Telomerase Promoter-Driven Cancer Cell Suicide

Abstract

Human telomerase is highly active in more than 85% of primary cancers, regardless of their tissue origins, but not in most differentiated somatic tissues. Because of this, telomerase recently has become a popular target of anticancer therapy and has been used as a marker of cancer. Similarly, telomerase promoters, especially telomerase reverse transcriptase (TERT) promoter, have been zealously tested for targeted cancer gene therapy. In vitro and in vivo studies have demonstrated that the human TERT (hTERT) promoter is highly active in human and murine cancer cells but not in normal differentiated human cells, normal human CD34 + progenitor cells, normal mouse fibroblasts, or normal mouse livers. Moreover, transcription factors can dramatically augment transgene expression from the hTERT promoter without the promoter losing its specificity. Thus far, telomerase promoters have been tested for targeted cancer gene therapy with proapoptotic, cytotoxic, and prodrug-activating genes and with replication-competent viral vectors. Here, we review recent achievements in telomerase promoter-based targeted cancer gene therapy.

Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice

“…The human telomerase promoter has been used successfully for this purpose (41). For breast cancer, estrogen and hypoxia-responsive promoters have been used to drive the expression of E1A (42,43).…”

Adenoviral mediated transduction of adenoid cystic carcinoma by human TRAIL gene driven with hTERT tumor specific promoter induces apoptosis

“…Some studies used the hTERT promoter to drive antitumor gene expression selectively in cancer cells without or little affecting normal cells or tissues. [24][25][26] For example, one study reported that the hTERT promotor can drive the TRAIL gene to suppress pancreatic tumor cell growth, preventing possible liver toxicity of the TRAIL gene. 27 The SG300 gene driven by the hTERT promoter expressed selectively in cancer cells resulted in apoptosis and necrosis of cancer cells without effects on normal cells.…”

Proof concept for clinical justification of network mapping for personalized cancer therapeutics

“…65,66 and, furthermore, more amenable to a second layer of tumor specificity via tumor-targeted vector control thereby minimizing nonmalignant cell uptake and potential toxic effect to nontarget agents. [67][68][69][70][71][72] Comparing patient-specific molecular profiles with known pathways and with networks derived from protein interaction databases provides a means for identifying oncotoxic targets. However, the majority of the data underlying our understanding of cancer and, especially, the characterization of cancer gene-protein-metabolic networks, are based on animal and cell line systems.…”