Introduction to Targeted Therapy

Transcription

1 Introduction to Targeted Therapy Cancer remains the second leading cause of death in the United States, despite the significant advances in cancer therapy made over the past several decades. Many factors contribute to our limited success in fighting cancer. Late diagnosis, often after the cancer has already spread to distant locations, is certainly a major reason why many patients are incurable. Equally problematic are the limitations of our current therapeutic armamentarium. The modern-day approach to cancer management is a multidisciplinary one, consisting primarily of surgery, radiation therapy and chemotherapy, in varying combinations. However, any approach is only as good as its components. All three of these treatments function within a limit called the "therapeutic window". This concept refers to the ability of a treatment to kill cancer cells while minimizing the toxicity to healthy, normal cells. Every surgical procedure, radiation course, and chemotherapy agent is bound by this window, and can not exceed it without causing undue harm to the patient. Thus, conventional therapies of today can only achieve so much success in the fight against cancer. Naturally, physicians and scientists are vigorously investigating ways in which to improve the efficacy of these treatment modalities. This includes things like modifying surgical techniques, refining radiation delivery methods (e.g.: see IMRT and Proton Therapy), and developing new chemotherapy agents. These efforts certainly help, but ultimately, there is still room for improvement. Both surgery and radiation therapy have often been described as physical solutions to a biological problem. Chemotherapy, often the cornerstone of treatment in advanced and palliative cases, can be viewed as more of a chemical solution to a biological problem. From the ongoing quest to improve our therapeutic arsenal, a newer, fourth weapon has emerged in the fight against cancer: targeted therapies. This is an ever-growing and exciting new field of research and development. This section will attempt to describe targeted therapies in general, and then take a closer look at some specific types of targeted agents. Many of these have received much publicity recently, and will undoubtedly revolutionize the future of clinical cancer trials and research. What is targeted therapy? Targeted therapy is a general term that refers to a medication or drug that targets a specific pathway in the growth and development of a tumor. By attacking or blocking these important targets, the therapy helps to fight the tumor itself. The targets themselves are typically various molecules (or small particles) in the body that are known or suspected to play a role in cancer formation.

2 How are targeted therapies named? The names of the major classes of targeted therapies typically include the word "anti-", or "inhibitor", together with the name of the target itself. This means that the drug blocks, (is "anti"), that particular target. Then within each class of inhibitors, there is/are the actual drug(s). It is important to realize that a single drug can have several names, including a generic name and a brand name, which can differ in various parts of the world. This can be confusing because often the generic and brand names are used interchangeably in the literature and the media. Throughout this educational section, we will use primarily the generic name of the drug. What are the different classes of targeted therapy? In other words, what are the different targets? There are a number classes of targeted therapies, with new potential targets being discovered all the time. Let s review a few of the major classes and some of the medications in those categories. I) Tyrosine kinase receptor inhibitors A tyrosine kinase receptor is a molecular structure or site on the surface of a cell that binds with substances such as hormones, antigens, drugs, or neurotransmitters. When it binds with one of these triggering substances, the receptor performs a chemical reaction, which in turn triggers a series of reactions inside the cell. These reactions include cell multiplication, death, maturation, and migration. In tumor cells, all of these reactions are critical for the tumor to survive, thrive and spread throughout the body. By blocking the receptor, the goal is to prevent the cascade of reactions and prevent tumor survival. There are many different types of tyrosine kinase receptors in the body. One family of tyrosine kinase receptors is called the human epidermal receptor family, or the HER family. The members of the family are: HER1 (also called the Epidermal Growth Factor Receptor or EGFR) HER2 (also called ErbB2 or HER2/neu), HER3 (also called ErbB3), HER4 (also called ErbB4), The first 2 family members, EGFR and HER2/neu, are the two most extensively studied targets in oncology. A) EGFR inhibitors Within this group, there are two types of inhibitors, small molecule inhibitors and antibody inhibitors.

3 Small Molecule inhibitors Iressa Gefitinib ZD1839 Tarceva Erlotinib OSI 771 Antibody inhibitors Erbitux Cetuximab C225 B) HER2/neu inhibitors Herceptin Trastuzumab NO 34 GW Tykerb Lapatinib *this drug targets HER2/neu and EGFR C) Bcr-abl inhibitors Another group of tyrosine kinase inhibitors inhibit the bcr-abl tyrosine kinase, which is formed in certain types of leukemia. Gleevec Imatinib mesylate STI 571 Sprycel Dasatinib BMS II) Angiogenesis inhibitors Tumor cells, like normal cells, need an adequate blood supply in order to perform vital cellular functions. In fact, as cells multiply and grow in number and size, access to nutrients and blood supply becomes increasingly critical for their continued survival. Actively dividing tumors secrete special proteins that signal the surrounding area to sprout new blood vessels. This new blood vessel formation is called angiogenesis, and the proteins that trigger this process are called pro-angiogenic factors. The main pro-angiogenic factor is VEGF, which stands for vascular endothelial growth factor. In essence, by secreting VEGF and other related proteins to stimulate new blood vessel

4 growth, tumors support and feed themselves, allowing them to grow. The concept behind angiogenesis inhibition, then, is to thwart this process and thereby fight tumor progression. Avastin Bevacizumab anti-vegf III) Proteasome inhibitors The proteasome is a structure inside the cell, which breaks down proteins that have been labeled to undergo degradation and recycling. This process is important because it removes possibly damaged or defective proteins. But more importantly, it is a required process for normal regulation of cellular growth, division, angiogenesis, death, etc. By binding part of the proteasome, a drug can inhibit the breakdown of some of these proteins that have been marked for destruction. This "wreaks havoc" in a sense, and can result in growth arrest or death of the cell. In fact, and fortunately, this tends to happen more so in cancer cells than in normal cells. For those of you who would like more detail, here's a specific example of how this effect works to control tumors: NF-kappa-B is a protein found in both normal and tumor cells. It is typically inactive because it is bound by another protein called inhibitor of kappa B (I-kappa B)-alpha. When this inhibitor protein is broken down by proteasomes, the NF-kappa-B is now active and can travel to the nucleus where DNA lives. Once there, the active NF-kappa-B starts a chain of events that can promote tumor growth and spread. A drug that inhibits the proteasome can block the breakdown of inhibitor I-kappa-B-alpha, and thus block activation of NF-kappa-B. The result is a block of growth factors in the tumor cell. Velcade Bortezomib PS-341 IV) Immunotherapy The classes of targeted therapies described above all bind to and block specific targets, thereby disrupting the chain of events needed for tumor cell proliferation. In contrast, targeted immunotherapy agents bind to their targets, not to interfere with growth signals, but rather to

5 trigger immune signals. By binding specific protein particles (antigens) that are found on the surface certain types of cancer cells, targeted immunotherapy agents can lead to a series of antitumor immune reactions in the body, ultimately causing the tumor cell to die. Furthermore, if these immunotherapy drugs are chemically attached to radioactive substances, you could launch a dual attack on the tumor cells, taking advantage of both the anti-tumor immune response and the antitumor radiation reaction. Targeted immunotherapy drugs are essentially a collection of monoclonal antibodies, all of which have different targets. Antibodies are proteins that seek out and bind to specific antigens; every antibody has a particular antigen with which it "fits". Antibodies are named for the antigen that they bind, e.g.: the anti-cd20 antibody binds to the antigen CD20. The term monoclonal means that a group of antibodies all came from one master cell. In other words, they are clones all derived from one cell line. When there is a radioactive substance (radioisotope) attached, these drugs are called radioimmunotherapy agents. Brand Name Rituxan, MabThera Generic Name Lab Development Name Rituximab anti-cd20 Bexxar Tositumomab I-131-radiolabelled anti- CD20 Zevalin Ibritumomab Y-90-radiolabelled anti-cd20 V) Other types Gleevec Imatinib mesylate STI 571