...Priority 3: Develop novel viral and non-viral strategies for brain tumor gene therapy.
Viral strategies include the use of adenovirus, herpes simplex virus, adeno-associated virus, and other virus vectors. To date, investigators conducting trials in humans have used virus gene formulations administered invasively, through intracerebral implantation. Work in experimental animals, however, has demonstrated that both intra-arterial and intravenous delivery can be efficacious and safe. Some of the new conditionally replicating virus vectors have the added advantage of virus amplification within the tumor after passage through the BBB, thus increasing the treatment volume.
The developments in Priorities 1 and 2 should be applied to improve the delivery of virus and non-virus vectors to tumors and to target the BTB. Current problems include the lack of information on the role of the immune system in limiting virus replication, enhancing tumor rejection, and potentially causing brain inflammation. Limitations also exist in the methodologies available for targeting specific tumor cells in order to minimize potential toxicity to normal brain and vasculature. Studies have demonstrated the synergistic effects of virus vectors with other modes of therapy, such as radiotherapy, chemotherapy, and immunotherapy, but to date these approaches have not been applied in humans.
RESOURCES NEEDED
Priority 1
The development of novel drug targeting systems in the brain that enhance brain tumor uptake of either small- or large-molecule diagnostics or therapeutic molecules requires the following:
• Inclusion of lipid-soluble drugs that penetrate the BBB and of brain tumors in industrial and government antitumor drug development programs.
• Novel forms of BTB disruption
• Drugs that access BBB carrier-mediated transport systems
• Drugs that inhibit BBB active efflux transporters such as p-glycoprotein
• New vectors (ligands) that are transported across the BBB by receptor-mediated transcytosis systems, which can act as "molecular Trojan horses" for transporting drugs across the BBB and BTB
Priority 2
Isolated brain capillaries from either animal or human brain and human brain tumor should be used as the starting point for preparing BBB-specific gene arrays and cDNA libraries from BBB and BTB. BBB gene-specific proteomic programs can also be developed in parallel. The focus on these genomics or proteomic programs should be molecular-based strategies for investigation of the following:
• Tissue-specific gene expression of the BBB of normal brain
• Differences in capillaries perfusing normal brain BBB and tumor capillaries (BTB)
• New endogenous BBB or BTB transporters for targeted drug delivery to brain tumors
• Novel mechanisms of tumor angiogenesis, invasion, cell adhesion, metastasis, and antigen presentation
Priority 3
Development of vectors and strategies for gene/viral delivery to brain tumors, taking into account the unique character of brain vasculature, extracellular space, and cell diversity, will require the following:
• Novel adenovirus, herpes simplex virus, adeno-associated virus, or other virus vectors that specifically target tumor cells in the brain and do not cause brain toxicity
• Virus or non-virus vectors that target brain tumors upon intraarterial or intravenous administration. Such strategies may utilize the ability of some virus vectors to cross the brain vasculature and specifically multiply within the tumor or may follow the development of novel BBB/BTB drug targeting systems.
• Vectors or molecules that specifically target the tumor vasculature without harm to the normal brain vasculature
• Strategies that utilize the above vectors in combination with radiotherapy, chemotherapy, or immunotherapy...
