New treatment strategies

Over the last decade, many novel approaches to therapy of brain tumors have been designed. While many of these new therapies are still at the early experimental stage, others are already being investigated in clinical trials. The majority of these new treatment strategies are based on the rapidly growing insight in molecular mechanisms of tumor development.

A. Tumor therapy targeting control of cell growth

Failure of cell growth control is thought to play a major role in the development of brain tumors. Encouraged by the remarkable success of ‘Gleevec’ ® (STI-571), an inhibitor of a growth-promoting receptor, in the treatment of a rare type of leukemia, research on treatment strategies specifically targeting the dysregulation of cell growth in brain tumors has been rapidly expanding. Cell growth control can be attacked at different levels: growth factors, growth factor receptors, molecules that ‘transmit’ the stimulating signal originating from the growth factor receptor to the compartment where the genetic information is stored (the cell nucleus), and proteins that control cell division. Various strategies are available to interfere with essential molecules at each level of growth control. Laboratory-designed antibodies, protein molecules usually produced by the immune system, directly target growth control proteins. Gene therapy may be able to restore function of defective cell-cycle control genes. ‘Small molecules’ such as ‘Gleevec’ ® are designed to bind to the active sites of growth factor receptors.

Growth Factor Receptors

A large number of malignant brain tumor cells carry an abnormally increased number of certain growth factor receptors (‘epideral growth factor receptor’, ‘platelet-derived growth factor receptor’) on their surface.

	Epidermal Growth Factor Receptor (EGFR). Various strategies have been developed to target dysregulated EGFR. Antibodies alone or linked to radioisotopes or toxins have shown efficacy in experimental models. ZD1839 (Iressa®) and tyrphostin (AG1478) are ‘small molecules’ preventing the transmission of growth stimulating signals from the EGFR molecule to its intracellular targets.
	Platelet derived Growth Factor Receptor (PDGFR) In addition to its effect on growth-regulating proteins in leukemia cells, Gleevec® is a selective inhibitor of PDGFR, a protein that is found on the surface of glioma cells. Its usefulness in the treatment of these brain tumors is currently being investigated.

Inhibition of ‘messenger’ molecules of growth-stimulating receptors

Tamoxifen Protein kinase C is a family of cell membrane bound proteins that is essential for the transmission of growth-stimulating signals originating from various growth factors and hormones. Inhibition of protein kinase C for the treatment of brain tumors has been attempted by using tamoxifen. Tamoxifen is better known for its use in the treatment of breast cancer.

Inhibition of the Ras signaling pathway. The Ras proteins play a central role as signal transducers for cell proliferation. Proper functioning requires anchoring of the protein in the cell membrane. Anchoring requires an enzyme called farnesyltransferase, another target of newly developed anti-cancer strategies. Farnesyl transferase inhibitors are currently in clinical trials. Two surprising inhibitors of Ras are lovastatin and simvastatin, well known for their use in patients with high cholesterol levels.

B. New Delivery Strategies

RMP-7 is an example for a drug that increases accessibility of chemotherapeutic agents to the brain. RMP-7 increases leakage through the walls of brain capillaries. Under physiologic conditions, these capillaries are sealed off preventing penetration of drugs into brain tissue.

C. Modulation of Drug Resistance

Several methods are under investigation to reduce resistance of brain tumor cells to chemotherapy agents. Brain tumors produce factors that counteract the effects of drugs frequently used for the treatment of brain tumors.

D. Inhibitors of angiogenesis and cell invasion

As all fast growing tissue, brain tumors are dependent upon the formation of new blood vessels in order to meet the increasing demand for nutrients and oxygen. This process is called angiogenesis. A number of strategies are currently being explored that attack brain tumors by cutting off their blood supply.
One of the first compounds to be identified as an angiogenesis inhibitor was thalidomide. Angiostatin and endostatin are fragments of proteins produced by the human body that counteract the formation of new blood vessels. Cyclooxygenase II inhibitors such as Vioxx^® or Celebrex^® are other examples of this line of research.

E. Gene therapy

Gene therapy of brain tumors includes a wide spectrum of various strategies. As a general principle, a therapeutic gene is packaged into a ‘vector’, typically a modified virus such as herpes (the virus that causes cold sores) or adenovirus (a virus that usually causes upper respiratory symptoms). Modification of the virus prevents it from replicating in an uncontrolled fashion and causing an illness. Viruses can be modified so that they can only divide in tumor cells. Vectors and their packaged genes are usually injected directly into the tumor or part of the tumor that can not be removed surgically.

The first clinical trial of gene therapy in brain tumors was done using viral vectors containing a gene encoding the enzyme thymidine kinase of herpes simplex virus. Injection of the vector was followed by intravenous infusion of the antiviral agent ganciclovir. The idea behind this so called 'suicide gene therapy' was the following: 'transfection' of brain tumor cells with the gene incorporated in the vector would lead to selective expression of thymidine kinase in tumor cells. Whereas normal brain cells would not be affected by ganciclovir, thymidine kinase in transfected tumor cells would transform ganciclovir into a compound inhibiting replication of genetic information and cell division and thus, tumor growth. The results of this first trial in humans were disappointing but similar strategies are being refined and may lead to more promising results.

F. Immune-mediated therapy

The majority of primary brain tumors are poorly recognized by the immune system. The goal of immune-mediated therapy strategies is to increase the immune response to the tumor.

Vaccination Strategies

Tumor vaccination strategies using tumor cells or immune cells loaded with tumor proteins are intended to elicit a more effective immune response to brain tumors.

Recombinant cytotoxins

Recombinant cytotoxins are genetically engineered substances that consist of a molecule that binds to tumor cells and a toxic compound (such as a bacterial toxin) that kills the tumor cell. One of the clinical trials currently open at Yale is based on this strategy. This treatment is given as an infusion directly into remaining tumor and surrounding brain tissue through catheters placed at the time of surgery. When the treatment is completed, the catheters are pulled out.

Antibody- and Cell-mediated Therapy of Gliomas

Antibodies are proteins that the human body produces to fight off infections. They can be produced in the laboratory and linked to toxic or radioactive compounds. Over the last fifteen years, modified antibodies targeting brain tumor cells have been developed but so far this strategy has not resulted in an improvement of tumor control.

G. Oncolytic viruses

Oncolytic viruses are modified viruses that preferentially infect and destroy cancer cells. Early clinical trials are ongoing.