|Introduction to Targeted Therapy|
|Neha Vapiwala, MD & Geoffrey Geiger, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
| Last Modified: September 10, 2010
The modern-day approach to cancer management is an increasingly multidisciplinary one, consisting primarily of surgery, radiation therapy and chemotherapy, in varying combinations. However, any approach is only as good as its individual components. All three of these treatment modalities function within the so-called "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, course of radiation, and cycle of chemotherapy agent is bound by this window, and cannot exceed it without causing harm to the patient.
Naturally, physicians and scientists are vigorously investigating ways 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 there is a great deal of 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. In the ongoing quest to improve cancer treatments, 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 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 in the media, and will undoubtedly revolutionize the future of clinical cancer trials and research.
What is targeted therapy?
Cytotoxic chemotherapy has long been the cornerstone of medical therapy for malignancies. This type of therapy preferentially selects for rapidly dividing cells, which means that it affects both highly proliferative normal tissues (e.g., hair, the linings of the gastrointestinal tract, bone marrow) and malignant cells. Ultimately, however, this type of treatment is toxic to all cells. On the other hand, 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 cell. 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. Monoclonal antibodies are antibodies directed against molecules that are either overexpressed or mutated (or Ã’brokenÃ“) in cancerous cells. Alternatively, small molecule inhibitors represent a different class of medications that interfere with similar pathways. Many of these targets are tyrosine kinases, which are enzymes found within cells that transfer phosphate groups and affect molecular signaling. We will explore this concept in much greater detail in the coming section.
Implications of targeted therapy
The development and integration of these therapies into widespread clinical use have had some significant effects on the outcomes of certain malignancies. Imatinib was one of the earliest and most impressive examples of the potential impact targeted therapies could have on cancer treatment, through itÃ•s use in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). Rituximab and trastuzumab have changed the treatment and survival for people with non-HodgkinÃ•s lymphoma (NHL) and HER2/neu overexpressing breast cancers, respectively. Furthermore, targeted therapies tend to be better tolerated than traditional cytotoxic chemotherapeutic agents. This permits treatment for some patients who might not otherwise be candidates for more toxic therapies.
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, or is "anti", that particular target. The agents are categorized into classes, which include therapies that have similar targets.
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 primarily use 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 of classes of targeted therapies, with new potential targets being discovered all the time. LetÃ•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 growth and 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:
The first 2 family members, EGFR and HER2/neu, are two of the most extensively studied targets in oncology.
A) EGFR inhibitors
Within this group, there are two types of inhibitors, small molecule inhibitors and antibody inhibitors.
Small Molecule inhibitors
B) HER2/neu inhibitors
* Note: Tykerb targets both HER2/neu and EGFR
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 growth, tumors support and feed themselves, which allows them to grow larger. The concept behind angiogenesis inhibition, then, is to interupt this process, and thereby fight tumor progression. As is the case with the EGFR therapies, within this group, there are two types of inhibitors: small molecule inhibitors and antibody inhibitors.
Small Molecule Inhibitors
III) Proteasome inhibitors
The proteasome is a structure inside the cell that breaks down proteins that have been labeled to undergo break down and recycling. This process is important because it removes possibly damaged or defective proteins. But more importantly, it is a required process for normal cell growth, division, angiogenesis, and death. 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. 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.
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 trigger the bodyÃ•s immune system. By binding specific protein particles (antigens) that are found on the surface of certain types of cancer cells, targeted immunotherapy agents can cause the immune system to attack the tumor cells, ultimately causing the tumor cell to die. Furthermore, some immunotherapy drugs have radioactive substances attached to them, causing a dual attack, with both an immune response and an anti-tumor 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.
V) Other types (including multitarget agents)
The following tables outline many of the currently FDA approved targeted therapies.
Table 1. Small Molecule Inhibitors for Cancer Treatment
* Following tables modified and adapted from Gerber, D. E. (2008). "Targeted therapies: a new generation of cancer treatments." AAFP 77(3): 311-319.
Table 2. Summary of Monoclonal Antibodies Used for Cancer Treatment