ANTI-ANGIOGENIC CANCER THERAPY

How To Starve a Tumor - new research targeting tumors' blood supply may lead to the most effective treatment yet.
by Susan H. Bertram, DVM

 

"The surgery was a success, but the patient didn't survive." is a familiar saying, unfortunately often illustrated by oncology cases.  Surgical removal of the primary tumor is possible, but the patient succumbs to metastatic disease months later, despite adjunctive chemotherapy to combat it.

Much of current oncology research is directed at metastatic cancer.  Recent discoveries about tumor biology have uncovered vulnerable targets for cancer therapy, and several new classes of anti-cancer agents show promise in treating and preventing the fatal spread of cancer.  Agents that block a tumor's ability to form its own blood supply have been successful in experimental models, and studies are underway to determine if they'll work as well in clinical veterinary oncology cases.

A significant physiologic difference between normal tissue and cancer is blood supply.  Some tumors can induce new growth of capillaries, termed angiogenesis, which enables expansion of the primary tumor by providing a nutrient blood supply to new tumor cells.  An incomplete endothelial basement membrane in these capillaries also allows free tumor cells to access the general circulation and is a factor in metastasis.

"When a tumor develops angiogenic ability, it is probably the defining moment when it goes from being a local or precancerous lesion to a truly malignant, metastatic lesion," said G. Neal Mauldin, DVM, Dipl. ACVIM {internal medicine and oncology}, Dipl. ACVR {radiation oncology}, assistant professor of veterinary oncology at Louisiana State University School of Veterinary Medicine.  Tumors that lack angiogenic ability rarely grow larger than a few cubic millimeters in size, and don't become clinically significant.

Tumors produce some angiogenic substances directly, or may induce the body to increase production of these factors that stimulate vascular endothelial cells.  Angiogenic factors that have been identified include Vascular Endothelial Growth Factor {VEGF}, Basic and acidic fibroblast growth factor, TNF-a and  angiogenic.  Of these, VEGF appears to be the most important because not only does it induce vascular endothelial cell mitosis, but also increases vascular permeability, critical to angiogenesis.

Blocking angiogenesis can be approached from different angles: by inhibiting release of angiogenic factors from the tumor, by neutralizing them after release or by inhibiting endothelial cells from responding to them.  Various classes of anti-angiogenic compounds have been discovered, and most act by blocking endothelial response.  Protease inhibitors, such as cartilage-derived inhibitor {CDI}, angiostatic steroids such as tetrahydrocortisol, fungus-derived angiogenesis inhibitors such as D-Penicillamine, and thalidomide, are examples.

Use of monoclonal antibiodies, directed against VEGE, which bind to the molecule thereby preventing it from binding to the endothelial receptors, is possible.  Angiostatin is a natural polypeptide, which also inhibits endothelial cells from responding to angiogenic stimuli.  "This is the one recently in the news, the one that has induced multiple remissions in the mice with transplanted tumors," Dr. Mauldin said.  These medications could be given orally and others by injection, but the frequency of administration needed to maintain remission isn't yet known.

When angiogenesis is blocked, tumor capillaries actually regress, and consequently, the tumor itself regresses due to oxygen and nutrient deprivation or "starvation."  Anti-angiogenic therapy could be used in conjunction with surgical removal of a primary tumor, and would be directed against occult or overt metastasis, Mauldin said or might be used to shrink a localized tumor, facilitating definitive surgery, radiation or chemotherapy as curative treatments.

Targeting angiogenesis for cancer treatment has distinct advantages over other forms of therapy.  "Since angiogenesis is a phenomenon in tumor tissue but not normal tissue, it is disease-specific therapy," Mauldin said, and therefore should have a wide margin of safety."  A second advantage is that anti-angiogenic therapy is directed against normal endothelial cells that are genetically stable, so you are less likely to see drug resistance develop as you do with antineoplastic agents."  The main disadvantage is lifelong therapy may be required.  When anti-angiogenic therapy is discontinued, dormant but viable foci of tumors can re-establish malignant and metastatic properties.

"Currently, there are no established protocols for anti-angiogenic therapy in veterinary patients," Mauldin said.  "What is needed now are some well-designed clinical trials, vs. studies using transplanted tumors, which are not the same as spontaneous tumors."

Researchers at LSU have studied thalidomide as a treatment for leprosy and are now investigating it for cancer therapy.  Mauldin said LSU hopes to initiate a controlled, randomized study of thalidomide as an adjunct therapy for canine osteosarcoma in early 1999, and veterinarians could expect to see some published results within the next two to three years.  "An advantage to studying veterinary patients is that they have a compressed life span, so more survival data can be collected in a shorter period of time, versus human patients," Mauldin said.  The development of anti-angiogenic therapy has the potential to be one of the first truly effective treatments for metastatic disease, a major breakthrough for oncology.

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