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).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
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.