"During clinical trials we made an important discovery ... that the compound wasn't working exactly as we had expected. PR-104 was not only activated by hypoxia but also by an enzyme not previously known to be able to metabolise these kinds of prodrugs at all."
Co-researchers in Sydney later found that the enzyme, AKR1C3, is highly expressed in T-cell acute lymphoblastic leukaemia (ALL). It is also expressed in some normal tissue.
ALL, although rare, is the most common form of childhood leukaemia. Around 15 per cent of cases are the T-cell version, which is generally less responsive to therapy and more likely to relapse.
Professor Wilson and colleagues in the United States are seeking funding for a new trial there among 30 young adults with T-cell ALL whose disease is resistant to conventional therapy.
"This is the kind of personalised medicine paradigm that is the fundamental sea-change between 20th century drug development and what we are seeking to do in the 21st century. It's got the potential to revolutionise drug development and the costs associated with it."
This drug is in the same line as several that have helped many cancer patients with a specific gene mutation to live longer, but their tumours eventually become resistant to the therapy.
Among non-small-cell lung cancer patients, the epidermal growth factor receptor (EGFR) mutations occur in about 15 per cent of Caucasians and 35 per cent of Asians.
Tarloxotinib uses the smart-bomb concept of being inactive until it reaches the low-oxygen zones of tumours, where it becomes highly toxic. In development for more than a decade, it is being put throughphase 2 trials in the US and Australia by US company Threshold Pharmaceuticals in patients with certain kinds of lung cancer, head-and-neck cancer or squamous cell skin cancer.
Developed by Associate Professor Adam Patterson and Dr Jeff Smaill, it is currently the Auckland research centre drug furthest along the trials pathway.
"Development of the compound started," says Dr Smaill, "with the idea that a class of drugs [EGFR inhibitors such as Tarceva and Iressa] were exciting, and getting approval for lung cancer."
But big enough doses couldn't be given because they became too toxic, inhibiting the normal use of EGFR in the skin and gut, causing rashes and diarrhoea. The aim with tarloxotinib, also called TH4000, was to give bigger doses that would activate only in the tumour.
Another drug, a third-generation EGFR inhibitor that treats "one flavour of resistance" to its predecessors, has been approved in a number of countries, says Dr Smaill.
"There are other types of resistance that that compound is not designed to deal with and that's the type of cancer that TH4000 is going after, in the lung cancer trial in particular."
The Smaill-Patterson team is part of an international group with Victoria University developing ways to activate new stealth prodrugs with the help of a harmless soil bacterium, clostridium sporogenes.
The bacteria's spores will germinate and grow in the no-oxygen zone of dead tissue in solid tumours.
Dr Smaill says: "We have demonstrated in pre-clinical models that we can administer spores, seed and colonise a tumour model and then administer a prodrug and see the activity achieved when the bacteria activate the prodrug to kill the tumour."
The bacteria are engineered to express an enzyme that will activate the drug. The drug, inactive while passing through areas of the body with normal oxygen levels, was newly made in the lab specifically to react with the bacterial enzyme.
Dr Patterson says a number of research groups are studying viruses and bacteria for treating cancer, but not for the activation of prodrugs.
"Replicating herpes simplex virus has been approved for the treatment of melanoma in terms of local injection into melanoma lesions. It's an Amgen product approved last year by the FDA [US Food and Drug Administration] so it's happening now, it's getting into the mainstream."
This research has been narrowed down to eight compounds based on some of the most toxic molecules known. Duocarmycin was isolated from soil bacteria in 1988.
"These natural products are spectacularly toxic," says Dr Moana Tercel. "At the time they were discovered they were the most potent small molecules known. There are possibly a few now that can top them. There's only four. From that group, four derivatives went into trials. They turned out to be too toxic to patients."
Over the last 20 years, she and colleagues, using the natural products as inspiration, have designed a group of so-called nitro-CBI (chloromethylbenzindoline) compounds that are activated by low oxygen levels.
Under these conditions, certain enzymes convert the compound into a chemical that binds to DNA.
"If there is CBI sitting on the DNA it is a disaster," says Dr Frederik Pruijn. "It's a bit like a train running into something on the tracks but it doesn't have to be big. The train runs off the rails and you get a big disaster that basically kills the cell."
The Tercel-Pruijn team have narrowed their compounds down to eight and are about to select the one they think will have the best anti-tumour action and the best features for drug production and use.
Tumours need blood. They create their own blood vessels to obtain blood carrying oxygen and nutrients, but they are generally disorganised and immature. This results in parts within many tumours being left with little oxygen.
What is hypoxia?
Starvation of oxygen. It occurs in most tumour types but not in every cancer patient. For instance, about half of lung cancer patients' tumours have oxygen-starved regions. Only parts of a tumour have little or no oxygen -- they're the areas furthest from blood vessels, because oxygen is consumed as it moves out of blood vessels and into tissue.
What are the effects of a lack of oxygen in tumours?
They are generally resistant to standard cancer therapies.
How can oxygen-starvation be exploited for cancer treatment?
Scientists at the Auckland Cancer Society Research Centre have pioneered using this lack of oxygen as a way of delivering toxic drugs to tumours without harming healthy tissue. They are designed to become toxic only when they reach the low-oxygen zones. The lack of oxygen triggers chemical reactions which convert the drug into a killer.
