We are developing a new approach to image tumors by selectively targeting the tumors in vivo with a telomerase-specific replication-competent adenovirus expressing green fluorescent protein (GFP) (OBP-401). OBP-401 contains a replication cassette in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of E1 genes and the GFP gene. When OBP-401 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice, para-aortic lymph node metastasis could be imaged by GFP fluorescence. Our results indicated that OBP-401 caused viral spread into the regional lymphatic area and selectively replicated in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes (Kishimoto et al. Nat. Med. 12, 1213-9, 2006 [ref. 29]). In preliminary experiments in an orthotopic model of colon cancer, when OBP-401 was injected intraperitoneally, we could visualize with GFP small peritoneal disseminated tumor nodules in nu/nu mice at laparotomy using a small-animal variable- magnification fluorescence-imaging chamber. Moreover, when OBP-401 was injected systemically or into the spleen or potal venous system, liver metastatic nodules could also be visualized with GFP. Our results indicate that OBP-401 can target the metastatic liver tumors via the circulation system and selectively replicate in tumor cells demonstrating tumor-specific GFP expression. These observations suggested that OBP-401 has clinical potential for cancer-surgery navigation. Toward this goal, the specific aims are as follows: (1) Compare various routes of administration of OBP-401 to effectively and selectively label metastatic colon cancer in orthotopic nude mouse models. (2) Compare survival outcome of resection with viral-labeled and unlabeled metastatic colon tumors in the orthotopic models. Successful completion of these feasibility studies will indicate strong clinical potential of OBP-401 which will be developed toward the IND in the Phase II application. Cancer surgery is among the most difficult of all operations since in order to cure the patient, all the cancer must be removed. This is often a daunting task since the cancer may be widely disseminated. In such a situation, the surgeon usually can not see all of the cancer and the cancer will grow back, often leading to demise of the patient. Our team has developed a virus that has been engineered to grow only in cancer cells. While growing in cancer cells, this virus also produces an engineered fluorescent protein that will allow the surgeon to see all the cancer in the patient by simply shining a blue light on the patient during the operation and using special-filtered magnifying eye-glasses. The fluorescent protein, called green fluorescent protein (GFP), was originally derived from a jellyfish. The gene from this jellyfish was cloned and engineered into the special virus, called OBP-401, which was tested in special mouse models containing metastatic human cancer. The virus was able to make the metastatic cancer fluorescent in the mice. This promising result will be confirmed in this grant application. In addition, we will compare cancer surgery in the mice with both metastatic cancer made fluorescent by the virus and non-fluorescent metastatic cancer. We anticipate a much more successful outcome with the mice that had fluorescent tumors. Having obtained these results, we can move forward in the Phase II grant application with experiments to bring OBP-401 to the clinic for use in cancer surgery in human patients.
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