Under the new agreement the lead compound, PR509, will be developed for non-small cell lung cancer. It is also likely to be evaluated in other cancers such as gastric, breast, and pancreatic cancer.
Designed by Auckland Cancer Society Research Centre staff members and Maurice Wilkins Centre Associate Investigators Dr Jeff Smaill and Dr Adam Patterson, the new class of compounds selectively targets low-oxygen (hypoxic) conditions found in many solid tumours and acts against a wide variety of cancer types.
“Standard treatments for cancer are indiscriminate in their attack against both cancer cells and healthy cells, and this toxicity in normal tissues limits the dose that can be safely administered to patients,” explains cancer biologist Dr Patterson. “Creating a prodrug that only becomes active once it reaches the tumour is an efficient way of overcoming this problem.”
“About two thirds of tumours contain zones that cannot be reached by oxygen,” says medicinal chemist Dr Smaill. “The cancer cells in these hypoxic zones are more resistant to treatment, making them an important cause of treatment failure and cancer relapse. Scientists have been searching for a way to eliminate these cells for many years.”
The new prodrugs target Human Epidermal growth factor Receptors (HERs), which are involved in normal cell growth and are overactive or mutated in many cancers. The process that converts the prodrugs to their active, toxic form cannot occur in the presence of oxygen, which means that vital healthy tissues are protected.
As well as the benefits conferred by hypoxic activation, the new prodrugs have several further advantages over other drugs that inhibit HER activity.
Unlike other anti-HER drugs approved to date, the new prodrugs once activated inhibit all members of the HER family of receptors, which means that they may be effective against a wider range of tumour types. Moreover, the prodrugs provide permanent rather than temporary inhibition of HER activity.
The prodrugs also ‘reside’ in tumours for an unusually long time. Preclinical research has shown that the active form of the drug is released slowly within tumours in response to changes in oxygenation.
“By preventing toxicity in healthy cells, and achieving a long residency and slow release within cancerous tissue, we can effectively deliver much more of our drug into a tumour than is possible with standard chemotherapy technologies,” says Dr Smaill “Our research to date suggests that this is associated with far greater efficacy against tumours.”
“We have been fortunate to work with a very talented and dedicated team of scientists who together have produced the evidence that the combination of hypoxia activation and prolonged residence within tumours appears to be particularly important in achieving the kind of preclinical activity that we have observed,” says Dr Patterson.
“Scientists have known for more than 50 years that the parts of a tumour distant from blood vessels are continuously hypoxic. There is now growing evidence that tumour zones that appear to be well oxygenated also ‘cycle’ through periods of hypoxia, which can last from minutes to hours or even days. These fluctuations in oxygenation are unpredictable and nearly impossible to target with conventional agents. However they are thought to be an important cause of cancer aggression and spread, as well as treatment failure.”
“Our prodrugs can be thought of as ‘stealth’ prodrugs, hiding in an inactive form until hypoxia arises. Because of this unusual property we believe that we have created the first bona fide hypoxia-activated prodrugs that are effective as single agents against human tumour models.”
Drs Smaill and Patterson announced the creation of the new class of prodrugs at an international conference in November 2009. They have subsequently selected PR509 as the most promising compound from the class and the development and commercialisation deal has now been reached.
PR509 is part of a pipeline of hypoxia-activated prodrugs licensed to San Diego-based pharmaceutical company Proacta from The University of Auckland. The new agreement between Proacta and Yakult Honsha relates to the collaborative research, development and commercialisation of PR509.
Drs Smaill and Patterson are based in the Auckland Cancer Society Research Centre at The University of Auckland’s Faculty of Medical and Health Sciences. They are Associate Investigators with the Maurice Wilkins Centre, which provided partial salary support for the prodrug research. Their work has also been supported by grants from the Foundation for Research, Science and Technology, The Health Research Council of New Zealand and by Proacta Therapeutics Ltd.