Cancer gene-therapy

Unfortunately cancer is omnipresent in our world. Almost everybody has seen people in their direct environment suffer because of this terrible disease. The object of current cancer therapies is to eliminate both primary tumours and metastases. For some reasons reasons, the later need to be treated by systemic agents (chemotherapy) which leads to significant systemic toxicity. This toxicity could be overcome by using more targeted approaches, such as gene therapy. In a recently published review-article Palmer et al. give an overview of gene therapy for cancer with a particular focus on the strategies that have entered clinical trials (Palmer et al. Cancer gene-therapy: clinical trials. Trends Biotechnol 24, 76-82, 2006).

There are several strategies possible in gene therapy for cancer. In Immunogene therapy researchers try to stimulate anti-cancer immune response, since the human body normally doesn’t develop a good immune response against tumours. Several gene therapy approaches using pro-inflammatory cytokines and co-stimulatory molecules have entered clinical trials. Other methods focus on overexpressing the tumour supressor gene p53, frequently mutated in human cancers. Antisense and RNA interference (RNAi) therapies target the inhibitation of the expression of mutant oncogenes, mutant genes crucial to the development of human malignancies. Pro-drug activation therapy focusses to express an activating enzyme within the tumour, locally activating a systemically delivered inactive pro-drug.
Most interesting is the use of genetically modified oncolytic virusses. An example is the use of a oncolytic adenovirus which replicates inside and lyses cancer cells but not normal cells. Gene therapy to manipulate apoptotic pathways focusses to induce cell-death in drug-resistant tumour cells. Several other approaches of cancer therapy are mentioned in the article, such as anti-angiogenic therapy (cutting the tumour of its blood supply), myeloprotective gene therapy (reducing the toxicity of chemotherapy) and transductional and transcriptional targeting of vectors.

The clinical trials of several gene strategies confirm that such treatments are safe and well tolerated. However with a few exceptions there is no impending evidence of significant clinical activity. A major obstacle is the ability to target tumour cells through systemic delivery. Transcriptional targeting might be chieved using tumour-specific promoters (micro-array technology and proteomics would identify novel tumour-specific targets) but this remains to be demonstrated by clinical trials. The article ends with a final remark that cancer-gene-therapy is likely to have the greatest impact as adjuvants and in combination with conventional therapies, presenting a major challenge for future clinical trial design requiring considerable investment in patient and financial resources.