Suicide gene therapy for cancer

Cutting-edge research at South Dakota State University may yield a new therapy that targets only cancer cells, leaving healthy cells unharmed.

Pharmacy associate professor Marek Malecki's "suicide gene therapy" recognizes cancer cells and specifically introduces genetic material to make those cells die by a process called apoptosis - orderly, programmed cell death.

This selectively targeted therapy is a major change from current cancer treatment options of surgery, radiation treatment, or chemotherapy, all of which cause collateral damage to healthy tissues and may fail to kill migrating (metastasizing) cancer cells.

“Current therapies are non-discriminatory. Depending on the dose, they may basically kill cells as they go, and cancer cells are simply more sensitive to some drugs or therapeutics or radiation than healthy cells,” says Malecki, a faculty member in SDSU's Department of Pharmaceutical Sciences.

Malecki, who holds an M.D. in addition to his Ph.D. in pharmaceutical biotechnology, has thought about the possibility of a new gene therapy for cancer since early in his career. In 2006 he became the first scientist ever to demonstrate in an animal model — in this case, a mouse that had a tumor in its shoulder — that a selectively targeted cancer suicide gene therapy can deliver the synthetic transgene treatment with the aid of genetically engineered antibodies to cancer cells. Importantly, it leaves healthy cells alone.

Malecki is among 15 faculty members in South Dakota's public university systems who received “seed grants” recently as part of Gov. Mike Rounds' strategy to build a higher level of competitive research. Eight of the 15 projects funded are the work of SDSU faculty members.

In Malecki's case, the seed grant will pay for release time from his teaching duties in order to focus on the research. With time for research Malecki believes the project will yield a treatment option that could advance to pre-clinical trials in humans in as early as two to three years.

Part of Malecki's ongoing research focuses on identifying the genetic markers for cancer cells. That knowledge can be used not only in therapy, but also in predicting the susceptibility to cancer, thus advising individuals at risk about the measures they can take to try to prevent cancer, as well as to diagnose cancer at its very early stage.

The other main focus of his current research is fine-tuning, by means of gene therapy, the regulation of signal transduction pathways that trigger cell death.

Malecki explains that when the cell functions, it normally generates ‘free radicals' as byproducts of cell respiration. Healthy cells and cancer cells both produce free radicals. The higher the cell metabolism, the higher the cell respiration, and consequently, the higher the level of free radical production. Cancer cells, which divide much more actively, produce far more free radicals than healthy cells.

There are four “anti-oxidative enzymes” that are involved in creating free radical processing pathways, similar to an assembly line process that changes free radicals into harmless molecules such as water. One strategy for treating cancer is to introduce something that blocks or interrupts these pathways so that free radicals are not processed.

Malecki's gene therapy introduces transgenes which, when expressed in cancer cells, block anti-oxidative enzymes. That causes an accumulation of free radicals in the cancer cells and triggers expression of suicide genes that ultimately cause the cancer cells to die.

Malecki's gene therapy is specific in that it scouts out only cancer cells. Malecki's transgene therapeutics are guided by his genetically engineered antibodies to specific markers on the cancer cells only. His genetically engineered antibodies are much smaller than the antibodies that are found in nature so that they travel more easily through the body — into the patient to scout out cancer cells. These antibodies guide and then transfer synthetic transgenes — called transgenes because they're transferred from outside into the cells —into the cancer cells.

“It's very specific,” Malecki said. “I designed the therapy step by step, introducing genes which interfere with the cell metabolism in such a way that this causes the cancer cells to die — to eliminate the cancer cells and leave the healthy cells unharmed.”

Malecki believes such a precise therapy may be especially valuable in treating cancer in sensitive organs of the body that are easily damaged by other treatments, such as in the brain, pancreas, prostate, ovary, or breast. It may be the only therapy applicable to some forms of cancer which spread rapidly through metastasis. For example, in more than 55 percent of patients diagnosed with pancreatic cancer, National Cancer Institute statistics say the cancer already has spread to such an extent that these patients will only live less than five months, while no surgery or other current therapy is practically possible.

Malecki's therapy would offer such patients hope that a new treatment option can find the cancer cells wherever they are and eliminate them. Malecki says gene therapy will be surgery-free, less expensive than other treatment options, and free of side effects.