Cancer research gets funding boost

18 June 2013

Research to develop more effective second generation drugs for a common cause of cancers was made possible recently by a $5 million programme grant from the Health Research Council.

Bill_D
Professor Bill Denny

This grant will fund a five-year research programme by a multi-disciplinary group from The University of Auckland’s Auckland Cancer Society Research Centre (ACSRC) and the Department of Molecular Medicine & Pathology (MMP), led by ACSRC director, Professor Bill Denny.

“Overall, it is an experienced and multi-disciplinary research grouping,” he says. “Naturally, we are delighted to have this opportunity to build on our past work and to try and improve cancer therapy.”

The research programme, ‘Rational design of kinase inhibitors to target cancer’ will focus on further developing drugs that inhibit the function of an enzyme called PI3 kinase (PI3K).

Genetic mutations in genes called oncogenes are major drivers in the development and progression of cancer.  More than 30 per cent of tumours contain mutations in genes that result in the activation of the PI3K signalling pathway in cells, driving the development of many forms of cancer.

PI3K has four subtly different subtypes, and those called alpha and delta are of particular interest (for different types of cancer) with several inhibitors of these already in clinical trial as potential cancer drugs.

“This enzyme controls many signalling pathways in cells, but is over-activated in cancer,” says Professor Denny. “Drugs that block this pathway are thus an important goal for many research groups, including our own. Our earlier work in the area on inhibitors of the alpha subtype (funded partly by HRC project grants) resulted in the creation of the biotech company Pathway Therapeutics (now head-quartered in San Francisco) which took one of our drugs (PWT33597) to clinical trial in the US,” says Professor Denny.

The new research programme will use this experience to answer major unresolved drug design questions relating to PI3K, including the degree of selectivity needed, the level to which it should be shut down, and how to overcome drug resistance mechanisms.

“We believe these drug design questions are important to guide the development of more effective "second generation" inhibitors of PI3K,” says Professor Denny.

The work is based on much previous research by Professor Denny’s group at the Auckland Cancer Society Research Centre and by Professor Peter Shepherd’s group in Molecular Medicine & Pathology.

The current programme grant is focused around new classes of potent inhibitors of both the alpha and delta sub-types, in work that is separate from Pathway Therapeutics.

There are three main themes:

  • Orally available inhibitors separately selective for alpha or delta subtypes of PI3K
  • Irreversible inhibitors of PI3K enzymes as targeted cancer therapies
  • Hypoxia activated prodrug forms of PI3K inhibitors as targeted cancer therapies

“While there is much other work published on inhibitors of the alpha or delta subtypes of PI3K, few are truly selective,” he says. “There is much less reported on irreversible inhibitors, and nothing on hypoxia activated pro-drug forms, but these are areas that we as a group have considerable expertise in.”

The multi-disciplinary group includes;

Name Affiliation Expertise
Bill Denny (PI) ACSRC medicinal chemistry
Peter Shepherd MMP PI3K biology
Gordon Rewcastle ACSRC medicinal chemistry
Jackie Kendall ACSRC medicinal chemistry
Jack Flanagan ACSRC medicinal chemistry
Christina Buchanan MMP PI3K biology
Peter Browett MMP clinical oncology
Chris Squire SBS structural biology

 

For more information contact:

Suzi Phillips, Media Relations Advisor Faculty of Medical and Health Sciences Communications, The University of Auckland Email s.phillips@auckland.ac.nz Tel +64 9 373 7599 ext 87383 or Mob 021416396