08:34pm Monday 25 September 2017

New Zealand-designed anti-tumour agent to enter clinical development

Auckland UniServices Ltd and California-based Centella Therapeutics, Inc., a subsidiary of Varian Medical Systems, Inc. have entered into a licensing agreement granting Centella exclusive rights to CEN-209. Centella has subsequently formed a partnership with Cancer Research UK (CRUK) and Cancer Research Technology (CRT) to develop, manufacture and trial CEN-209 under Cancer Research UK’s Clinical Development Partnership scheme.

CEN-209 is designed to enhance the effectiveness of radiotherapy and chemotherapy in solid tumours that are starved of oxygen (hypoxic). Hypoxia occurs in most types of tumours, but not necessarily in every patient with a particular tumour type. In lung cancer patients for instance, approximately 50 percent of tumours have hypoxic regions. Hypoxic tumours are generally resistant to standard cancer therapies and currently there is no effective treatment for these tumours.

The new agent acts by damaging the DNA of hypoxic cancer cells. It is a “prodrug” designed to be given to patients in inactive form and “switch on” in hypoxic regions. This means that it specifically targets the treatment-resistant tumour cells and leaves normal, healthy tissues alone. It is envisaged that in future the successful treatment of hypoxic tumours may involve indentifying affected patients and giving them a hypoxia-specific drug, such as CEN-209, in addition to standard treatment.

CEN-209 was designed and created by a team of researchers in the Auckland Cancer Society Research Centre (ACSRC) at The University of Auckland. Over the past 25 years Professor Bill Wilson, Professor Bill Denny and colleagues at the ACSRC have pioneered the use of hypoxia as a means of selectively targeting new treatments to tumours, and CEN-209 is part of their broader research programme. Professor Wilson says that CEN-209 was created by improving upon a prodrug (tirapazamine) that showed initial promise in attacking hypoxic cells but did not significantly improve patient outcomes in late stage clinical studies. Tirapazamine had limited ability to reach hypoxic cells, which are generally the cells furthest away from blood vessels.

Together with Drs Kevin Hicks and Frederik Pruijn, he studied how different prodrugs behaved as they diffused from the blood vessels to hypoxic tumour cells. Dr Hicks’ computer models of drug transport within tumours accurately predicted the anti-tumour activity of these prodrugs. Research chemists at the ACSRC, led by Associate Professor Michael Hay, used the models to design and make analogues with optimal transport properties, leading to the identification of CEN-209.

“Our computer models of drug transport developed in-house allowed the synthetic chemists to test their design theories and considerably shortened the discovery process,” says Dr Hay. “CEN-209 improves markedly on previous agents in this class in terms of its ability to penetrate tumours, and this is reflected by its improved activity in the laboratory, when combined with long or short courses of radiotherapy,” says Professor Wilson.

“Building on the ACSRC data, we look forward to seeing how well CEN-209 performs in humans,” said Dr Thorsten Melcher, President of Centella Therapeutics. “One of the most exciting aspects of the planned clinical research will be the integration of a partner diagnostic, Centella’s PET imaging agent CEN-109, to identify hypoxic tumours. This builds on recent preclinical studies by Dr Jingli Wang at the ACSRC demonstrating that CEN-109 can predict sensitivity of tumours to CEN-209, which opens the way for a personalised medicine approach to targeting tumour hypoxia”.

The work on CEN-209 is the culmination of a ten year research program initiated under a U.S. National Cancer Institute grant to Professor J. Martin Brown, professor of radiation oncology and radiation biology at Stanford University and Professors Wilson and Denny at the ACSRC. More recently, funding from the Maurice Wilkins Centre for Biodiscovery, of which Professors Wilson and Denny, Associate Professor Hay and Dr Pruijn are members, ensured that the CEN-209 development process was completed. Ongoing preclinical research on CEN-209 and a backup compound is funded by grants from the Auckland Medical Research Foundation, Genesis Oncology Trust and Health Research Council of NZ.

“The success of the Auckland Cancer Society Research Centre’s hypoxia research programme reflects the importance of cross disciplinary collaboration between experts in tumour biology and chemists who can design new drugs,” says Maurice Wilkins Centre Director Professor Rod Dunbar. “CEN-209 entering clinical development is a significant milestone that provides further proof of the strength of drug discovery in New Zealand, and an indication of its global reach.”

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