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.”

Auckland Cancer Society Research Centre (ACSRC)

The ACSRC was established in 1956 by the Auckland Cancer Society. Based in the Faculty of Medical and Health Sciences at The University of Auckland, the ACSRC is regarded internationally as one of the world's leading anti-cancer drug development laboratories. The Centre houses over 80 scientists dedicated to discovering new treatments to help improve the lives of patients diagnosed with cancer. Since its inception it has published nearly 1,000 papers in international scientific and medical journals, and filed more than 100 patent applications for new anti-cancer drugs. In that time, the centre has developed eight cancer drugs which have gone into clinical trials. The ACSRC has the distinction of being the first laboratory in the Southern Hemisphere to discover, trial, and bring an anti-cancer drug into clinical use.

Research Team

A multidisciplinary team of scientists collaborated to discover CEN-209. Biological evaluation of the analogues was led by Professor Wilson and Drs Kevin Hicks, Frederik Pruijn, Bronwyn Siim and Jingli Wang. Associate Professor Hay, along with Drs Adrian Blaser, Ho Lee,Karin Pchalek, and Shangjin Yang, designed and synthesized the analogues.

Centella Therapeutics

Centella Therapeutics, Inc. is a wholly owned subsidiary of Varian Medical Systems, Inc. (Varian). Varian, headquartered globally in Palo Alto, California, is the world's leading manufacturer of medical devices and software for treating cancer and other medical conditions with radiotherapy. Centella, which was previously known as Centella biotechnologies, inc., is a dedicated enterprise focused on discovery and development of cancer treatments at the intersection of radiotherapy and pharmaceutical therapeutics. Centella’s mission is to develop a portfolio of drugs with a focus on enhancing the effectiveness of radiotherapy, making Centella the first Radiation Oncology Biotechnology company.

Cancer Research UK

Cancer Research UK is the world’s leading cancer charity dedicated to saving lives through research. Its groundbreaking work into the prevention, diagnosis and treatment of cancer has helped save millions of lives. This work is funded entirely by the public. Cancer Research UK has been at the heart of the progress that has already seen survival rates double in the last forty years. It supports research into all aspects of cancer through the work of over 4,000 scientists, doctors and nurses. Together with its partners and supporters, Cancer Research UK's vision is to beat cancer.

Cancer Research Technology

Cancer Research Technology Limited (CRT) is a specialist commercialisation and development company, which aims to develop new discoveries in cancer research for the benefit of cancer patients. CRT works closely with leading international cancer scientists and their institutes to protect intellectual property arising from their research and to establish links with commercial partners. CRT facilitates the discovery, development and marketing of new cancer therapeutics, vaccines, diagnostics and enabling technologies. CRT is wholly owned by Cancer Research UK, the world’s leading cancer charity dedicated to saving lives through research. Under the terms of the CEN-209 partnership with Centella, Cancer Research UK’s Drug Development Office will complete pre-clinical development of the drug and take it through the first Phase I clinical trial, which will be conducted through the charity’s Experimental Cancer Medicine Centres.

Auckland UniServices Ltd

Auckland UniServices Limited is the largest research and development company of its kind in Australasia, and a wholly owned company of The University of Auckland. UniServices manages the University’s intellectual property and is responsible for all research-based consultancy partnerships, commercialisation, and contract education. In this agreement, UniServices acted on behalf of the ACSRC, an operating unit of The University.