Transcriptionally targeted gene therapy to detect and treat cancer

Abstract

The greatest challenge in cancer treatment is to achieve the highest levels of specificity and efficacy. Cancer gene therapy could be designed specifically to express therapeutic genes to induce cancer cell destruction. Cancer-specific promoters are useful tools to accomplish targeted expression; however, high levels of gene expression are needed to achieve therapeutic efficacy. Incorporating an imaging reporter gene in tandem with the therapeutic gene will allow tangible proof of principle that gene expression occurs at the correct location and at a sufficient level. Gene-based imaging can advance cancer detection and diagnosis. By combining the cancer-targeted imaging and therapeutic strategies, the exciting prospect of a 'one-two punch' to find hidden, disseminated cancer cells and destroy them simultaneously can potentially be realized.Multiple genetic alterations that confer growth advantages to tumor cells are accumulated during the transformation from normal to neoplastic growth [1]. The loss of growth suppressive genes or gain of oncogenes constitutes a common mechanism of oncogenesis. Based on this information, a rational therapeutic approach is to re-introduce the defective growth control genes into tumor cells. In addition, approaches of inducing apoptotic responses and enhancing anti-tumor immune responses have also been employed [2]. Due to the availability of multiple flexible therapeutic strategies, gene therapy is being actively investigated in clinical settings.Among the ~ 40 ongoing gene therapy clinical trials for cancer (searched via www.clinicaltrials.gov/), 18 of the trial protocols involve an immune activating scheme, ten studies employ a genetic correction strategy and five use a cytotoxic gene. With regard to genetic correction strategies, p53 is a major target. The recombinant adenovirus is the dominant viral gene delivery vector, and it is employed in 18 protocols. However, none of 40 protocols use a cancer-specific gene expression strategy. An oncolytic adenovirus CN706 containing prostate-specific antigen (PSA) promoter driven viral replication [3] is being evaluated in phase II clinical trial for prostate cancer [4].Because the goal of cancer gene therapy is to eradicate cancer cells, many therapeutic genes could be detrimental if unintentionally expressed in normal cells. Selectively targeting the cancer cells is useful to achieve safety and efficacy, especially when the gene therapy vector is directly delivered into patients. Based on features that distinguish cancerous from normal cells, three targeting strategies could be employed. Transcriptional targeting takes advantage of the fact that some cancer cells express a subset of exclusive genes, and uses these cancerspecific promoters to express the desired transgenes [5]. Transductional targeting refers to surface modification on the gene delivery vehicle to enhance interactions with the cancer cell membrane antigen, thereby improving gene transfer into the cancerous cell. A third promising approach is to exploit cancer-a...

Therapeutic effect of targeted Fas-expressing adenoviruses method combining γδ T cells in a mouse model of human ovarian carcinoma

“…By contrast, the human telomerase reverse transcriptase (hTERT) promoter is only activated in ovarian cancer cells with high telomerase activity, and therefore is highly suitable for the gene therapy of ovarian cancer (4,5). However, the activity of tumor-specific promoters is often too weak to mediate the desired gene therapy (6). Recent studies have shown that the recombinant TSTA containing a transcriptional activator (RTA) may effectively enhance the activity of tumor-specific promoters (7,8).…”

Regulation of Rad51 promoter

“…For this approach to be safe and effective, the expression must be driven by cancer-specific promoter/regulatory elements. 42,43 This approach has been slow to transition into the clinic, mainly due to safety and efficacy issues. These promoter constructs must be highly specific to cancer cells as well as strong enough to express the transgene in high levels.…”

Use of the Rad51 promoter for targeted anti-cancer therapy

“…This approach has been attempted with several promoters, most notably with the hTERT (human telomerase) promoter (reviewed in refs. 22,23). These approaches, however, are slow to transition into clinical trials because of several challenges that need to be overcome, most important being safety and efficacy.…”

“…Transcriptionally targeted anticancer therapy employs an elegant approach to selectively destroy cancer cells by placing a reporter and/or cytotoxic gene/oncolytic virus under the transcriptional control of the cancer or tissue-specific promoters (reviewed in refs. [21][22][23][24]. Examples of promoters that have been used in previous studies include the telomerase RNA subunit hTER and catalytic subunit hTERT (25)(26)(27)(28)(29)(30), tyrosinase (31), prostate antigen (32), survivin (33), and midkine genes (34).…”