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The H2 region II binding protein (H-2RIIBP) can alter the DNA binding or transcriptional inducing activity of rat thyroid hormone receptor alpha (rTHR-alpha). Further investigation of this process in the rat malic enzyme system showed the presence of H-2RIIBP-rTHR-alpha complexes in solution bound to the malic enzyme-TH response element. These results suggest that the mechanism involved in DNA binding and induction of transactivation is heterodimerization. Furthermore, maximal hormone-specific gene regulation from particular hormone receptor elements require binding of the TH receptor to specific partners.

Background Numerous clinical trials have demonstrated that oncolytic viruses can elicit antitumor responses when they are administered directly into localized cancers. However, the treatment of metastatic disease with oncolytic viruses has been challenging due to the inactivation of viruses by components of human blood and/or to inadequate tumor selectivity. Methods We determined the cytolytic potential and selectivity of Seneca Valley Virus-001 (SVV-001), a newly discovered native picornavirus, in neuroendocrine and pediatric tumor cell lines and normal cells. Suitability of the virus for intravenous delivery in humans was assessed by blood inactivation assays. Safety was evaluated in vivo using an immune-competent mouse model, and efficacy was evaluated in vivo in athymic mice bearing tumors derived from human small-cell lung cancer and retinoblastoma cell lines. Results Cell lines derived from small-cell lung cancers and solid pediatric cancers were at least 10000-fold more sensitive to the cytolytic activity of SVV-001 than were any of the adult normal human cells tested. Viral infectivity was not inhibited by human blood components. Intravenous doses up to 1 × 1014 virus particles (vp) per kg were well tolerated, and no dose-limiting toxicity was observed in immune-competent mice. A single intravenous dose of 1× 108 vp per kg into athymic mice bearing preestablished small-cell lung or retinoblastoma tumors resulted in complete, durable responses in ten of ten and five of eight mice, respectively. Conclusions SVV-001 has potent cytolytic activity and high selectivity for tumor cell lines having neuroendocrine properties versus adult normal cells. Systemically administered SVV-001 has potential for the treatment of metastatic neuroendocrine cancers. [ABSTRACT FROM AUTHOR]

An abstract of the article "Seneca Valley Virus, a Novel Systemically Deliverable Oncolytic Virus for the Treatment of Small Cell Lung Cancer and Other Neuroendocrine Cancers," by Paul L. Hallenbeck, Seshidhar P. Reddy and Shanthi Ganesh is presented.

Purpose: Seneca Valley Virus (SVV-001) is a novel naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. We conducted a first-in-human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer., Experimental Design: Clinical evaluation of single intravenous doses in patients with cancers with neuroendocrine features was performed across five log-increments from 10(7) to 10(11) vp/kg. Toxicity, viral titers and clearance, neutralizing antibody development, and tumor response were assessed., Results: A total of 30 patients were treated with SVV-001, including six with small cell carcinoma at the lowest dose of 10(7) vp/kg. SVV-001 was well tolerated, with no dose-limiting toxicities observed in any dose cohort. Viral clearance was documented in all subjects and correlated temporally with development of antiviral antibodies. Evidence of in vivo intratumoral viral replication was observed among patients with small cell carcinoma, with peak viral titers estimated to be >10(3)-fold higher than the administered dose. One patient with previously progressive chemorefractory small cell lung cancer remained progression-free for 10 months after SVV-001 administration, and is alive over 3 years after treatment., Conclusions: Intravenous SVV-001 administration in patients is well tolerated at doses up to 10(11) vp/kg, with predictable viral clearance kinetics, intratumoral viral replication, and evidence of antitumor activity in patients with small cell lung cancer. Phase II clinical evaluation in small cell lung cancer is warranted, and has been initiated., (©2011 AACR.)

The use of oncolytic adenoviruses as a cancer therapeutic is dependent on the lytic properties of the viral life cycle, and the molecular differences between tumor cells and nontumor cells. One strategy for achieving safe and efficacious adenoviral therapies is to control expression of viral early gene(s) required for replication with tumor-selective promoter(s), particularly those active in a broad range of cancer cells. The retinoblastoma tumor suppressor protein (Rb) pathway is dysregulated in a majority of human cancers. The human E2F-1 promoter has been shown to be selectively activated/derepressed in tumor cells with a defect in the Rb pathway. Ar6pAE2fE3F and Ar6pAE2fF are oncolytic adenoviral vectors (with and without the viral E3 region, respectively) that use the tumor-selective E2F-1 promoter to limit expression of the viral E1A transcription unit, and, thus, replication, to tumor cells. We demonstrate that the antitumor activity of Ar6pAE2fF in vitro and in vivo is dependent on the E2F-1 promoter driving E1A expression in Rb pathway-defective cells, and furthermore, that its oncolytic activity is enhanced by viral replication. Selective oncolysis by Ar6pAE2fF was dependent on the presence of functional E2F binding sites in the E2F-1 promoter, thus linking antitumor viral activity to the Rb pathway. Potent antitumor efficacy was demonstrated with Ar6pAE2fF and Ar6pAE2fE3F in a xenograft model following intratumoral administration. Ar6pAE2fF and Ar6pAE2fE3F were compared with Addl1520, which is reported to be molecularly identical to an E1B-55K deleted vector currently in clinical trials. These vectors were compared in in vitro cytotoxicity and virus production assays, after systemic delivery in an in vivo E1A-related hepatotoxicity model, and in a mouse xenograft tumor model after intratumoral administration. Our results support the use of oncolytic adenoviruses using tumor-selective promoter(s) that are activated or derepressed in tumor cells by virtue of a particular defective pathway, such as the Rb pathway.