Topics:

Ribozyme Gene Therapy for Cancer Nears Clinical Trials

Ribozyme Gene Therapy for Cancer Nears Clinical Trials

New research that is bringing ribozyme therapy closer to clinical trials was presented at the recent meeting of the American Association for Cancer Research (AACR) by Kevin Scanlon, PhD, director of Biochemical Pharmacology at the City of Hope National Medical Center in Duarte, California, and editor of the journal Cancer Gene Therapy. The presentation was entitled "Therapeutic Applications of an Anti-Oncogene Ribozyme in Cancer."

The RNA enzyme is very precise and seeks out and cleaves mutated RNA, halting its ability to launch a complex cascade of events leading to cancer. Ribozyme therapy is one of the new gene therapy strategies that holds promise for significantly improving treatment of solid tumors, such as melanoma, colon, breast, lung, bladder and pancreatic cancer, by targeting specific molecular sites within cancer cells, resulting in more effective treatment and fewer side effects than conventional chemotherapy and radiation therapy.

Until now, ribozyme studies have mostly been confined to tissue cultures and animals; however, within the next year Dr. Scanlon expects to begin clinical trials at San Diego Regional Cancer Center, in collaboration with Robert E. Sobol, MD, and at the University of California, San Francisco, in collaboration with Mohammed Kashani-Sabet, MD.

Ribozymes are a class of small enzymes the normal function of which is to cut out unwanted segments of RNA, a step in the synthesis of protein from RNA. Research in the late 1980s led to the approach of modifying ribozymes to cut oncogene RNA at the mutation sites, thereby disrupting production of the oncogene protein products but not affecting normal gene function. Researchers accomplished this by designing ribozymes that bind and cleave only the mutated portion of oncogene RNA. In addition, they attached a molecular structure--"a hammerhead"--borrowed from plant viroid ribozymes. Inside the cancer cell, the modified ribozyme binds to the mutated RNA; immediately, the hammerhead "snaps" and cleaves the oncogene RNA in two, preventing production of the oncogene protein product.

Oncogenes contain mutations and contribute to cancer by expressing mutated proteins. Like other genes, these oncogene proteins are expressed in two steps: DNA is transcribed into mRNA, which, in turn, controls protein synthesis. Ribozyme gene therapy differs from other forms of gene therapy because it does not replace or repair oncogene DNA, but instead works by inhibiting the second step of this process--synthesis of the oncogene protein product from mRNA. Describing the basic approach to using ribozymes in cancer treatment, Dr. Scanlon notes, "We have to sequence the oncogene DNA to define the mutation, and then design the ribozyme to specifically cleave the mutation."

From the Lab to the Clinic

In his presentation at the AACR, Dr. Scanlon focused on currrent research aimed at making ribozyme therapy more clinically relevant. One of the tasks has been unraveling the complexity of oncogene interactions. "Our early assumption was that if a ribozyme targeted to a specific oncogene worked in one type of cancer that it would work in all types of cancer, and in reality that's not true," reports Dr. Scanlon. "Every time we treat a cancer, we have to define which oncogene is most important--is it ras, fos or one of the 50 or more oncogenes identified to date? When we have identified the key oncogene(s), and prevented its expression using ribozyme gene therapy, we know we can have an impact on cancer cell growth."

In ribozyme gene therapy, as in other types of gene therapy, one of the key challenges is delivering the therapeutic agent. "The fundamental problem is delivery to all cancer cells, and expression of the ribozyme at a high enough level for a long enough time to be therapeutic." Currently, Dr. Scanlon's group is studying three viral vectors--retrovirus, adenovirus, and adeno-associated virus (AAV)--that deliver the ribozyme "package" by infecting cancer cells. But because the viral vectors can infect healthy as well as malignant cells, researchers are seeking ways to ensure that the vectors selectively "target" cancer cells in order to minimize possible damage to normal cells and to design mechanisms for switching on ribozymes. This approach depends on the identification of "promoters"--substances unique to each type of cancer cell. The ribozyme package, which includes the nucleic acid sequence of the ribozyme, is designed so that the ribozyme is expressed only when the tissue-specific promoter is present in the diseased tissue.

 
Loading comments...
Please Wait 20 seconds or click here to close