The present and future for gene and viral therapy of directly accessible prostate and squamous cell cancers of the head and neck

Abstract

Gene therapy has been in a continuous evolutionary process since the first approved trial occurred in 1990 at the National Institute of Health. In the USA, as of March 2004, there were 619 approved gene therapy/transfer protocols and 405 of these were for cancer treatment. Another 294 trials are in progress worldwide, with most concentrated in Europe. However, cancer gene therapy is in its relative infancy when compared with the well-established use of chemo-radiotherapy for treating cancer. As the field develops it is becoming clear that using gene therapy in conjunction with established chemo-radiotherapy approaches is yielding the best results. This concept shall be reviewed in the context of the status of the field, and a future direction based on a combination of gene therapy with small molecule modification of sphingolipid metabolism shall be discussed.

Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report

“…The mechanism of resistance lies in part with the observation that tumor cells frequently upregulate genes involved in inhibition of apoptosis, including FLIP s , 22 Survivin and cIAP1. 18,[22][23][24][25] This led to the concept discussed below, in which FasL gene therapy is combined with agents that downregulate the anti-apoptotic phenotype of tumors creating a more pro-apoptotic phenotype which facilitates bystander activity. This has already been tested in prostate tumor xenograft using TRAIL, Apoptin and FasL [23][24][25] and in head and neck xenografts (unpublished).…”

“…In this regard, we have successfully developed and tested a series of acid ceramidase inhibitors that enhance FasL killing both in vitro and in vivo. 18,19,24,25 The following provides the reasoning for this concept.…”

“…Ceramide is generated in the cell by de novo synthesis, by action of sphingomyelinases or through salvage pathways. 24,27 Ceramide can be metabolized by ceramide kinase, glucosylceramide synthase, ceramidases and sphingomyelin synthases. Ceramidases (acid, neutral and alkaline) have all been shown to deacylate ceramide generating sphingosine.…”

“…These results are evidence that targeting both the lysosomes and ceramide signaling pathways with molecules such as LCL204 can serve as a viable treatment option for prostate and HNSCC and we have now demonstrated that LCL204 augments and sensitizes both prostate and HNSCC to FasL-Fas activation. 24 …”

FasL gene therapy: a new therapeutic modality for head and neck cancer

“…Gene therapy has been continuously advancing since the first trial occurred in 1990 at the National institute of Health. 3 As of January 2005, there were 1020 approved gene therapy protocols in the USA and 675 of them were devoted to cancer treatment protocols. 3 The present report describes our investigation of the potential use of Fas ligand (FasL) gene therapy for the treatment of head and neck cancer.…”