Molecular targets and targeted therapies for malignant mesothelioma
Wednesday, May 14th, 2008.
Current medicinal chemistry. 2008;15(9):855-67. [Link]
Palumbo C, Bei R, Procopio A, Modesti A.
Department of Experimental Medicine and Biochemical Sciences, Tor Vergata University, Via Montpellier 1, Rome, Italy. camilla.palumbo@uniroma2.it
Abstract
Malignant mesothelioma is a highly invasive tumor originating from the mesothelial linings of the pleura, peritoneum and pericardium. It is seldom amenable to surgical intervention and poorly responsive to radiotherapy, leaving chemotherapy as the main therapeutic option for most patients. The development of effective drug regimens against mesothelioma has proven extremely difficult and a standard first-line treatment for patients with unresectable tumors has not been established until recently. Despite the benefits obtained with this newly validated standard of care, which is based on the combination of pemetrexed and cisplatin, the prognosis for mesothelioma patients remains poor, median survival is still less than two years and more active treatments are urgently needed. This article will focus on the molecular basis providing the rationale for targeted interventions against mesothelioma and will review targeted agents under evaluation as new potential therapeutic options for mesothelioma patients. Such agents include inhibitors of growth factor receptors, ligands and intracellular effectors. The agents targeting vascular endothelial growth factor signaling are of particular interest, due to the involvement of this pathway both in tumor angiogenesis and autocrine stimulation of mesothelioma cell growth. Alternative approaches are based on inhibitors of the ubiquitin-proteasome pathway and of histone deacetylases which, notwithstanding the functional divergence of the corresponding targets, share the ability to determine a wide modulation of the cancer cell phenotype that can lead to cell cycle arrest, apoptosis and sensitization to different antineoplastic treatments. A recombinant immunotoxin targeted to the membrane antigen mesothelin is an additional agent whose activity is being evaluated in mesothelioma patients.
Glossary
- prognosis
- (prog-no-sis) a prediction of the course of disease; the outlook for the cure of the patient. For example, women with breast cancer that was detected early and who received prompt treatment have a good prognosis.
- pleura
- (pler-uh) the membrane around the lungs and lining of the chest cavity. (Pleural mesothelioma.)
- chemotherapy
- (key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.
- cell
- the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.
- cancer
- malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.
- antigen
- (an-tuh-jen) a substance that causes the body's immune system to react. This reaction often involves production of antibodies. For example, the immune system's response to antigens that are part of bacteria and viruses helps people resist infections. Cancer cells have certain antigens that can be found by laboratory tests. They are important in cancer diagnosis and in watching response to treatment. Other cancer cell antigens play a role in immune reactions that may help the body's resistance against cancer.
- angiogenesis
- (an-gee-o-JEN-uh-sis) the formation of new blood vessels. Some cancer treatments work by blocking angiogenesis, thus preventing blood from reaching the tumor.
- tumor
- an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).
- mesothelioma
- a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.
- pemetrexed
- chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.
- apoptosis
- a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.
