$2.3 million grant from the National Cancer Institute funds new viral-based gene therapies for lung cancer at Massey
Mutations in the p53 gene are found in more than half of all cancers, yet it has proven to be very difficult to target the gene with therapeutic drugs even 40 years after its discovery. VCU Massey Cancer Center researchers Sumitra Deb, Ph.D., and Brad Windle, Ph.D., are hoping to turn the tide with an innovative viral-based strategy, and they recently received more than $2 million from the National Cancer Institute to fund their work.
Though research has shown that p53 acts as a tumor suppressor in its natural state, gain of function (GOF) mutations turn it into an oncogene that causes cells to replicate uncontrollably. Other scientists have tried inhibiting or blocking GOF p53 expression in cancer cells with limited success. In contrast, Deb’s and Windle’s approach is to target cancer with a virus specially designed to kill cells containing the mutated gene while leaving cells with normal versions of the p53 gene unscathed.
“Initial studies have shown that our viruses have remarkable oncolytic ability and specificity for lung cancer cells with GOF p53, with no effect or viral growth whatsoever in normal cells,” says Deb, a member of the Cancer Molecular Genetics research program at Massey and professor in the Department of Biochemistry and Molecular Biology at the VCU School of Medicine. “We are working to enhance the potency of the virus in several ways and the preliminary results have been very promising.”
Oncolytic viruses are viruses that have been adapted to selectively attack cancer cells. Deb’s and Windle’s viral therapies use a unique GOF p53 inducible promoter that they developed. A promoter is a sequence of DNA that essentially provides genetic instructions for the downstream regulation of proteins or cellular functions. Their promoter can direct the expression of any gene as long as it is cloned in cells that have a GOF p53 mutation.
The team has two goals with their research. Their first goal is to test their virus in a variety of cell lines and animal models. They have placed two genes under the control of their promoter, E1A and E1B. These genes are required for adenoviral replication and ensure the virus only replicates and destroys cells with GOF p53 mutations. Their second goal is to further develop a different virus that kills cancer cells by inducing them to commit suicide.
“While our experiments are focusing on lung cancer, the potential of these therapies is far reaching, considering the prevalence of p53 mutations across all cancer types,” says Windle, who is also a member of the Cancer Molecular Genetics research program at Massey and an associate professor in the Department of Oral and Craniofacial Biology at the VCU School of Dentistry. “We plan to refine these viral-based therapies in hopes of creating new, more effective treatments without the serious side effects associated with many cancer drugs.”
The grant, R01CA238515-01A1, will fund the scientists’ work for a period of 5 years. Additional members of the research team include Catherine Vaughn, Ph.D., postdoctoral fellow.