My research programs focus in three broad areas, including cancer, neurodegeneration and infectious diseases. In the context of cancer, experiments are designed to mechanistically understand the complex molecular basis of tumor development and progression and to utilize this accrued knowledge to create improved ways of preventing and treating neoplastic diseases, including the ultimate stage of this disease- metastasis. In the area of neurodegeneration, our focus is on the critical role of glutamate in inducing toxicity to neurons (excitotoxicity) and developing through sophisticated high throughput screening paradigms non-toxic drugs to prevent this process. These neuroprotective drugs could potentially impact on the treatment and prevention of a wide-spectrum of neurodegenerative processes and diseases. In the realm of infectious diseases, we have cloned one of the major patent receptors for double-stranded RNAs associated with specific pathogenic viruses, a gene called mda-5." Mda-5 with retinoic acid inducible gene-I (RIG-I) play direct roles in interferon induction and innate immunity. We have identified the regulatory regions of both mda-5 and RIG-I and are now using high throughput chemical library screening approaches to identify small molecules that can induce these genes and prevent viral pathogenesis.

We have developed innovative approaches for identifying genes of relevance in the carcinogenic process and have created effective gene-based therapies for cancer, which have translated into the clinic with promising early results. My laboratory has pioneered innovative genomic approaches, including rapid subtraction hybridization, reciprocal subtraction differential RNA display , and overlapping pathway screening, culminating in the identification of novel genes involved in cancer cell growth and cell cycle control, programmed cell death and senescence. Once discovered, we have focused on understanding the role of these genes in important physiological processes employing loss-of-function and gain-of-function strategies in cell culture and in animal models. These discoveries have resulted in several active research programs being pursued in our laboratory to analyze the molecular determinants of cancer development and progression and to develop innovative strategies for the gene therapy of cancer. We cloned mda-9/Syntenin a positive regulator of metastasis and a novel target for developing therapies preventing cancer spread; human polynucleotide phosphorylase an enzyme targeting RNA degradation involved in apoptosis and senescence; and AEG-1, a novel gene intimately associated with multiple cancer phenotypes.

We created therapeutic viruses that selectively replicate in cancer cells and simultaneously produce a therapeutic cytokine (mda-7/IL-24) with potent "bystander" anti-tumor activity that results in not only death of primary tumors but also distant tumors (metastases). These viruses are called Cancer Terminator Viruses (CTVs). To enhance infectivity of the CTVs we genetically engineered tropism modified cancer-selective replicating adenoviruses containing parts of adenovirus type 5 and parts of adenovirus type 3 (Ad.5/3) that express mda-7/IL-24, Ad.5/3-CTV (ILCT-5307) exert profound cancer-selective destroying properties. These viruses were expanded for use in patients and have shown no toxicity in pre-clinical animal modeling studies involving injection in the brains of experimental animals. Studies are planned for testing this therapeutic virus in patients with recurrent glioblastoma (GBM), a currently fatal form of brain cancer without effective therapies. This work emphasiszes our ability to take laboratory findings from the laboratory into the clinic to potentially treat patients with aggressive cancers.