A Wayne State University School of Medicine professor and researcher has published an editorial in Expert Review of Anticancer Therapy that examines why his recently developed cancer therapy can serve as the mainstay of personalized gene-based therapy for a wide range of cancers. The therapeutic approach, first published in the Jan. 14 online edition of Cancer Gene Therapy, a Nature Publishing Group journal, is based on a naturally occurring human enzyme that has been genetically modified to fool cancer cells into killing themselves.

Karli Rosner, M.D., Ph.D., assistant professor and director of Research in the Department of Dermatology, devised a method to seek out and destroy cancer cells. The method is based on genetic constructs that encode a genetically modified form of DNase1 protein. His unique concept, for which Wayne State University has applied for patent protection, was successfully demonstrated on melanoma cancer cells resistant to treatments such as chemotherapy or radiotherapy. Considering melanoma’s exceptionally aggressive nature, the success of the therapy in killing melanoma cells, while leaving non-attacked cells undamaged, suggests a similar outcome in treating other drug-resistant cancers.

Dr. Rosner modified the genetic code for DNase1 -- a highly potent DNA-degrading enzyme -- by mutating a part of the code, deleting another part and adding an artificial piece of code. When delivered into cancer cells, this altered DNA program is translated into a modified DNase1 protein, which, in contrast to the natural protein, resists deactivation by cell inhibitors, cannot be eliminated from the cancer cell and has access to the cell’s nucleus. The cancer cell, unaware of the destructive potential of the modified code, has now produced a deadly protein that evades the cell’s defense mechanisms and enters the nucleus. In the nucleus, the protein damages DNA by chopping it into fragments without the need for other medications. Following damage to the DNA, the cell’s organelles disintegrate and the cancer cell dies. In this way, Dr. Rosner’s technology leads cancer cells into committing suicide because he tricks them into generating the protein that causes their own death.

Dr. Rosner elaborates in his editorial by explaining that genetic elements able to restrict lethal DNase1expression can also be incorporated into already-existing genetic-based therapies, as well. Though restrictive genetic elements may direct a therapy to a specific cell type, they cannot prevent current genetic-based therapies from killing neighboring healthy cells. This is because many of these therapies kill cells through the non-selective processes of necrosis and the “bystander effect.” In contrast, the therapy created by Dr. Rosner targets cancer cells and fools them into destroying themselves through the physiological mechanism of apoptosis. Apoptosis is a selective killing process that leaves healthy cells intact. This mode of cancer cell elimination leaves no residual debris to alert the immune system to kick in, negating many of the side effects of current anti-cancer therapies.

“At present, genetic-based therapies do not attain apoptotic elimination of cancer in most patients owing to the vast redundancy in signaling networks that control proliferation, differentiation and cell death. Once a therapy disrupts a pathway at a single component, interpathway connections circumvent the point of disruption by activating a parallel pathway. Thus, there is an unmet medical need for novel and efficacious personalized therapies that can overcome this defense mechanism of cancer,” Dr. Rosner writes in his editorial. Due to the very nature of its mechanism of action, DNase1 therapy bypasses this defense mechanism altogether, thereby offering an effective solution.

“The era of personalized therapy has not yet emerged for most cancer types,” Dr. Rosner writes. “Instead, the ‘one size fits all’ therapeutic approach -- central to conventional treatments such as chemotherapy and radiotherapy -- continues to drive the development of new anti-cancer treatments, despite producing unsatisfactory clinical results.”

The “one-size-fits-all” approach continues to fail because patients diagnosed with the same cancer type frequently show different responses to the same anti-cancer agent. The biological characteristics of the same cancer type can vary from patient to patient. Moreover, within a patient, the biological characteristics of different metastases that have disseminated from the same primary tumor can vary as well. This contributes to the partial response observed in many patients treated with current drugs. These inter- and intra-personal differences in cancer characteristics make it difficult to design a “one-size-fits-all” therapy that is equally effective in all patients. As a result, it is necessary to change course in the field of cancer drug development, and pursue the development of patient-tailored treatments like DNase1 therapy, he said.

The structure of Dr. Rosner’s DNase1 therapy is flexible in that it contains interchangeable Lego-like pieces that, when combined, form a genetic construct. Each piece can be replaced by one of several others that perform the same task, but differ slightly in their genetics. In the future, Dr. Rosner explains, a patient will be tested for his or her response to various combinations of these genetic pieces. The multiple options available for each genetic piece will allow the physician to custom-build DNase1 therapy for a patient based on the specific genetic profiles of his or her metastases.

“Selecting the most appropriate human recombinant DNase1 gene construct for treating tumors in a patient is similar to selecting the appropriate antibiotic for treating an infection,” Dr. Rosner said. “Because DNase1 therapy is designed to be flexible, he said, “hrDNase1 can serve as the mainstay of personalized gene-based therapy for melanoma, as well as for other malignancies.”

To read the complete editorial, visit http://www.expert-reviews.com/doi/full/10.1586/era.11.90.