Turning the gene tap off; implications of regulating gene expression for cancer therapeutics

Curtin, James F.; Candolfi, Marianela; Xiong, Wei; Löwenstein, Pedro R.; Castro, María G.

doi:10.1158/1535-7163.mct-07-2328

Cited by 26 publications

(30 citation statements)

References 55 publications

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“…9,43,44 We previously constructed and characterized a novel HC-Ad vector platform using a modified tetracycline-dependent inducible system (TetOn) that enables efficient and tightly regulated transgene expression in vitro and also in the central nervous system in vivo. 10,11,31,45 The use of DOX as the transcriptional activator of the Tet-On-inducible system ensures an added layer of safety in the gene therapeutic approach proposed by allowing therapeutic transgene expression, that is, Flt3L to be turned ''on'' or ''off'' in the presence or absence of DOX, respectively, and in line with medical need.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn “On” Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model

VanderVeen

Raja

et al. 2016

Human Gene Therapy Methods

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Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn “On” Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model

VanderVeen

Raja

et al. 2016

Human Gene Therapy Methods

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“…Native DT was examined using either the tetracycline-dependent Tet-Off promoter or a lactose-dependent promoter, and DT expression was found to be more tightly regulated by the Tet-Off system (47). Attenuated DT was tested using the Tet-Off system; however, toxicity was not totally abolished (46), perhaps due to the leakiness of the Tet-Off system (48). …”

Section: Gene Therapeutic Targets For Glioblastomamentioning

confidence: 99%

Adenoviral vector-mediated gene therapy for gliomas: coming of age

Castro

Candolfi

Wilson

et al. 2014

Expert Opinion on Biological Therapy

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Introduction Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults; it carries a dismal prognosis. Adenoviral vector (Ad)-mediated gene transfer is being developed as a promising therapeutic strategy for GBM. Preclinical studies have demonstrated safety and efficacy of adenovirus administration into the brain and tumor mass in rodents and into the non-human primates’ brain. Importantly Ads have been safely administered within the tumor resection cavity in humans. Areas Covered Background on GBM and Ad vectors; we describe gene therapy strategies for GBM and discuss the value of combination approaches. Finally we discuss the results of the human clinical trials for GBM that have used adenoviral vectors. Expert Opinion The transduction characteristics of Ad vectors, and their safety profile, added to their capacity to achieve high levels of transgene expression have made them powerful vectors for the treatment of GBM. Recent gene therapy successes in the treatment of retinal diseases and systemic brain metabolic diseases, encourages the development of gene therapy for malignant glioma. Exciting clinical trials are currently recruiting patients; although it is large randomized phase III controlled clinical trials that will provide the final decision on the success of gene therapy for the treatment of GBM.

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“…HC-Ad-TK expresses herpes-simplex thymidine kinase under the constitutive mouse cytomegalovirus promoter; when administered together with the oral prodrug valacyclovir, highly proliferating tumor cells are preferentially killed. The other vector, HC-Ad-TetOn-Flt3L, expresses human soluble Flt3L under the control of the DOX-inducible rtTA2 S M2/ tTS Kid promoter system; transcription of the immunostimulatory Flt3L is turned on with oral administration of DOX (Candolfi et al, 2006;Xiong et al, 2006;Curtin et al, 2008b;Muhammad et al, 2010Muhammad et al, , 2012.…”

Section: Clinical Trialmentioning

confidence: 99%

“…The implementation of this therapy in the clinic will involve injection of both HC-Ads in the tumor bed after total tumor resection, followed by systemic administration of Valacyclovir, as the thymidine kinase (TK) prodrug (Fujita et al, 2006;Hinata et al, 2006;Shirakawa et al, 2007;Chiocca et al, 2011), and doxycycline (DOX) as the transcriptional activator of Fms-like tyrosine kinase 3 ligand (Flt3L) from the TetOn promoter (Candolfi et al, 2006;Xiong et al, 2006;Curtin et al, 2008b;Muhammad et al, 2010Muhammad et al, , 2012. Importantly, the DOX-regulatable expression of Flt3L is an added safety feature of the treatment, and allows us to turn ''on'' and ''off'' gene expression upon the addition or withdrawal of DOX, respectively (Candolfi et al, 2006;Xiong et al, 2006;Curtin et al, 2008b).…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, the DOX-regulatable expression of Flt3L is an added safety feature of the treatment, and allows us to turn ''on'' and ''off'' gene expression upon the addition or withdrawal of DOX, respectively (Candolfi et al, 2006;Xiong et al, 2006;Curtin et al, 2008b). In addition, the use of HCAds is expected to reduce the generation of anti-Ad antibodies; this may simultaneously improve efficacy and safety.…”

Section: Introductionmentioning

confidence: 99%

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Effectiveness and Preclinical Safety Profile of Doxycycline to Be Used “Off-Label” to Induce Therapeutic Transgene Expression in a Phase I Clinical Trial for Glioma

VanderVeen

Paran

Krasinkiewicz

et al. 2013

Human Gene Therapy Clinical Development

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Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults; it carries a dismal prognosis despite improvements in standard of care. We developed a combined gene therapy strategy using (1) herpes simplex type 1-thymidine kinase in conjunction with the cytotoxic prodrug ganciclovir to kill actively proliferating tumor cells and (2) doxycycline (DOX)-inducible Fms-like tyrosine kinase 3 ligand (Flt3L), an immune stimulatory molecule that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we examined the efficacy and safety of this approach (Muhammad et al., 2010(Muhammad et al., , 2012. In the present article, we investigated the efficacy and safety of the ''off-label'' use of the antibiotic DOX to turn on the high-capacity adenoviral vector (HC-Ad) encoding therapeutic Flt3L expression. DOX-inducible Flt3L expression in male Lewis rats was assessed using DOX doses of 30.8 mg/kg/day (low-DOX) or 46.2 mg/kg/day (high-DOX), which are allometrically equivalent (Voisin et al., 1990) to the human doses that are recommended for the treatment of infections: 200 or 300 mg/day. Naïve rats were intracranially injected with 1 · 10 9 viral particles of HC-Ad-TetOnFlt3L, and expression of the therapeutic transgene, that is, Flt3L, was assessed using immunohistochemistry in brain sections after 2 weeks of DOX administration via oral gavage. The results show robust expression of Flt3L in the rat brain parenchyma in areas near the injection site in both the low-DOX and the high-DOX groups, suggesting that Flt3L will be expressed in human glioma patients at a DOX dose of 200 or 300 mg/day. These doses have been approved by the U.S. Food and Drug Administration to treat infections in humans and would thus be considered safe for an off-label use to treat GBM patients undergoing HC-Ad-mediated gene therapy in a phase I clinical trial.

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Turning the gene tap off; implications of regulating gene expression for cancer therapeutics

Abstract: Cancer poses a tremendous therapeutic challenge worldwide, highlighting the critical need for developing novel therapeutics.

Cited by 26 publications

References 55 publications

Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn “On” Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model

Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn “On” Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model

Adenoviral vector-mediated gene therapy for gliomas: coming of age

Effectiveness and Preclinical Safety Profile of Doxycycline to Be Used “Off-Label” to Induce Therapeutic Transgene Expression in a Phase I Clinical Trial for Glioma

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