BY DR. DAVID SAMADI
Scientists have engineered a sort of “biological barbell” that can get inside cancer cells and do damage to two proteins that work independently and together to enable cancer’s spread.
Their therapeutic strategy includes a molecule on either end called an aptamer that targets, in this case, prostate cancer. Sandwiched in between are two smaller molecules “siRNAs” that, once delivered inside the cell, can destroy the messenger RNA making those proteins. This novel combination also provides a new template for more effective, less toxic gene therapies for a wide range of cancers, like lung and breast cancer, which are common, complex and often deadly, said the research team at the Medical College of Georgia and Georgia Cancer Center at Augusta University.
“With two missiles, the binding power is increased,” said Dr. Hong Yan Liu, immunologist, biochemist and biomedical engineer at MCG’s Center for Biotechnology and Genomic Medicine. “It’s also a way to get more siRNA to and inside the cell,” said the author of the study in the journal Scientific Reports.
Giving the therapeutic system two arms makes it a more powerful weapon against cancer agreed Dr. Jin-Xiong She, director of the Center for Biotechnology and Genomic Medicine and Georgia Research Alliance Eminent Scholar in Genomic Medicine.
Liu used a three-dimensional aptamer targeting prostate-specific membrane antigen, or PSMA to help the siRNA find and enter the cancer cells.
“We then targeted two tumor-dependent genes,” said Liu. She is talking about epidermal growth factor receptor, or EGFR, and the aptly named survivin gene since it prevents cells from committing suicide. Overexpression of EGFR is associated with prostate cancer that is resistant to current treatment strategies and prone to spreading to the bone. Survivin overexpression is associated with treatment resistance, recurrence and disease spread.
While the two function independently, they also can partner, sharing several signaling pathways. In fact, when EGFR inhibitors have been used previously, tumors may switch to the survivin pathway for survival.
But the simultaneous attack on both by the scientists translated to suppressing the growth of cancer and the blood vessels it needs to survive in models where human prostate-cancer cells were placed in immunodeficient mice and human cells were treated in a dish. Their model mimics middle-to late-stage prostate cancer, which is when this cancer is diagnosed and when many existing therapies don’t work.
“The small interfering RNAs, or siRNAs, used to interrupt EGFR and survivin’s support of prostate cancer have potential for ‘undruggable’ cancer targets and there are plenty of them,” said Dr. Daqing Wu, study co-author and cancer biologist at the Georgia Cancer Center and in the MCG Department of Biochemistry and Molecular Biology.
Many of these cancer promoters hide inside cells where many drugs can’t reach. Receptors on the cells surface, including EGFR, are considered “druggable,” Wu said. Monoclonal antibody drugs already in use typically bind to the outside-membrane part of receptors, and can’t get inside cells where proteins like survivin also are found, Wu said. Small molecule drugs can get inside cells but typically lack specificity, which reduces their effectiveness and increases side effects. “This kind of delivery system is more practical for targeting undruggable targets,” Wu said.
Cancer requires certain proteins to proliferate that are different from healthy cells. “With this approach, you can specifically target the proteins that cancer cells are addicted to,” She said.
DNA- or RNA-based therapies stop or reduce excessive production of these proteins most typically by blocking or reducing gene expression or production of the messenger RNA that ultimately makes the proteins.
“When you stop protein production, cancer cells will divide and die,” She said. Like other approaches, this one isn’t perfect: The siRNA can degrade rapidly and needs clear directions to find the target messenger RNA inside cancer cells.
Next steps, which are under way, include identifying missiles and protein targets for other cancers and more for prostate cancer as well.
Cancers evolve, utilizing more pathways to survive, which is why most current treatments are combinations of drugs and targets. Pathways and proteins can even vary from one patient to the next, so finding multiple proteins for targeting enhances efficacy, Wu said.
Dr. Samadi is a board-certified urologic oncologist trained in open and traditional and laparoscopic surgery and is an expert in robotic prostate surgery. He is chairman of urology, chief of robotic surgery at Lenox Hill Hospital and professor of urology at Hofstra North Shore-LIJ School of Medicine.