On November 18, 2002 Researchers from the internationally renowned Netherlands Cancer Institute (NKI) in Amsterdam, reported to 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 (Press release, Cancer Research Technology, NOV 18, 2002, View Source [SID1234523464]). 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).

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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.

On November 18, 2002 Cancer Research Technology Limited ("CRT") and the University of Cambridge (UK) reported a collaboration with Cyclacel Limited and a top 5 Pharmaceutical company to develop tools for target validation and drug discovery based on the technique of RNA interference (Press release, Cancer Research Technology, NOV 18, 2002, View Source [SID1234523466]).

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The term RNA interference ("RNAi") describes the cellular response to double-stranded RNA that results in sequence-driven gene specific silencing. Originally established as an important tool for functional genomics in the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster, the potential for this technology was recently recognised in higher eukaryotes. In late 1999, Dr. Magdalena Zernicka-Goetz and colleagues (Dr. Florence Wianny, Professors David Glover and Martin Evans) at the University of Cambridge (UK) provided the first definitive demonstration of RNAi-mediated inhibition of endogenous genes in mammalian cells. This work in oocytes and early stage embryos sparked a flurry of research in the area, culminating recently in the use of short interfering double stranded RNA (siRNA) to achieve knockdown of a wide range of mammalian genes, and the development of specific vectors to express these effectors.

There are a number of published patents on techniques for performing RNAi, and undoubtedly more applications in the pipeline. CRT is the holder of two key patent applications in the field, one of which relates to the work of Dr. Zernicka-Goetz and colleagues. The second patent filing from CRT covers pSUPER, a vector for long-term expression of RNAi effectors in mammalian cells, developed at the Netherlands Cancer Institute (Amsterdam) in the group of Professor Rene Bernards. CRT is offering licenses to this portfolio of intellectual property, branded the SUPER RNAiTM System, for target validation, drug discovery and therapeutics. Several pharmaceutical and biotechnology companies are working with CRT towards generating RNAi-based systems to meet the current demands of the industry for higher throughput analysis of mammalian gene function and rapid production of disease models to aid drug discovery. In addition, CRT is exploring the potential for a new class of therapeutics, using RNAi for the inhibition of genes that are aberrantly expressed in cancers.

The collaboration announced today is funded in part by Cancer Research UK. The partners aim to build on the pioneering work in the Cambridge laboratory, and the recent exciting discoveries in the field, to establish RNAi as a viable tool for transient or persistent gene knockdown in mammalian cells and whole animals (e.g. the mouse). The successful development and optimisation of RNAi in mammalian systems will facilitate gene analysis in the academic laboratory, meanwhile use of this technology for commercial target validation and drug development will accelerate the gene-to-drug process.

On October 2, 2002 Cancer Research UK reported its new technology transfer company with a remit to exploit the fruits of its world class research programme into preventative strategies, diagnostic kits and new therapies for the benefit of cancer patients (Press release, Cancer Research Technology, OCT 2, 2002, View Source [SID1234523468]).

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Cancer Research Technology (CRT) is formed through the merger of Cancer Research Ventures (CRV) and Imperial Cancer Research Technology (ICRT), the respective technology transfer companies of the Cancer Research Campaign and the Imperial Cancer Research Fund who themselves merged on February 4, 2002, to become Cancer Research UK.

Harpal Kumar has been appointed as Chief Executive. David Newbigging, Deputy Chairman of the Council of Cancer Research UK, has been appointed non-executive Chairman and it is intended that Melanie Lee, who is a non-executive Director of CRT and Research and Development Director of Celltech plc, will succeed him in due course

On August 19, 2002 De Novo Pharmaceuticals Ltd, The Northern Institute for Cancer Research at the University of Newcastle and Cancer Research Ventures Ltd are pleased to reported that they have entered into a collaborative agreement for the discovery of small molecule inhibitors of the MDM2-p53 interaction (Press release, Cancer Research Technology, AUG 19, 2002, View Source [SID1234523469]). The MDM2-p53 pathway is a target which is implicated in the suppression of abnormal cell proliferation, and therefore may have therapeutic potential in several forms of cancer.

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Under the terms of the collaboration, full details of which have not been disclosed, De Novo Pharmaceuticals will provide drug discovery expertise through their suite of proprietary software to develop small molecule inhibitors based on seed molecules provided by The Northern Institute for Cancer Research. The Northern Institute for Cancer Research and Cancer Research Ventures have considerable expertise in this research area and will provide medicinal chemistry and screening for the output of the collaboration.

Dr Ian Hardcastle of The Northern Institute for Cancer Research commented, "We are delighted to have the opportunity to work with De Novo Pharmaceuticals in our quest for novel small molecule drug candidates against this important protein target. We believe this collaboration with De Novo will enable the Northern Institute for Cancer Research and Cancer Research Ventures to accelerate research against this important therapeutic target".

Dr Steven Beasley, Chief Operating Officer of De Novo, added, "Our discovery portfolio concentrates on key target areas where there is an urgent need for high quality leads with potential for rapid progression into development. As we move forwards, we are building a network of efficient and flexible collaborations with academic groups and Universities where this adds value to the Company. We are delighted to be working with The Northern Institute for Cancer Research and Cancer Research Ventures Ltd, who have done much of the pioneering work on this important target.”

"CRV are delighted to be able to facilitate this collaboration which highlights the quality of Cancer Research UK-funded science at The University of Newcastle, a leading institution in the fight against cancer" said Dr Guy Wood-Gush, CRV Chief Executive.

On July 1, 2002 Cancer Research Ventures ("CRV") reported that it had signed a non-exclusive license with Exelixis, Inc, USA for the rights to two patent families relating to the use of certain transposon-based technologies, which can be used to transfer DNA across the species barrier (Press release, Cancer Research Technology, JUL 1, 2002, View Source [SID1234523471]). The technology was jointly developed by the Netherlands Cancer Institute, Amsterdam and Crucell, bv, Leiden (formerly IntroGene).

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CRV was pivotal in mediating a mutually acceptable revenue sharing agreement between the two inventing parties and assigned in the intellectual property to act as the exploitation partner on their behalf. CRV ensures that all revenues received from licensing the invention are returned to both parties in a proportion reflecting their contribution to the invention.

Simon Youlton, the project manager responsible for this technology at CRV said that he "was expecting this to be the first non-exclusive license to a technology that will have considerable utility to any company wishing to validate gene targets in various different animal models. It may also prove to be a very versatile system for the construction of gene delivery vehicles for research and possibly gene therapy".

CRV’s CEO, Dr. Guy Wood-Gush added that "this validates the international role CRV plays in facilitating the transfer of key technologies for the benefit of future developments in the pharmaceutical industry whilst ensuring the inventors and their respective institutions are adequately rewarded for their efforts".