Since 1999, cancer has surpassed heart disease as the number one cause of death in the US for people under the age of 85. The purpose of this proposal is to create a novel cancer treatment targeted to tumor specific transcriptional signatures and to evaluate this therapeutic in preclinical studies of efficacy and toxicity. Both neuroblastoma (Nb), the most common extra-cranial solid tumor in children, and Malignant Peripheral Nerve Sheath Tumor (MPNST), a common malignancy in patients with Neurofibromatosis, are tumors with high mortality rates and specific transcriptional signatures. To date, minimal toxicity has been observed in clinical trials utilizing oncolytic HSV vectors (oHSV). To target tumors of a specific transcriptional signature, the proposed virus will contain the HSV-1 neurovirulence ICP34.5 transgene driven by a cancer specific promoter. In addition, there is evidence that HIJ-1a potently increases certain transcriptional signatures in human placental adenocarcinoma cells. The central hypothesis of this proposal is that the tumor-specific transcriptional profile of a cancer cell can be exploited to drive tumor-enhanced virus replication and oncolysis. Viral replication should be tumor enhanced through two distinct mechanisms: (1) the upregulation of HIF-1a protein under local hypoxic conditions commonly found with solid tumors, and (2) transcriptional targeting of ICP34.5 in tumor cells with a specific transcriptional signature. The following aims have been designed to test this hypothesis:
AIM 1 : To determine the specificity of an oHSV with a cancer specific promoter driving ICP34.5 in tumor cells versus normal cells.
AIM 2 : To determine whether tumor lysis by this oHSV-34.5 construct is enhanced by hypoxia, via HIF-1 upregulation.
AIM 3 : To determine the anti-tumor effects and biosafety of this novel oHSV-34.5 vector xenograft models of Nb and MPNST.
| Maldonado, Arturo R; Klanke, Chuck; Jegga, Anil G et al. (2010) Molecular engineering and validation of an oncolytic herpes simplex virus type 1 transcriptionally targeted to midkine-positive tumors. J Gene Med 12:613-23 |
