London, 18th November 2002
SIGNIFICANT MILESTONE ON THE ROUTE TO DESIGNER DRUGS FOR CANCER
Netherlands Cancer Institute researchers silence mutant protein and block development of cancer
Background
Researchers from the internationally renowned Netherlands Cancer Institute (NKI) in Amsterdam have recently published a paper in the leading journal Cancer Cell [Cancer Cell 2, 243-247 (2002)] showing that specific inhibition of cancer-causing genes (oncogenes) results in inhibition of the growth of human pancreatic cancer cells in experimental mice. This is the first evidence in living animals that cancer can be controlled by blocking the expression of a single mutant protein using the technique of RNA interference (RNAi).
The paper, entitled "Stable suppression of tumorigenicity by virus-mediated RNA interference", is the second from the group led by Dr. Reuven Agami and Professor René Bernards describing their pSUPER vector system for performing RNAi. Together with the lead author, Thijn Brummelkamp, they were the inventors of the pSUPER vector system, which allows researchers to perform long-term experiments to study the effect of blocking the production of specific proteins within cells and whole organisms, and may lead to the development of RNAi as a major new therapeutic weapon against many diseases including HIV, cancer and other genetic disorders. The pSUPER vector was first described in a paper published in the prestigious journal Science in April. Such was its impact that the NKI received an unprecedented 1500 requests from other scientists asking for access to the vector for their own studies. As a result the pSUPER vector is becoming a standard workhorse in laboratories worldwide, providing insight into the essential proteins involved in a wide range of diseases from neurodegenerative diseases such as Alzheimer’s and Parkinsons, through infectious diseases such as HIV and hepatitis, to cancer and other genetically based diseases.
Summary of the Cancer Cell paper
Most human tumors harbor multiple genetic alterations, including dominant mutant oncogenes. It is often not clear which of these oncogenes are continuously required and which, when inactivated, may inhibit tumourigenesis. One oncogene that is frequently mutated in human cancer is named K-RAS. A activated mutant of this gene, known as K-RASV12, carries a single mutation in the gene encoding the protein. The normal form of K-RAS appears to be essential for cell viability and therapies which do not differentially target the normal K-RAS protein and the oncogenic K-RASV12 protein are likely to be toxic.
Using a retroviral version of the pSUPER vector the NKI group were able to specifically and stably inhibit expression of only the oncogenic K-RASV12 allele in human pancreatic cancer cells, without affecting the normal K-Ras protein.
Importantly, the researchers found that loss of K-RASV12 protein in the pancreatic carcinoma cells leads to loss of anchorage-independent growth and tumourigenicity. These results indicate that viral delivery of small interfering RNA’s can be used for tumor-specific gene therapy to reverse the oncogenic phenotype of cancer cells, and is the first study to demonstrate the power of vector mediated RNAi to treat cancer in vivo.
Brief note on RNA interference (RNAi)
The ability to interfere with expression of proteins in cells using double-stranded RNA (dsRNA) was first shown in plants and lower eukaryotes such as the fruit fly and nematode worms. In 1998 Andrew Fire and colleagues working at the Carnegie Institute in the US first used the term RNA interference to describe the particular mechanism which operates in eukaryotes. Whilst the technique worked well in simple organisms, it was not possible to perform RNAi in mammalian cells until groundbreaking research at the University of Cambridge performed by Dr. Magdalena Zernicka-Goetz and Prof. David Glover showed that the technique worked in selected mouse cells and in whole mouse embryos. This catalyst was followed by studies showing that short dsRNA molecules were the mediators of RNAi, culminating in the development of the pSUPER vector by the NKI research team (see above).
There are several patents filed on techniques for performing RNAi. Cancer Research Technology Limited (CRT) is the holder of two key patent applications relating to the work of Zernicka-Goetz and Glover, and the pSUPER vector developed by the Agami/Bernards group. CRT is working with several major pharmaceutical companies and numerous biotechnology companies to translate the potential of vector-mediated RNAi across the whole drug discovery and development pathway, including development of new therapeutic modalities for the treatment of cancer.
CRT has entered into an exclusive license with Seattle, Washington based DNAengine to distribute the pSUPER vector to the academic research community (visit www.oligoengine.com or www.pSUPER.com for further information.
About the Netherlands Cancer Institute:
The Netherlands Cancer Institute (www.nki.nl) is a non-profit organization, which consists of both a specialized cancer hospital and a basic cancer research center. The organization employs over 500 scientists and 1100 hospital staff.
About Cancer Research Technology:
Cancer Research Technology (CRT) is a specialist technology transfer company which aims to develop new discoveries in cancer research for the benefit of cancer patients. CRT is owned by the charity, Cancer Research UK. CRT works closely with cancer researchers and their institutes to protect the intellectual property arising from their research and to establish links with commercial partners. CRT facilitates the discovery, development and marketing of new cancer therapeutics and diagnostics.
Further information about Cancer Research Technology can be obtained from:
Dr Jenni Yule
Business Manager
Cancer Research Technology Limited
5 Alfred Place
London WC1E 7EB
Tel: 020 7291 3600
Email: jyule@cancertechnology.com
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