23. Gene therapy of glioblastoma multiforme

The poor prognosis of glioblastoma multiforme (GBM) in spite of the progresses of surgery, radiotherapy and chemotherapy is giving considerable impulse to the identification of gene therapy strategies for this malignancy. Genes to be transferred into tumor cells and vectors used for such transfer constitute the most relevant variables to be considered when analyzing the different therapeutic approaches. One of such approaches implies the attempt of modifying the genome of tumor cells by increasing the expression of tumor suppressor genes, such as p53, or by down-regulating oncogene expression using antisense constructs. However, the multiplicity of genetic pathways leading to malignancy can hardly be modified by replacing only one of the altered genes. In principle, strategies targeted to the elimination of the neoplastic cells seem more rewarding. In this case genes to be transferred can be: i. "suicide" genes, that is genes like Herpes Simplex thymidine kinase whose product transforms a prodrug such ganciclovir in a toxic substrate causing apoptosis of neoplastic cells; ii. cytokine genes, that may help to counteract tumor strategies to escape immune surveillance; iii. genes that may act to down-regulate or suppress tumor angiogenesis. Among vectors retrovirus and adenovirus are the most used but considerable efforts have also been dedicated to the preparation of new vectors derived from Herpes virus or Adeno-associated virus. None of these engineered virus has demonstrated its superiority to others and in all cases none of them is expected to reach the totality or even the majority of target neoplastic cells. Thus, only therapies causing a relevant "bystander effect" seem to have the potential to restrain significantly the growth of GBM. From this point of view gene therapies based on up-regulation of the immunological responses against the tumor seem to be particularly promising.