Highly potent inhibitors of MDM2 achieve complete tumour regression in animal models of solid tumours and leukaemia

A poster at the 102nd AACR meeting from Dr. Wang (University of Michigan) and researchers at Sanofi-Aventis described the 'release on the brakes' on p53, a protein often called the 'master watchman' because of its importance in repairing damaged DNA. The compounds shrank tumours in mice grafted with human cancer cells.

p53 is important in regulating the cell cycle and, thus, functions as a tumour suppressor that is involved in preventing cancer. Over half of all human tumours carry mutations in the protein, and activating p53 in mice wipes out tumours.

Activation of p53 by blocking it's interaction with a protein, called MDM2, that inhibits it, is being pursued as a promising new cancer therapeutic strategy. Although genetic activation of p53 has been shown to achieve complete tumour eradication in mice, the best small-molecule inhibitors of the MDM2-p53 interaction reported to date have only inhibited tumour growth but fail to achieve significant tumour regression in animal models. For the first time, 2 compounds have been discovered that are able to cause complete tumour regression in multiple xenograft models of human cancer (sarcoma, leukaemia, prostate) without causing any significant signs of toxicity to animals. These compounds block the interaction between p53 and MDM2, releasing inhibition of p53 and resulting in p53-dependent cell cycle arrest and apoptosis of the cells. The original isolation and purification of the 2 compounds was the work of Dr. Wang and thereafter sanofi's scientists built on work. The result: two spirooxindole compounds with potent anti-tumour activity in mice. Molecular profiling studies demonstrated that primary AML cells with wild-type p53 were extremely sensitive to apoptosis induction by our MDM2 inhibitors, suggesting an interesting clinical trial rationale.

It is early days yet for Sanofi's drugs; so far they have only been tested in cell cultures and mice, and researchers will have to conduct additional animal studies to detect possible side effects and determine optimal doses before the drug could be tested in the clinic.

But these results represent an achievement on several fronts. Cancer researchers have searched for decades to find a viable drug that can stimulate p53. And it is also particularly difficult to design drugs that specifically block the interaction between two proteins.

Sanofi is exploring which cancers are most likely to respond to such a drug, one likely candidate is liposarcoma, a disease that is highly resistant to chemotherapy and most liposarcomas contain extra copies of the MDM2 gene.