Under the new agreement, the National Cancer Institute (NCI)’s Division of Cancer Treatment and Diagnosis and Astex, a UK-based biotechnology company developing targeted therapies for oncology, will evaluate AT13387 in multiple Phase I and Phase II clinical trials, both as a single agent and in combination, in patients with tumours that are expected to be sensitive to the inhibition of HSP90. Non-clinical studies designed to enhance the development of AT13387 as a new therapeutic option for cancer patients will also be pursued. The five-year programme will enable NCI and Astex to fully explore the potential of AT13387 in the treatment of a wide range of cancers.
AT13387 is currently being investigated in a Phase I clinical trial in patients with solid tumours at three centres in Boston. AT13387 is retained by and becomes concentrated in tumour cells, creating the opportunity for a targeted cancer treatment.
Dr Harren Jhoti, Chief Executive Officer of Astex Therapeutics, said, ‘The announcement of this CRADA for AT13387 is a significant milestone in the development of our novel HSP90 inhibitor, supporting its potential as a “best in class” treatment option for patients with cancer.’
Heat shock protein 90 (HSP90) is induced under conditions of cellular stress to ensure a cell has an increased capacity to maintain proper protein folding. HSP90 is a member of a family of molecular ‘chaperones’ that are required for the functional stabilization and activation of numerous ‘client proteins’, many of which are intimately involved in the regulation of cell growth and division. These client proteins function as oncogenes in a variety of tumour settings: for example, providing growth factor independence (Raf-1, HER-2), invasion and metastasis (MMP2, MET), sustained angiogenesis (VEGFR, HIF-1), cell survival (AKT, RIP, Survivin), resistance to anti-growth signals (CDK4) and unlimited replicative potential (hTERT).
The precise manner in which HSP90 influences the folding of these proteins is not fully understood, but the process is known to be ATP dependent. Inhibition of the binding of ATP to HSP90 induces the degradation of these client proteins, ultimately resulting in cell death, and thus presents a potential therapeutic opportunity. It has been shown that HSP90 is expressed at levels two- to tenfold higher in tumour cells than in normal cells, and overexpression of HSP90 has been correlated with decreased survival in breast cancer. Furthermore, HSP90 seems to protect tumour cells that have an increased genetic instability that would otherwise lead to a rise in the level of mutated client proteins. Because most tumours are characterized by multiple mutations conferring significant redundancy in crucial signalling pathways, inhibition of a single target might not be sufficient to limit growth and metastases. HSP90 inhibitors hold the promise of affecting multiple aberrant signalling pathways and might prove to be of clinical benefit in the treatment of a wide range of cancers.
Inhibition of HSP90 with AT13387 has been shown to result in client protein degradation, suppression of cytoplasmic signalling, cell-cycle arrest and apoptosis. Some of these pharmacodynamic actions can last as long as three days in tumour xenografts after treatment with a single dose of AT13387. AT13387 has also demonstrated anti-proliferative effects in vitro in a panel of cancer cell lines.