 Targeted therapies are transforming the way people treat cancer. These carefully designed drugs have already begun to make personalized medicine a reality and will continue to help doctors tailor cancer treatment based on the characteristics of each individual's cancer. It is important that healthcare professionals become familiar with the concept of targeted therapies so they can communicate with their patients about these new approaches and help patients make better informed treatment decisions. This tutorial focuses on the variety of targeted therapies that have been and are being developed to treat multiple myeloma. By completing this tutorial, you will learn the answers to the following questions. What molecules and pathways in multiple myeloma cells are being targeted? What agents are being developed to target these molecules and pathways? Which targeted therapies are currently approved by the FDA for treatment of multiple myeloma? How can I find clinical trials of targeted therapies for multiple myeloma? Multiple myeloma is a cancer that begins in plasma cells, which are a type of white blood cell. In this cancer, abnormal plasma cells, called myeloma cells, accumulate in the bone marrow and may eventually interfere with the production and function of normal blood cells. Myeloma cells may also collect in the solid part of the bone. The disease is called multiple myeloma because it affects many of the marrow-containing bones in the body, including arm and leg bones, the pelvis, ribs, vertebrae, and skull. Treatment for multiple myeloma depends on the stage of the disease and the patient's symptoms. Patients who do not have any symptoms may not undergo treatment but will be monitored closely by their doctor. Standard treatment for multiple myeloma includes chemotherapy in the administration of steroids. Because these treatments destroy both myeloma cells and normal cells, many patients also receive blood stem cell transplants. In recent years, new treatments for multiple myeloma have come into wide use. These include the lidomid or cinnivir and the related drug revlamid, which are immune system modulators that have anti-angiogenic activity, as well as the targeted agent Velcade, which will be discussed in this tutorial. Preclinical experiments and clinical trials are underway to evaluate additional targeted therapies and to find out how best to use these drugs in combination with each other and with standard therapies. This tutorial describes several strategies being pursued for the treatment of multiple myeloma. Many of these strategies are also relevant for, and being tested in, other types of cancer. The balance between the synthesis and degradation of key regulatory proteins determines the activities of several cellular signaling pathways. The ubiquitin proteasome system is one mechanism cells use to degrade damaged or unneeded proteins. This system targets proteins involved in such key cellular processes as cell proliferation, growth and survival. One example of a protein targeted by the ubiquitin proteasome system is NF Kappa B. NF Kappa B is normally sequestered in the cell's cytoplasm by a protein called inhibitor of NF Kappa B, or I Kappa B. In this state, the NF Kappa B pathway is inactive. A number of signaling pathways activate NF Kappa B. They do so by phosphorylating I Kappa B, which makes it a target for ubiquitin elation. The added ubiquitin molecules mark I Kappa B for degradation by proteasomes. Once I Kappa B has been degraded, NF Kappa B is free to move to the cell's nucleus, where it helps induce expression of a number of genes that promote cell survival and proliferation. The NF Kappa B signaling pathway is highly active in multiple myeloma as well as in many other cancers. Inhibition of this pathway has been shown to undermine the survival of myeloma cells, making NF Kappa B an attractive therapeutic target. Interfering with the activity of the ubiquitin proteasome system is one strategy for inhibiting NF Kappa B activity in cancer cells. For reasons not fully understood, cancer cells seem to be more sensitive to proteasome inhibition than normal cells. Velcade is an example of a proteasome inhibitor. Velcade binds strongly to the proteasome, preventing it from degrading I Kappa B and other target proteins. This allows I Kappa B to accumulate in the cytoplasm and keep NF Kappa B in its inactive state. The reduction in NF Kappa B activity and the modification of other signaling pathways upon proteasome inhibition collectively reduce cell proliferation and increase the apoptosis of multiple myeloma cells. Velcade has been approved by the FDA for the treatment of multiple myeloma based on evidence from clinical trials that the drug can delay disease progression and increase overall survival in myeloma patients. Velcade continues to be studied in clinical trials for multiple myeloma and other cancers as both a single agent and in combination with standard therapies, including immune system modulators such as the linimid and synovir and other targeted therapies. Heat shock proteins or HSPs are called molecular chaperones because they help maintain the stability and activity of cellular proteins by modulating their three-dimensional shapes. HSP90, like most heat shock proteins, acts as part of a multi-protein complex that includes other molecular chaperones. HSP90 stabilizes its so-called client proteins so they can participate more effectively in their signaling pathways. Thus, although not a signaling molecule itself, HSP90 can enhance the activity of certain signaling pathways. HSP90 and other heat shock proteins also help stabilize cellular proteins in the presence of environmental stresses such as increased temperatures or glucose deprivation that can threaten cell survival. Multiple myeloma cells and many other types of cancer cells have more HSP90 than normal cells. This is most likely because cancer cells must cope with numerous external and internal stressors that are not experienced by normal cells such as low levels of oxygen or mutation of important regulatory proteins. There is evidence that HSP90 is an integral part of the machinery that allows cancer cells to grow uncontrollably. Its client proteins are associated with processes that contribute to all of the hallmarks of cancer, growth factor independence, resistance to anti-growth signals, unlimited replicative potential, tissue invasion and metastasis, avoidance of apoptosis and angiogenesis. Because HSP90 supports many of the biochemical mechanisms used by cancer cells to survive and grow, drugs that interfere with HSP90 may provide better cancer control than drugs that target only a single pathway. HSP90 inhibitors have been examined in preclinical models of multiple myeloma and other types of cancer. These studies have shown that HSP90 inhibitors reduce the viability of myeloma cells, even those that are resistant to standard therapies for this cancer. As expected, numerous proteins and pathways are affected by HSP90 inhibitors, including many suspected to play a role in multiple myeloma. One protein affected by HSP90 inhibition is AKT. The HSP90 complex binds to and stabilizes AKT in cancer cells, allowing the protein to promote cell proliferation and survival. However, in the presence of an HSP90 inhibitor, the interaction between HSP90 and AKT is altered, and AKT becomes a target for ubiquitinylation and degradation by proteasomes, a fate shared by many other HSP90 client proteins when the activity of this molecular chaperone is inhibited. Although no HSP90 inhibitors have been approved by the FDA, they are being tested in clinical trials of multiple myeloma. The activity of proteins can be altered in several ways, including by chemical modification. Phosphorylation is one common type of modification. Another common modification is called acetylation, in which acetylchemical groups are added to proteins. Acetylation and deacetylation, the removal of acetyl groups, can influence the stability or function of proteins or alter their capacity to interact with other molecules. One group of proteins that is frequently modified by acetylation is the histone family. Histones are proteins that interact closely with DNA and help package it inside the nucleus. Genes located within regions of the tightly wound DNA associated with unaccelerated histones are usually not expressed because the DNA is so tightly packaged, they are inaccessible to the cellular machinery that drives gene expression. Acetylation of histones loosens the close association between these proteins and DNA, thereby allowing the DNA structure to relax. Consequently, other proteins are able to reach the DNA and activate gene expression. On the other hand, gene expression can be shut down if cellular enzymes called histone deacetylases, or HDACs, remove the acetyl groups from the histones. Although named for their interaction with histones, HDACs participate in the regulation of acetylation of a wide variety of proteins that are involved in virtually all cellular processes. The activities and expression of many proteins implicated in cancer are regulated by acetylation. The importance of acetylation in cancer is illustrated by the finding that cancer cells cultured in the laboratory undergo cell cycle arrest and ultimately die when treated with HDAC inhibitors, whereas normal cells are relatively unaffected. The apoptotic death of myeloma cells in response to treatment with HDAC inhibitors is likely due to changes in the activities and expression of numerous proteins. For example, through their effects on histones, HDAC inhibitors are thought to promote expression of P21, a cell cycle inhibitor, and BACs, a protein that promotes apoptosis. In addition, HDAC inhibitors affect the activity of HSP90, one of a number of cytoplasmic proteins regulated by acetylation. Acetylated HSP90 is unable to form stable complexes with its client proteins, leading to their degradation by proteasomes. HDAC inhibitors, in combination with standard chemotherapy or other targeted therapies, are being tested in clinical trials of multiple myeloma. Because multiple signaling pathways are often disrupted in cancer cells, many clinical trials are testing combinations of targeted therapies. It is hoped that targeting multiple pathways might reduce the development of drug-resistant tumor cells. For example, HSP90 inhibitors are being tested in combination with a proteasome inhibitor, Velcade, in clinical trials of myeloma. Preclinical studies have shown that myeloma cells treated with Velcade reduce more HSP90 to help protect themselves from the stress caused by the accumulation of undegraded proteins. Inhibiting HSP90 caused the cells to be more sensitive to the apoptotic effects of Velcade. Combination approaches that include one or more targeted therapies are almost certainly the future of cancer treatment. The possibilities are exciting, but clinical trials are needed to establish optimal dosages and schedules for combination therapies. One targeted therapy for treatment of multiple myeloma, Velcade, has already been approved by the FDA. Several other targeted therapies are being developed for use against multiple myeloma. Doctors should consider whether a clinical trial of innovative targeted therapies might be a good option for their patients. Targeted therapies for multiple myeloma are in all phases of clinical study. There are a number of ways to find clinical trials. The National Cancer Institute's website, www.cancer.gov.clinicaltrials, contains information about clinical trials sponsored by the National Cancer Institute, pharmaceutical companies, medical centers, and other groups from around the world. For information on cancer clinical trials being conducted at the National Institutes of Health Clinical Center, visit www.bethesda-trials.cancer.gov. Information about clinical trials can also be found on the clinicaltrials.gov website, which is operated and maintained by the U.S. National Library of Medicine. Cancer patients and their families may also contact NCI's Cancer Information Service, or CIS, if they have questions about cancer and clinical trials. The CIS can be reached by calling 1-800-4-CANCER, or patients can use the live chat feature on the cancer.gov website.