Long-Term Research Aims

To successfully treat solid tumors employing gene transfer techniques.

Mid-Term Research Aims

1. To construct retroviral vectors encoding for the measles virus proteins F and H, test them in preclinical glioma models and compare them with the HSV-tk/ganciclovir system.
2. To target the F/H retroviruses to glioma cells, exploiting the overexpression of matrix metalloproteinases in gliomas.
3. To test the potential of fusogenic membrane glycoproteins in clinical gene therapy trials.
4. To continue with the current and new phase I/phase II gene therapy clinical trials in solid tumors by testing promising transgene/vector systems such as replicating viral vectors.

Approach

Laboratory Research Measles virus exerts its cytopathic effect by cell-cell fusion which eventually leads to cell death. We have cloned the cDNA for the measles F and H fusogenic membrane glycoproteins into eukaryotic expression vectors and have shown significant cytotoxicity through induction of cell-cell fusion in the glioma cell lines U87 and U118 and suppression of tumorigenicity. In addition, we have shown significantly higher bystander effects as compared to the herpes simplex thymidine kinase (HSV-tk) ganciclovir system.

The laboratory component of my research focuses on investigating the use of fusogenic measles virus proteins F and H as novel therapeutic transgenes using the U87 and U118 glioma models. Gliomas were selected because they are highly lethal tumors despite the therapeutic use of surgery, radiation therapy, and chemotherapy. They also have the further advantage of their limited metastatic potential that makes them appropriate targets for intratumoral gene transfer/gene therapy. We plan to a) construct retroviral vectors encoding the F and H transgenes, b) compare the developed vectors with the gold standard of cytotoxicity which is HSV-tk producing retroviral vectors in both glioma cell lines and tumor xenografts, and c) target vectors to the tumor environment by exploiting the over-expression of matrix metalloproteinases in gliomas. A longer term goal is to introduce this novel transgene system into clinical trials as a new therapeutic alternative.

Clinical Trials I am principal investigator or co-investigator in several clinical trials through the Division of Medical Oncology, examining the therapeutic potential of (1) gene transfer mediated immunotherapeutic approaches in patients with renal cell carcinoma and melanoma employing the human IL-2 gene or the combination of the HLA-B7/b2-microglobulin genes, (2) use of the provisionally replication competent adenovirus Onyx-015 in combination with chemotherapy in patients with sarcomas, and (3) treatment of metastatic gastrointestinal malignancies to the liver by intraarterial administration of Onyx-015 alone and in combination with chemotherapy.