Brain Tumors: Primary

Description

Alternative Names

Other Treatments

A number of drugs that target specific mechanisms associated with brain cancer are being tested. Combinations of some of these drugs with or without standard chemotherapy and radiotherapy may prove to be more effective than the use of any one treatment. It should be noted that none of these drugs at this time are producing cures, although some are improving survival.

Immunotherapy

Immunotherapy aims at using modalities that boost the patient's own immune system's ability to seek out and destroy cancerous cells.

Radioimmunotherapy with Monoclonal Antibodies. Radioimmunotherapy is showing special promise as a treatment approach to brain tumors. It typically employs monoclonal antibodies (MAbs), which are genetically engineered antibodies designed to work against a specific target. MAbs are bound with radioactive substances and delivered directly into the brain and sometimes into the tumor. The MAbs are specifically designed to lock with the surface of certain cells in the tumor. Once they do so, the radioactive substances destroy the cell. The approach is essentially mini-radiation therapy without the damage or severe side effects of standard radiation treatments. A number of different radioimmunotherapies are being investigated, and trials of some are reporting improved survival rates in high-grade gliomas. Some experts believe this approach could prove to be the most effective therapy against these cancers.

Interleukins. Interleukins are natural proteins created by the immune system. Certain tumor cells carry receptors for specific interleukins, which are being investigated for a possible therapeutic role. For example, some drugs combine an interleukin with an agent that is toxic to cancer cells. The interleukin locks onto the receptor on the cancer cell and the toxic chemical enters the tumor with the intent to kill it. Some interleukins are also being investigated alone for their own tumor-cell killing properties.

Tumor Vaccines. Tumor vaccines are also being created, in which tumor cells are removed from the patient and inactivated; when they are transferred back to the patient, they are harmless but can elicit a powerful immunologic response against the tumor. For example, a vaccine that combines tumor proteins with the patients nerve cells is being tested in astrocytomas.

Cell Growth and Angiogenesis Inhibitors

Much research is focusing on drugs that block small molecules involved with the growth of blood vessels that feed the tumor (a process called angiogenesis). Such agents, when effective, would starve tumors of vital nutrients and oxygen.Angiogenesis is particularly important in the growth of glioblastomas, the most malignant brain tumors. Of particular promise are agents that inhibit enzymes called tyrosine kinase, farnesyl protein transferase, and matrix metalloproteinase, which play critical roles in angiogenesis.

Farnesyl Protein Transferase Inhibitors. Farnesyl protein transferase inhibitors, such as tipifarnib, also called R115777 (Zarnestra) and lonafarnib (Sarasar), are drugs in a new class that block a mutated gene called the Ras gene, which is responsible for about 30% of cancers. Lonafarnib is in early trials in combination with temozolomide. Tipifarnib is also currently in early trials and may prove be effective as radiosensitizer.

Tyrosine Kinase Inhibitors. Agents that target receptors of growth factors, such as one called tyrosine kinase, interfere with the pathway leading to angiogenesis. Some tyrosine kinase inhibitors, including erlotinib (Tarceva), imatinib (Gleevac), gefitinib (Iressa), and others. are being investigated in early trials. Some are showing specific promise as radiosensitizers. Side effects include rash, diarrhea, nausea and vomiting. Some may reduce white blood cell count or produce liver toxicity.

Matrix metalloproteinase Inhibitors. Matrix metalloproteinase is an important enzyme in angiogenesis. Inhibitors of these enzymes, including marimastat, metastat, and prinomastat, are in early trials. Marimastat has been studied and has shown some benefits in early trials for patients with recurrent glioblastoma and anaplastic gliomas, particularly in combination with temozolomide.

Phophoinositide 3-Kinse (Pi3K) Inhibitors. Rapamycin and its analog (CCI-779) inhibit Pi3K, an enzyme involved in cell growth. Early trials using CCI-779 are underway. (Another rapamycin analog, everolimus, has different effects but is also being studied for its actions in inhibiting cell growth.)

Other Drugs that Block Angiogenesis. Thalidomide was one of the first drugs used to inhibit angiogenesis and has undergone several trials. There is some evidence that it may work more effectively for metastasized brain tumors than primary tumors. Other agents in early trials with various effects on tumor growth include suramin, cilengitide, semaxanib, PTK787, and atrasentan.

Other Investigative Agents

Retinoids. Retinoids are vitamin A derivatives and act as differentiating agents in cancer treatments. That is, they can convert immature, dividing tumor cells into mature cells, stopping tumor growth. Studies suggest that they have little benefits as single agents. Combination with radiotherapy and other drugs may hold promise.

Inactivated Viruses. Investigators are finding that certain genetically inactivated viruses, such as the poliovirus or herpesvirus, may prove to be valuable fighters of brain cancers. Such viruses can enter cells and destroy them but do not pose any danger for infection. For example one specially designed herpes virus targets the enzyme thymidine kinase (an enzyme that promotes tumor growth). Some researchers believe that a combination of this virus with retinoids may be effective with few serious side effects. Other viruses are being investigated. A drug based on this model is years away, however.

Immunnotoxins. Agents called immunotoxins use natural toxins to kill malignant brain cells.

Agents that employ diphtheria toxins, including TransMID-107R and DAB(389)EGF), are the first immunotoxins to show some promise. Clinical trials are investigating them for gliomas and metastatic brain cancers. Other toxins under investigation include irofulven (a mushroom toxin) and chlorotoxin (a substance derived from scorpions).

COX-2 Inhibitors. Celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra) are known as COX-2 (cyclooxygenase-2) inhibitors, or coxibs. They inhibit an inflammation-promoting enzyme called COX-2. Coxibs are commonly used to relieve pain, but they also appear to have effects that inhibit tumor cell growth, including gliomas. Such effects may be similar to retinoids and trials are investigating combinations of these two agents. The value of COX-2 inhibitors in the treatment of patients with brain tumors is unknown.

Taurolidine. Taurolidine is a unique agent that prevents tumor formation and growth in animals. An early clinical trial in patients with high-grade gliomas is under way.

Protein-Blocking Drug. Another development is the discovery of a protein called BEHAB (Brain-Enriched Hyaluronan Binding Protein). BEHAB is produced only by invasive glioma tumor cells, not by normal brain tissue or noninvasive tumor cells. Breakdown of BEHAB releases a substance called HABD (hyaluronan-binding domain), which appears to give glioma cells the ability to invade other areas of the brain. Both BEHAB and HABD represent potential targets for new therapies.

Transplantation Procedures and High-Dose Chemotherapy

Chemotherapy destroys not only cancer cells, but also healthy cells, including special blood cells in the bone marrow called stem cells, which are immature cells from which all blood cells develop. Transplantation procedures using bone marrow or stem cells allow high-dose chemotherapy to be administered while protecting blood cells. The procedures are being tested for patients with brain tumors that are responsive to the effects of chemotherapy. A 2003 study, for example, reported long-term survival in some patients, but it is not clear if such rates are any better than other treatments. The procedure has serious, sometimes life-threatening, side effects.

Photodynamic Therapy

Photodynamic therapy employs a special agent (Photofrin) that is absorbed by the tumor and causes the cancer cells to become fluorescent when a laser is directed at them. It is being investigated in late-stage trials in combination with other treatments. A 2003 study reported encouraging results, notably with patients with recurring glioblastoma multiforme. In the study, more than half of these patients survived for at least a year.