New cancer treatment drug enabled by University of Canterbury research   13 Dec 2010

The New Zealand Lissodendoryx sponge, the natural source of halichondrin
B – the active compound used to underpin the newly-approved
breast cancer treatment drug Halaven.

Development and release of new cancer treatment drug enabled
by UC research

The development and release on November 15 of the new cancer
treatment drug Halaven by USA company Eisai Inc., would not have
happened without the input of University of Canterbury researchers.

“Without the New Zealand material and the work done in New
Zealand, none of the future development would have occurred,”
said Dr David Newman, Chief of the Natural Products Branch at
the USA’s National Cancer Institute.

Dr Newman organised the New Zealand supply contract for the natural
product halichondrin B, isolated from a deep-water marine sponge
off Kaikoura, which was used in underpinning the development
of the drug that was released last month.

This supply of halichondrin B to the NCI was just part of a large
effort by University of Canterbury chemists, doctoral and postdoctoral
researchers since 1983. These efforts have been directed by Emeritus
Professors of Chemistry at the University of Canterbury, John
Blunt and Murray Munro who say that it is very gratifying to
see the study of natural products at UC contributing to the release
of a drug that will greatly assist cancer patients around the
world.

“This release to market of Halaven is another example of the
value of the study of natural products in the development of
drugs for human and animal use. Halaven is currently approved
for use for the treatment of refractory breast cancer but its
makers have said that it is likely to command a US$1-billion
per year market when it is approved for treatment of other cancers.”

Initial work undertaken by UC postdoctoral researcher Dr Rob
Lake in the mid 1980s identified a sponge sample that yielded
an extract with what is described as “exquisitely potent activity”
against cultured cancer cells. In an animal model it provided
a remarkable life extension of 250 per cent. In 1988 Dr Lake
went on to identify the active compound as halichondrin B which
had very recently been identified by Japanese workers and then
from US researchers from different sponges.

Dr Lake’s work was published in 1994 after further work at
UC by postdoctoral researcher Marc Litaudon and PhD researcher
Jo Hart identified a new version of the halichondrin, isohomohalichondrin
B.

“The USA’s National Cancer Institute was very interested
in obtaining a large supply of halichondrin B to extend studies
they had initiated which indicated a novel mode of action for
this compound in arresting the growth of tumour cells. The yields
of this compound from the Japanese and US collections of sponges
were extremely small, whereas the New Zealand Lissodendoryx sponge
had a ten-fold better return.

“The NCI then organised a contract with the University of Canterbury
group to supply much larger quantities of the halichondrin B.
Following surveys conducted by UC postdoctoral alumnus Dr Chris
Battershill at NIWA, approval was given by the New Zealand Government
for the collection of 1,000 kg of the sponge by deepwater dredging
off the coast of Kaikoura.

“Extraction of the sponge was carried out by Dr Stephen van
Eyk at NZ Pharmaceuticals in Palmerston North. Dr van Eyk and
New Zealand Pharmaceuticals’ then CEO Dr Richard Garland and
Manager Dr Selwyn Yorke are all UC chemistry graduates.

“Final purification of 310 mg of halichondrin B was achieved
at the UC by Sarah Hickford. This supply to the NCI enabled them
to carry out xenograft experiments in mice, the early results
of which caught the attention of the Eisai Company in 1998. Head
to head comparisons, in the NCI xenograft experiments, of the
New Zealand-supplied halichondrin B with some synthetic analogues
of the halichondrin that Professor Kishi (Harvard University)
and Eisai had prepared showed that one of the Eisai compounds
was quite superior to the natural product. Eisai were about to
discontinue their development of the synthetic compound, but
these experiments encouraged them to continue with the project.
Following extensive clinical trials by Eisai, some in collaboration
with the NCI, the US FDA finally gave approval for the release
of Halaven in November.

“Without research undertaken at the University of Canterbury
this new drug would not have been developed further and would
not have made it the market. We can be proud of the many UC researchers
and alumni over the past 25 years who have contributed to this
outcome.”

Source: University of Canterbury

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