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Treatment Options > Targeted Therapies > Targeted Therapy Basics

Introduction to Targeted Therapy

Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: August 24, 2005

Cancer remains the second leading cause of death in the United States, even 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 (eg: see IMRT), 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.

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. 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 several major classes of targeted therapies:

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 all over 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. Here,

we will focus on just one family of tyrosine kinase receptors 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)

We will now focus only on the first 2 family members: EGFR and HER2/neu, because these 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.

B) HER2/neu inhibitors

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 proangiogenic factors. The main proangiogenic 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, allowing them to grow. The concept behind angiogenesis inhibition, then, is to thwart this process and thereby fight tumor progression.