Evaluation of systemic targeting of RET oncogene-based MTC with tumor-selective peptide-tagged Ad vectors in clinical mouse models

Abstract

Significant advantage of targeted antitumoral treatment consists in the possibility to restrict maximum therapeutic efficacy to the malignant cell population by reducing toxicity in healthy tissues. Using different clinical models for aggressive medullary thyroid carcinoma (MTC), we have recently identified peptide ligands that bind highly selective to tumor cells. By linking the most convincing SRESPHP peptide to an adenoviral (Ad) vector expressing the MTC-related oncogene inhibitor RETDTK, gene transfer was specifically directed to neoplastic tissue after systemic virus administration. We show that peptide-mediated delivery of RETDTK significantly enhanced apoptosis, resulting in a strong inhibition of orthotopic and xenograft tumor growth. Conversely, tumors treated with controls expanded their initial size without notable cell death. According to the therapeutic effect, strong virus accumulation was found exclusively in thyroid carcinomas. Strikingly, application of native tropism depleted viral vector linked to tumor-selective peptide was accompanied by a substantial reduction of Ad binding to the liver. Of note, single systemic injection of a low dose (10e8 pfu/mouse) of MTC-specific Ad.RETDTK induced regression of multiple tumors at different sites in all treated animals. In sum, our results open up the possibility for an efficient cancer cell-specific therapy of primary MTC, their migrating populations and potentially metastases.

Peptide-Based Technologies to Alter Adenoviral Vector Tropism: Ways and Means for Systemic Treatment of Cancer

“…The last step of Ad entry into target cells depends on the interaction between RGD motif at the penton base protein and the host cell integrins [100]. Ad vectors containing this RGD peptide in the HI loop of the fiber showed higher yields of gene transfer than vectors containing the identical peptide attached at the fiber‘s C-terminus, due to the easy access to the receptor [39,101,102]. Many groups transduced effectively different types of tumor cells by inserting this RGD motif into the HI loop of the Ad fiber in vitro [103] and in vivo [104,105].…”

“…The ligand, which also binds efficiently to human MTC cells was covalently linked to the Ad capsid that carried a RET inhibitor as therapeutic gene. Systemic delivery of this peptide-tagged Ad vector led to the substantial growth reduction of orthotopic and disseminated xenograft tumors, while the interaction with other organs, such as the liver, was largely abolished [39]. This precedent opens a road towards using peptide-mediated adenoviral gene transfer to achieve an efficient and selective antitumoral response, even at the stage of metastatic disease.…”

“…Redirecting vectors towards cells of interest can also enhance the therapeutic potential with increased safety by reduction of immune responses, since simultaneous re- and de-targeting allows lower vector doses to be administered systemically [37,38,39,40]. In this review, we present and discuss three different methods to alter the natural Ad vector tropism by: (i) genetic integration of peptide sequences into the fiber; (ii) chemical peptide conjugation via polyethylene glycol (PEG); and (iii) bridging the vector and cell with bispecific adapter molecules.…”

An easy method for preparation of Cre-loxP regulated fluorescent adenoviral expression vectors and its application for direct reprogramming into hepatocytes

“…In addition, adenovirus tends to be removed by the immune system, due to pre-existing antibodies [14]. Better adenoviruses for in- vivo use are being generated, by modifying tropism and immuno-susceptibility [3], [7], [10], [11], [17], [18]. Recently, it was reported that chemical coupling of adenovirus with a peptide that has a high affinity for a hepatic stellate cell (HSC) surface protein drastically facilitates infection of the corresponding cells [16].…”

Molecular Diagnostics in Treatment of Medullary Thyroid Carcinoma

“…Injection of an Ad vector expressing dominant-negative RET protein into MTC of the thyroid glands significantly decreased the tumor size after two weeks (Drosten et al, 2004). To enhance tumor specificity of anti-RET Ad vectors in order to target systemically spreaded medullary thyroid carcinoma cells, we have recently identified a number of MTCspecific peptides that can be used to efficiently redirect the therapeutic gene to primary MTC, their migrating populations, and potentially tumor metastases under in vivo conditions (Böckmann et al, 2005a;Böckmann et al, 2005b;Schmidt et al, 2011).…”