INGN 241 drug provides multiple routes to cancer cell death in a single drug
AUSTIN, TX, July 16, 2003 -- A series of publications resulting from ongoing research and development activities at Introgen Therapeutics, Inc. were made available during the recently concluded annual meeting of the American Association of Cancer Research (AACR). Several of the publications demonstrated that mda-7, the gene that is the active component in INGN 241, kills a broad array of cancer cells by inducing cell death directly, and also illustrate the multiple cancer killing activities of INGN 241 related to its anti-angiogenic and radiosensitizing properties.
The activation of two independent pathways that kill cancer cells is due to the potent activity that mda-7 has in inducing apoptosis (cell suicide) and providing cytokine functions. The cytokine activity of mda-7, discovered by scientists at Introgen, has resulted in the classification of mda-7 as interleukin 24 (IL-24), a member of the interleukin family of immune stimulating proteins. Another member of the interleukin family, IL-2, is approved for the treatment of several cancers. INGN 241 is currently undergoing phase 1 and phase 2 clinical testing for multiple tumor types. The studies were initially published in the 1st edition of the Proceedings of the AACR.
Dr. Sunil Chada, Introgen's director of research and development, said, "We have known for some time that mda-7 is a potent activator of apoptosis and efficiently kills tumor cells by causing them to self-destruct. The more recent discovery that mda-7 also is a potent cytokine and anti-angiogenic agent enhances the potential utility of INGN 241 in treating a variety of cancers.
"What we find especially promising is the ability of INGN 241 to induce cancer cell death via multiple independent tumor-killing pathways. In addition to direct apoptosis induction by INGN 241, the secreted MDA-7 protein blocks tumor angiogenesis and starves the tumor of nutritive support. The MDA-7 protein appears to activate a systemic immune response that provides a mechanism to kill metastatic cells that have migrated out of the primary tumor and may lead to the formation of tumors at other sites in the body. Given that oncologists are looking to develop 'cocktail' regimens that attack cancer from multiple directions, we believe that INGN 241 holds great promise as an anti-cancer agent that can provide multiple cancer killing mechanisms in a single drug."
The publications define the mechanisms of action of INGN 241 in several types of cancer and also suggest anti-cancer activity against those cancers. The highlights include the following studies:
- Introgen evaluated molecular mechanisms underlying tumor-specific cell death in both lung and breast cancer cells and discovered that treatment of tumor cells with INGN 241 activates other tumor suppressor proteins, known as PTEN, APC and GSK-3. It also inactivates important growth promoting genes, such as P13K and beta-catenin. (Abstract 2029) By learning what happens after treatment with INGN 241 in the pathways which allow cancer cells to grow, a more effective cancer treatment may be developed.
- In breast cancer, significant growth inhibition and the apoptotic effect of INGN 241 on breast cancer tumors in animal models was confirmed. (Abstract 2187) The preclinical data demonstrate in vivo that INGN 241 can down- regulate certain signaling pathways that promote cancer growth. This data expands and corroborates our cell culture findings in animal models and is important because it demonstrates the broad utility of INGN 241 as a possible treatment for cancer that can influence the development of cancer at a molecular level.
Introgen has developed methods to highly purify MDA-7 protein so that the researchers know that the protein is not contaminated. (Abstract 5662) This information has allowed the evaluation of purified MDA-7 protein in angiogenesis. MDA-7 is 50 fold more potent than endostatin at blocking angiogenesis using cell culture and in vivo assays. It was shown that tumor growth is suppressed by treatment with MDA-7 protein, suggesting that INGN 241 may have activity against metastatic disease.
In addition to killing cancer cells via apoptotic and immune pathways, preclinical studies have shown that INGN 241 may enhance treatment options for cancer patients by providing supra-additive or synergistic activity with existing cancer treatments such as chemotherapy and radiotherapy. Preclinical studies demonstrated that INGN 241 kills a broad spectrum of cancer cells, yet has minimal toxicity to normal cells. When induced, programmed cell death appears to be selective for tumor cells. INGN 241 has an unusual combination of attributes; it can directly cause cancer cells to die and then the MDA-7 protein released from tumor cells can stimulate the immune system to attack additional metastatic tumor cells. This two-pronged approach to killing cancer cells may provide clinical benefit to patients with advanced cancers.
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 to the mda-7 gene from the Corixa Corporation.
Introgen is a leading developer of biopharmaceutical products which use non-integrating genes to produce a therapeutic protein to treat cancer and other diseases. Introgen maintains integrated research, development, manufacturing, clinical and regulatory departments and operates a commercial- scale, CGMP manufacturing facility.
Source: Introgen Therapeutics www.introgen.com
Posted: July 2003
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