This article was first published in The Straits Times on July 17, 2015, and was updated on July 21, 2015.
A potential new cancer drug developed from scratch by the Experimental Therapeutics Centre and Drug Discovery and Development unit at the Agency for Science, Technology and Research (A*Star) and researchers at the Duke-NUS Graduate Medical School is a source of hope for cancer patients, and much more besides.
It is also an affirmation that Singapore's biomedical sector has come of age, say experts.
The drug candidate, which aims to help up to 5 per cent of patients whose cancer is caused by particular genetic mutations, is the first publicly-funded one developed from scratch in Singapore to be tested on patients.
"It is especially nice because the idea was born in Singapore, the compounds were developed in Singapore and the clinical trials start in Singapore," said Professor Alex Matter, chief executive of the Experimental Therapeutics Centre and Drug Discovery and Development unit. He is one of two lead scientists in the effort.
"This is a Singapore baby."
Wnt genes' role in embryonic development, adult tissue self-renewal
Wnts were identified more than 30 years ago in both fruit flies and mice. In flies, mutation of the Wnt gene led to the loss of wings (in fact, the name for Wnts in flies is wingless). The study of breast cancer in mice led to the identification of the first mammalian Wnt gene, named Wnt1.
Humans have 19 Wnt genes. The Wnt genes provide instructions for making Wnt proteins, important signalling molecules that are active in early embryonic development, and also in adult tissue self-renewal.
Wnts are short-range signals; they signal from one cell only to nearby cells. In contrast, other signalling proteins, for example, insulin, signal all over the body.
Inherited mutations of Wnts or Wnt pathway components can cause limb malformations, hair loss and osteoporosis, while too much Wnt signalling can cause cancer. Current strategies inhibiting Wnt signalling have mostly focused on anti-cancer therapies. However, researchers say it is possible that with further understanding of these pathways, aberrant Wnt signalling may be targeted as potential treatments of diseases such as neurodegenerative diseases, degenerative bone diseases, and cardiovascular diseases.
The team from A*Star and Duke- NUS is targeting a protein called Wnt, where each Wnt protein is a signalling molecule that orchestrates and influences a myriad of cell processes, including cell proliferation and differentiation into different cell types. When the protein is produced in excess, it causes cancer. So the drug works by blocking the Wnt signals.
It was Professor David Virshup, director of the Programme in Cancer and Stem Cell Biology at Duke-NUS and the other lead scientist in the effort, who came up with the idea to target Wnt.
He said that while it has been known for a long time that Wnt are drivers of cancer, most researchers have focused their efforts on drugs that are further downstream that block only one of many possible consequences of Wnt signalling.
His idea, shared by a few other research groups internationally, was to start at the beginning.
"Instead of targeting far downstream consequences, we wanted to target the root cause: which is too much Wnt," said Prof Virshup.
This eureka moment came in 2007, but he faced the challenge of moulding that idea into something tangible. "The thing in science is that it is not hard to have a good idea but what's hard is actually to get it into a final product," he said.
It was only after discussions and biology experiments to show that the idea held water that an agreement was inked with the Experimental Therapeutics Centre two years later.
And creating a drug is also no walk in the park, as Prof Matter told The Straits Times.
Not all drug targets, in this case Wnt proteins, can be modulated by drugs; they can be very resistant to drug action or at times there are simply no known compounds that have the ability to modify the target.
"If you find compounds that modulate the drug target activity then you are basically in business," he pointed out. "We call that druggability, and that's a high hurdle."
To find compounds that might have the desired effect, the team had to first sieve through its library of some 500,000 compounds, of which fewer than 0.1 per cent turned up as hits. These compounds were then studied and 500 new compounds were handmade individually by medicinal chemists.
Eventually, six were tested on mice and a single compound emerged as the one with the most promise. The drug then had to undergo rigorous tests on, among other things, toxicity and taste, before it was granted permission to enter clinical trials on cancer patients last month. It has taken around eight years to reach this point, but Prof Matter is far from fazed.
"There are a thousand and one ways to fail because the traps are all over the place, so you have to be vigilant," he said.
Drug development - from conception to pre-clinical development to clinical trials and, finally, to market - typically spans a period of 10 to 15 years, so the team, which is in its eighth year, can be said to have made significant headway.
But it could be a further five years or more before it hits the market, noted Prof Virshup, depending on how fast the trials are completed. And even then, the drug's success is uncertain.
The last made-in-Singapore anti- cancer drug which showed promise was patented by biotech company S*BIO in 2006. Called SB1518, the drug inhibits the action of a protein enzyme known as JAK2, which is linked to various cancers and auto- immune diseases.
S*Bio’s SB1518 (now called Pacritinib) was acquired by American company CTI BioPharma Corporation in 2012 for Phase 3 clinical development and commercialisation, and recently announced positive results from the first arm of its Phase 3 clinical trials, placing it on track for FDA approval to address an unmet medical need for patients with myelofibrosis - a bone marrow cancer.
S*Bio continues to actively monitor the progress of SB1518 and other anti-cancer drugs in its portfolio which have been licensed or acquired by various pharmaceutical companies for further clinical development.
Prof Matter said: "Hopefully (this drug) will live and thrive and grow."
The latest clinical trial for the compound comes on the back of approval given by the Food and Drug Administration this year to another made-in-Singapore drug, finafloxacin, which treats "Swimmer's ear" - an outer-ear infection.
And just as cancer drug research was given a boost with this successful A*Star and Duke-NUS collaboration, more global pharmaceutical companies are pumping money into research and development collaborations in Singapore.
United States-based Merck, for instance, has set up a research and development unit here, and formed a Merck-Singapore Joint Steering Committee with representatives from A*Star, National University Health System, SingHealth and the Biomedical Sciences Industry Partnership Office to discuss possible collaborations.
Earlier this year, Chugai Pharmaceuticals announced an investment of $476 million in its R&D unit in Singapore over the next seven years. Also, more pharmaceutical companies, including Britain's GlaxoSmithKline, are using Singapore as their global headquarters for Asia.
Dr Tadataka Yamada, chief medical and scientific officer of Takeda Pharmaceuticals, which is using Singapore as its regional R&D centre, said it is the strong science base coupled with an excellent workforce and a robust regulatory environment which contributes to the trend of pharmaceutical companies coming here.
The Japanese company is also expanding its staff strength with its move into Biopolis.
"I can foresee the day in the not-too-distant future when there will be many projects such as the Wnt-inhibitor project moving forward rapidly into new start-up companies and big-pharma company tie-ups," said Dr Yamada, who is also chair of Experimental Therapeutics Centre's advisory committee.
Prof Matter credits the team's own chemistry for the smooth drug-development process.
"Funnily it is usually not the science, not the technology; the most important thing is that the team works together over long periods of time," he said. "People somehow must remain friends. And if that doesn't happen then nothing will work and things will just fail."