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Publications in Molecular Therapy Identify Molecular Pathway


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Publications in Molecular Therapy Identify Molecular Pathways Underlying Activity of Introgen's INGN 241 Anti-Cancer Therapy

AUSTIN, Texas, June 7 /PRNewswire-FirstCall/ -- Researchers at Introgen Therapeutics, Inc. (Nasdaq: INGN) and The University of Texas M. D. Anderson Cancer Center have identified the molecular pathways by which mda-7, the active component of INGN 241, induces growth arrest and programmed cell death (apoptosis) in cancer cells. Preclinical studies using lung cancer cells have demonstrated, for the first time, that MDA-7 protein binds to a critical cellular enzyme called PKR. The binding of MDA-7 to PKR is essential for the anti-cancer activity of INGN 241 and the identification of this binding partner demonstrates a significant advancement in understanding how this therapeutic can be effective against cancer. Additional studies identified bystander killing of pancreatic cancer cells by MDA-7 protein. Bystander killing involves killing of neighboring pancreatic tumor cells by MDA-7 protein released from adjacent INGN 241 treated cells. The receptor on pancreatic tumor cells that mediates this killing was identified.

The data appear in two separate papers in the current issue of Molecular Therapy.

Sunil Chada, Ph.D., associate vice president, Clinical Research at Introgen said, "Pancreatic cancer is a particularly aggressive cancer and average survival from diagnosis is less than a year. New treatments for this devastating disease are urgently needed. We have shown that INGN 241 potently kills pancreatic cancer cells and also identified a bystander effect whereby neighboring cancer cells are also killed by secreted MDA-7 protein. The bystander effect observed in pancreatic cells indicates that INGN 241 induces cell death through two independent mechanisms in these cells, which may translate into enhanced efficacy."

One study evaluated the mechanism by which INGN 241 activates the cell death pathway in lung cancer cells. Previous studies performed by Dr. Stephen Swisher, associate professor in the Department of Thoracic and Cardiovascular Surgery at The University of Texas M. D. Anderson Cancer Center demonstrated that INGN 241 up-regulated a critical cellular enzyme, PKR, in lung cancer cells. PKR is an essential enzyme called a kinase that can alter the function of cell and virus proteins by adding chemicals called phosphate groups (in a process called phosphorylation). In this study, administration of INGN 241 led to time- and dose-dependent induction of PKR which caused the lung cancer cells to die. Further studies demonstrated that MDA-7 protein produced by INGN 241 physically interacts with PKR protein, and that both MDA-7 and PKR are phosphorylated. The data suggests that MDA-7 binding can alter the activity of PKR, resulting in apoptosis in lung cancer cells. This study identified the first known binding protein for MDA-7 and indicates that phosphorylation of MDA-7 is important for its activity.

"By delineating the specific pathways through which INGN 241 induces apoptosis in particular cancers, the preclinical data reported today may expand our understanding of how best to utilize this novel investigational cancer therapy in various cancer indications," said Dr. Swisher. "Furthermore, we have identified the first binding partner for MDA-7 and it is intriguing that it is the PKR kinase, which regulates many critical cellular functions."

A second study evaluated the anti-cancer mechanisms of action of mda-7 in pancreatic cancer cell lines. Data from this study show that treatment of pancreatic cancer cells with INGN 241 leads to rapid cell death via apoptosis, or programmed cell death. Furthermore, INGN 241-treated cells secrete MDA-7 protein, which binds to the IL-20 receptor on neighboring pancreatic cancer cells and triggers apoptosis and cell death.

The mda-7 gene was discovered by the laboratory of Dr. Paul B. Fisher, professor of clinical pathology and the Michael and Stella Chernow Urological Cancer Research Scientist in the Departments of Neurological Surgery, Pathology and Urology at Columbia University. Introgen holds an exclusive worldwide license for all gene therapy applications from the Corixa Corporation. INGN 241 currently is being evaluated in a Phase 2 trial in patients with malignant melanoma.

Introgen is a leading developer of biopharmaceutical products designed to induce therapeutic protein expression using non-integrating gene agents for the treatment of cancer and other diseases. Introgen maintains integrated research, development, manufacturing, clinical and regulatory departments and operates a commercial-scale, CGMP manufacturing facility.

Introgen holds a licensing agreement with M. D. Anderson to commercialize products based on licensed technologies, and has the option to license future technologies under sponsored research agreements. The University of Texas System Board of Regents own stock in Introgen. These arrangements are managed in accordance with M. D. Anderson's conflict of interest policies.

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