December 16, 2003
A Couple Of Novel Cancer Therapies Reported

Cancer is a particularly difficult disease to treat because cancer cells are host cells. It is hard to develop methods to selectively kill some host cells while not killing too many of the normal cells. Reports of interesting approaches for doing so are always interesting. The first here is the use of stem cells to go to where the cancer is located to deliver a treatment payload.

SAN DIEGO -- Genetically engineered stem cells can find tumors and then produce biological killing agents right at the cancer site, say researchers at The University of Texas M. D. Anderson Cancer Center, who have performed a number of successful "proof of concept" experiments in mice.

Their novel treatment, presented at the annual meeting of the American Society of Hematology (ASH), may offer the first gene therapy "delivery system" capable of homing in on and then attacking cancer that has metastasized -- wherever it is in a patient's body. And the stem cells will not be rejected, even if they are not derived from the patient.

The researchers have tested the system in mice with a variety of human cancers, including solid ones such as ovarian, brain, breast cancer, melanoma and even such blood-based cancer as leukemia. "This drug delivery system is attracted to cancer cells no matter what form they are in or where they are," says Michael Andreeff, M.D., Ph.D., professor in the Departments of Blood and Marrow Transplantation and Leukemia. "We believe this to be a major find."

M. D. Anderson has filed patent applications on the system, which uses human mesenchymal progenitor cells (MSC), the body's natural tissue regenerators. These unspecialized cells can migrate to an injury by responding to signals from the area. There they develop the kind of connective tissue that is needed to repair the wound, and can become any kind of tissue required.

Tumors are "never-healing wounds" which use mesenchymal stem cells to help build up the normal tissue that is needed to support the cancer, says Andreeff. "There is constant remodeling of tissue in tumors," he says. So researchers turned the tables on the cancer, taking advantage of a tumor's ability to attract the stem cells.

In their novel delivery system, researchers isolate a small quantity of MSC from bone marrow, and greatly expand the quantity of those cells in the lab. They then use a virus to deliver a particular gene into the stem cells. When turned on, this gene will produce an anti-cancer effect. When given back to the patient through an intraveneous injection, the millions of engineered mesenchymal progenitor cells will engraft where the tumor environment is signaling them, and will activate the therapeutic gene.

In the study reported at ASH, the researchers examined whether MSC producing human interferon-beta can inhibit the growth of metastatic tumors in the lungs of mice that do not have a functioning immune system. They used an adenovirus vector to deliver the gene that expresses interferon-beta, which can prevent cell reproduction. Andreeff and his team found that when mice were treated with just four weekly injections, their lifespan doubled, on average. They also discovered that when treated cells were placed under the skin of the mice, there was no effect. "The cells need to be in the immediate environment of the tumor to work," which suggests that normal tissue will not be adversely affected, says Andreeff.

Other studies being reported by Andreeff that used different therapeutic "payloads" found a doubling of survival in mice with one kind of ovarian cancer and a cure rate of 70 percent in mice with a different kind of ovarian tumor. Another study demonstrated that when the gene therapy was injected into the carotid (neck) artery of mice with human brain cancer, the genes incorporated themselves into the cancer, not into normal brain tissue.

This is a very cool result. One question is whether the stem cells will stick around to cause problems by expressing their payload genes. But if the stem cells come from another host then the body's own immune system will probably eventually wipe out the foreign stem cells after they have done their job.

Another treatment approach utilizes the fact that many cells in a tumor tend not to be well fed. A rapidly growing tumor usually has areas where some cells are not near capillaries and that are therefore oxygen starved. Those cells actually have a survival advantage against many chemotherapeutic agents because either agents can't be given in high enough dosages to seep into those cells or the chemo works better on active cells by reacting to oxygen in order to activate or for some other reason related to metabolism of active cells. KuDOS Pharmaceuticals and Novacea are working with a compound that is activated by a metabolic pathway that is typically only active in cells that lack oxygen.

South San Francisco, Calif. and CAMBRIDGE, United Kingdom, Dec. 11, 2003 -- Novacea Inc. and KuDOS Pharmaceuticals announced today that Novacea has licensed from KuDOS the North American rights to develop and commercialize AQ4N, a novel proprietary hypoxic cell-activated agent with broad potential in a variety of cancers.

...

As a first-in-class hypoxic cell-activated anti-tumor therapy, AQ4N represents a new approach to cancer treatment. The drug is considered inactive when administered and is selectively converted into its active cytotoxic form, known as AQ4, once it reaches hypoxic tumor cells (cells that are oxygen starved), reducing potential systemic toxicity. AQ4 is a potent topoisomerase II inhibitor and DNA intercalator.

More than two million patients each year are estimated to present with tumors in the U.S. and Europe. The large majority of these tumors have hypoxic components, which are relatively resistant to standard anti-cancer treatment, including radiotherapy and chemotherapy. As a result, a specific agent like AQ4N that can treat the hypoxic fractions should enhance the overall efficiency of cancer cell killing and reduce tumor recurrence.

Preclinical data demonstrate that AQ4N markedly enhances the effects of radiation and chemotherapy when administered in combination with either treatment. Data further suggest anti-tumor activity as a monotherapy. The agent is currently being evaluated in a Phase 1 clinical trial in combination with radiation in esophageal cancer. Sixteen patients have been treated to date and AQ4N has been well tolerated, with no serious drug-related adverse events reported.

AQ4N was originally discovered by Prof. Lawrence Patterson of the School of Pharmacy, at University of London, working in collaboration with BTG International plc (BTG). KuDOS acquired a worldwide license for AQ4N from BTG in March 2001.

While AQ4N is at best only going to kill a subset of cancer cells that targetted subset too often escapes death from current chemotherapeutic agents. So in combination with existing chemotherapeutic agents it might turn out to be a useful treatment.

Update: Another unusual anti-cancer therapy under development by Dr. William Wold of the Saint Louis University School of Medicine and his colleagues genetically engineers adenoviruses that cause common colds to instead selectively kill cancer cells.

Dr. Wold, chair of the department of molecular microbiology and immunology, and his colleagues Karoly Toth, Konstantin Doronin, Ann E. Tollefson, and Mohan Kuppuswamy have found a way to convert the relatively benign "adenovirus" that causes the common cold into an anti-cancer drug that attacks and destroys cancerous cells.

"Human cancer is currently treated with surgery, radiation therapy, or chemotherapy, depending on the cancer type," Wold said. "These treatments can be highly successful, but new therapies are required, especially for tumors that have become resistant to chemo- or radiation-therapy."

Wold's group has developed several new "adenovirus cancer gene therapy vectors," changing these genes so the virus will attack cancer cells.

"Some of our vectors are designed to destroy many different types of cancers, others are designed to be specific to colon or lung cancer. In preclinical testing these vectors were highly effective against cancerous tumors and did not harm normal tissues."

Wold and his colleagues have done this by modifying one gene so that the virus can grow in cancer cells but NOT normal cells and by boosting the activity of another gene that the virus normally uses to disrupt the cells it has infected. "When the virus infects cells, it takes the altered genes with it, and those genes attack cancer cells while leaving normal cells intact," Wold explained.

A U.S. patent (No. 6,627,190) was awarded this fall to Dr. Wold and his team of researchers. Pre-clinical testing is complete and is expected to move soon into clinical trials.

Now this patented technology has been issued and exclusively licensed to a company, Introgen Therapeutics, which made the announcement this morning. Introgen and VirRx, a biotechnology company founded by Wold and with a primary interest in cancer gene therapy, are collaborating on new therapies for cancer and other diseases.

The adenovirus is genetically engineered to express a gene that causes tumor cell death.

AUSTIN, Texas, Dec. 16 /PRNewswire-FirstCall/ -- A patent that covers an important class of replicating adenoviruses relating to Introgen Therapeutics' anti-cancer product candidate INGN 007 (VRX 007) has been issued and exclusively sub-licensed to Introgen, the company announced today. The United States patent, U.S. 6,627,190, emanates from research performed at VirRx, Inc. and Saint Louis University under the direction of Dr. William S.M. Wold, one of the world's leaders in replicating oncolytic virus technology. Introgen and VirRx are collaborating on new therapies for cancer and other diseases. VirRx, LLC was founded by Dr. Wold.

INGN 007 is an oncolytic virus product that over-expresses the ADP gene, the protein responsible for the rapid disruption (oncolysis) of tumor cells and, hence, is an important therapeutic activity of oncolytic viruses. Oncolytic viruses are viruses that kill cancer cells by replicating at high levels and cause a cancer cell to break apart. In animal models, INGN 007 has demonstrated that it saturates the entire tumor treated and has shown it can eradicate cancer. Introgen and VirRx initiated their collaboration in order to develop a series of potential products emanating from VirRx and the Wold laboratory. Preclinical testing of INGN 007 is now being completed and the product is being readied for clinical development.

It isn't clear why this cell death effect is specific to cancer cells. A couple of Journal of Virology abstracts of Wold and his colleagues here and here refer to Transforming growth factor β1 (TGF-β1) but are they trying to turn it off or on in cancer cells and why is the mechanism not also going to kill normal cells? Again, it is not clear. Anyone have any insights on this?

Share |      Randall Parker, 2003 December 16 06:23 PM  Biotech Therapies


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