Pathotropic targeting advances clinical oncology: Tumor-targeted localization of therapeutic gene delivery

Abstract

Abstract. The advent of pathotropic (disease-seeking) targeting has transported genetic medicine across the threshold of history with the progressive clinical validation of Rexin-G, a tumor-targeted nanosized anti-cancer agent. Achieving noteworthy single-agent efficacy and survival benefits in otherwise intractable cancers, the molecular biotechnology platform has stimulated intense interest in the underlying mechanisms-of-action. This report exhibits the effective localization of Rexin-G nanoparticles within a metastatic liver lesion, as observed upon its surgical excision. IntroductionRexin-G is a pathotropically-targeted replication-incompetent retroviral vector encoding a dominant-negative mutant form of the human cyclin G1 gene, an essential component of the executive cell cycle control pathways that are fundamental to cell growth (1,2). By targeting and thus aborting this critical regulatory component of the cell's universal replication machinery, Rexin-G is invariably lethal to cancer cells derived from all three germ layers, including their associated proliferative vasculature, which empowers Rexin-G with potent anti-angiogenic properties (3,4), as well as broad spectrum tumoricidal activity (5-7). Each therapeutic nanoparticle incorporates a highly efficient and exquisitely specific targeting function to seek out and accumulate in cancerous tissues, using the abnormal or 'pathological' properties of the disease itself, specifically, the newly exposed collagenous proteins associated with cancer growth, metastasis, and tumor-associated blood vessel formation (8). The first targeted genetic medicine of its kind to be tested in the clinic (9), Rexin-G has achieved regulatory approval in the Philippines for the treatment of all chemoresistant solid tumors, and is approaching regulatory approval in the USA for pancreatic cancer, osteosarcoma, and soft tissue sarcomas, where it has been granted FDA Fast Track designation and Orphan Drug status, respectively.The clinical performance of Rexin-G is a function of the multiple levels of safety and efficacy embodied in its design engineering (1), as is its broad-spectrum anti-cancer activity (10). In terms of safety: i) the stealth vector platform allows repeated infusions without untoward immune responses; ii) the limitations of the retroviral platform become a virtue, as the vector is capable of enforcing gene expression in proliferative/dividing cells only; iii) the growth-associated designer gene is active against cancer cells and proliferative vasculature but not against normal non-dividing cells; and iv) the pathotropic accumulation in cancerous tissues essentially sequesters the vector away from non-target organs. In terms of efficacy: i) the cell cycle gene knockout provides for broadspectrum anti-cancer activity; while ii) the anti-angiogenic activity destroys tumor-associated vasculature; and iii) the pathotropic targeting leads to accumulation and high local concentrations where it is needed most, i.e., in the tumor microenvironment.In this communication...