 tumour suppressor pathway
Early clinical trials underway
- Date : 21 Mar 2013
- Topic : Anticancer agents & Biologic therapy
p53 is a key tumour suppressor that induces cell cycle arrest, senescence and/or apoptosis upon cellular stress and thus eliminates incipient tumour cells. p53 is also implicated in regulation of processes such as cell metabolism, angiogenesis and aging. A large fraction of human tumours carry mutant p53, allowing evasion of apoptosis or senescence and further malignant progression. p53 mutation is often associated with increased resistance to commonly used therapy. Functionally, it is unquestionable that drugging p53 will render tumour-specific interventions, and this article summarizes few recent examples on targeting p53. It seems to be by decades long effort of committed researchers.
A study of a quinuclidinone derivative APR-246
At the recently held 11th International Congress on Targeted Anticancer Therapies (TAT) in Paris, K. Wiman from the Karolinska Institutet, Stockholm, Sweden, reported on findings from his more than a decade long research efforts on drugging the p53 pathway. His team previously identified mutant p53-targeting small molecules including PRIMA-1 and PRIMA-1Met = APR-246 that restore wild type conformation to mutant p53, induce apoptosis in tumour cells, and inhibits tumour growth in mice. These findings were published in Nature Medicine in 2002.
These molecules synergise with conventional chemotherapeutic drugs in cultured tumour cells and in vivo. The researchers found that both PRIMA-1 and APR-246 are converted to MQ, a reactive compound with Michael acceptor activity that can bind covalently to cysteines in mutant p53. The results were published 7 years later, in 2009, in the journal Cancer Cell.
After that, APR-246 was tested in a phase I/II clinical trial in patients with haematological malignancies or hormone-refractory prostate cancer. Tumour cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes. Microarray analysis revealed changes in genes that control proliferation and cell death. One patient with AML and a p53 core domain mutation showed significant reduction of blast cells in the bone marrow and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response. The researchers conclude that APR-246 is safe, has a favourable pharmacokinetic profile, and can induce p53-dependent biological effects in patient tumour cells in vivo. They published the study results in October 2012 in the Journal of Clinical Oncology.
A study of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination
A new phase I trial published recently in the British Journal of Cancer by Warso MA and colleagues has shown that a small, 28-amino-acid peptide called p28, which stabilizes p53 to protect it from degradation, is well-tolerated in patients with advanced solid tumours. The work – a first-in-class, first-in-human trial – also demonstrated that some tumour control could be achieved.
The peptide p28 acts by binding to p53 at its DNA-binding domain, which stabilizes the protein and prevents its degradation. This stabilisation leads to an increase in p53, which leads to an increase of its downstream targets (such as p21 and p27) and inhibition of the cell cycle at G2/M.
The phase I study was initiated after favourable preclinical study data, and made use of the accelerated titration design, which meant that patients who did not experience a dose-limiting toxicity could be kept on study to receive the next dose. Included in the study were 15 patients who had a range of advanced cancers, including melanoma, lung cancer and pancreatic cancer. No patient experienced a dose-limiting toxic event. Seven patients demonstrated extended periods (7–61 weeks) of stable disease and three patients had a partial response that lasted 44–125 weeks. One patient had a complete response that lasted more than 2 years.
Evidence of anti–tumour activity indicates a highly favourable therapeutic index and demonstrates proof of concept for this new class of non–HDM2–mediated peptide inhibitors of p53 ubiquitination. The promising results are due to be followed up with an efficacy trial.
Thank you for rating!
You have already rated this page, you can only rate it once!