%u25BA New Research Targets “Natural” Biological Systems Via Cancer-Killing Viruses, Gene Therapy
and Agents That Affect Cellular Signaling Pathways
Targeted cancer therapies use drugs that block the growth and spread of cancer. They interfere with specific molecules involved in carcinogenesis and tumor growth. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than current treatments and less harmful to normal cells. Targeted cancer therapies interfere with cancer cell growth and division in different ways and at various points during the development, growth, and spread of cancer. Many of these therapies focus on proteins that are involved in the signaling process. By blocking the signals that “tell” cancer cells to grow and divide uncontrollably, targeted cancer therapies can help to stop the growth and division of cancer cells.
Targeting specific defects in cancer has been the focus of cancer researchers for the better part of a decade. At the annual meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007, the results of several studies that examined the therapeutic potential of targeting specific biologic systems were presented. These novel therapeutic strategies included the use of gene therapy, cancer-killing viruses, and agents that affect cellular signaling pathways.
%u25BA Cancer-Killing Viruses and Gene Therapy for the Treatment of Prostate Cancer:
A Dual-Targeting Approach
Devanand Sarkar, MBBS, PhD and colleagues at Columbia University, New York, NY studied a dual cancer-specific targeting strategy that facilitated the eradication of both primary and distant resistant prostate cancers.1
They infected xenografts derived from athymic nude mice with Ad.PEG-E1A-mda-7, an adenovirus in which the expression of adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of the progression elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the virus.
Overexpression of Bcl-2 or Bcl-xL is frequently observed in patient-derived prostate cancer samples and is associated with resistance to conventional therapy.2
Infection of Ad.PEG-E1A-mda-7 in normal prostate epithelial cells and prostate cancer cells, including Bcl-2– or Bcl-xL–overexpressing cells such as Du-145-Bcl-xL, PC-3-Bcl-xL and LNCaP-Bcl-2, confirmed cancer cell–selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 into xenografts derived from Du-145-Bcl-xL cells in athymic nude mice completely eradicated both the primary tumor and distant tumors (established on the opposite flank of the animal). The dual cancer-specific targeting strategy facilitated the eradication of both primary and distant resistant prostate cancers, thereby demonstrating potential for translational application of this strategy for treating terminal prostate cancer patients.
Gene therapy may eventually be used against cancer in a variety of ways. Strategies under investigation include: (1) adding functioning genes to cells that have abnormal or missing genes; (2) preventing oncogenes or other genes important in the pathogenesis of cancer from working; (3) adding genes to cancer cells to make them more vulnerable to chemotherapy or radiation therapy; (4) adding genes to tumor cells so they are more easily detected and destroyed by the body’s immune system; and (5) stopping genes that play a role in angiogenesis, or adding genes that stop it.
According to Dr. Sarkar, “The beauty of this approach is that two methods are being used to destroy a tumor. The virus we designed replicates within a tumor, and at the same time produces a massive amount of a cancer-killing compound. Either action alone is damaging and potentially deadly, but together they are lethal.”
Added Dr. Sarkar, “When the viral gene therapy was injected into tumors growing in the mice, the virus replicated and produced mda-7/IL-24, which then killed the tumors, releasing millions of newly produced, loaded viral particles throughout the blood circulation to settle into distant tumors, where the process was repeated. It also worked on prostate cancer resistant to other therapy because the two-pronged attack overwhelmed their defense mechanisms.”
These results are exciting, but additional research is needed prior to evaluate the dual approach in animal models and in humans. While a primary immune system response against the virus may eliminate some of the loaded particles, the researchers say that the mda-7/IL-24 will likely heighten a secondary therapeutic immune response, offering a much stronger cancer-killing potential.
%u25BA Angiogenesis Inhibition for the Treatment of Glioblastoma Multiforme