By David T. Curiel, MD, PhD, Director, Division of Human Gene Therapy, Gene Therapy Center, University of Alabama at Birmingham
&
Casey Cunningham, MD, Associate Director, Gene Therapy Program, US Oncology, Mary Crowley Medical Research Center, Dallas, Texas

Question:
What is gene therapy and how does it work on cancer?

Answer:
Although each cell in the body performs specific functions (such as producing hormones, killing bacteria, etc.), almost all cells carry within their DNA the information needed to make the proteins necessary to carry out all other functions.

A gene is that portion of DNA that encodes the blueprint for a single protein. So in individual cells performing specific functions with specific proteins, only certain genes are active. But regardless of their primary function, nearly all cells have other genes that are active to encode proteins that maintain the cell in a healthy state and allow it to respond to changing conditions. Some of these proteins form signaling circuits within the cell (called pathways) that tell the cell when it’s appropriate to perform its functions, while other pathways signal the cell to divide to form new cells, change location, or even die as conditions warrant.

Over the past several decades, one of the great developments in cancer research and therapy has been the discovery that mutations in some of these signaling-protein genes are very common in cancer cells and produce abnormal proteins that lead to inappropriate signaling of cells. This causes the cells to divide excessively, migrate throughout the body, and enjoy vastly prolonged lifespans. As these characteristics are the hallmarks of malignant cells, it has become apparent that the production of these abnormal proteins is instrumental in the transformation of cancer cells from normal cells.

This recognition forms the basis of “targeted therapeutics,” a new method of anticancer therapeutics that seeks to act only on the abnormal proteins produced by the mutated genes, while sparing normal cellular proteins and, thus, minimizing toxicity. Examples of such targeted therapies include monoclonal antibodies that recognize cell surface markers expressed exclusively by specific cancer cells and small molecule inhibitors designed to interrupt abnormal signaling pathways in cancer cells.

However, much research has also concentrated on correcting the underlying genetic mutations that give rise to the altered proteins of cancer cells in the first place. Such techniques were first developed to treat inherited genetic disorders, such as cystic fibrosis and hemophilia, where replacement of abnormal, disease-causing genes with normal counterparts should theoretically correct the manifestations of the disease. But the techniques were rapidly adapted to cancer therapy so that, after its first two decades of history, more than three-quarters of all people treated with gene therapies have been cancer patients.

Examples of these trials include delivery of a normal, functional tumor-suppressor BRCA1 gene to patients with breast and ovarian cancers whose tumor cells contain mutated BRCA1 genes, and delivery of the tumor-suppressor gene p53 directly to head and neck tumors, where a high percentage of p53 mutations are found.

Another gene therapy approach is molecular chemotherapy, where genes that encode toxic proteins are delivered to tumors. If expression of these death-causing genes can be restricted to the malignant cells or if the encoded proteins are not harmful to normal cells, side effects should be minimal. A related approach employs delivery of genes encoding for proteins important to the immune system to seek to stimulate an effective antitumor immune response.

Overall, most gene therapy studies have been extremely encouraging in that therapy-associated toxicities have indeed been minimal. However, these trials have also revealed that the major hurdle to achieving effective gene therapy is the limitation of current methods for delivering the therapeutic gene to tumor cells.

Research is ongoing to determine the best gene delivery vehicles, or “vectors.” The most popular vectors have been modified viruses, but other techniques such as coating the gene with lipid molecules are also being tried.

Nevertheless, despite these difficulties, the promise of being able to target the very underpinnings of cancer, while sparing normal cells, has oncologists excited about the future of gene therapy.