Molecular-Targeted Therapy

Molecular Targeted Therapy


The treatment of cancer is currently undergoing a dramatic shift not seen since the advent of chemotherapy around 60 years ago. Spurred by advances in the study of genetics and molecular biology, this new approach—called molecular targeted therapy—is changing not only the way cancer is diagnosed and treated but also our entire perspective on the nature of cancer and its relationship to health and the human body.


For decades the standard treatment for most advanced cancers—that is, cancers that have invaded surrounding tissues and/or spread to other parts of the body (metastasized)—has been chemotherapy. Although chemotherapy may be effective in some patients, its efficacy varies dramatically from individual to individual—some are cured, others experience no significant improvement whatsoever, and others go into remission for variable lengths of time before the cancer returns. In addition, along with a highly unpredictable and variable success rate, many chemotherapeutic agents are associated with severe, sometimes life-threatening, side effects. To learn more, see Why is chemotherapy so toxic?

The unpredictable efficacy and potentially severe side effects of chemotherapy have challenged oncologists and researchers to seek the answers to two key questions that could possibly resolve these limitations:

  1. Why does chemotherapy work for some patients and not for others with the same type of cancer?
  2. Is there a therapeutic alternative to chemotherapy for advanced cancers that causes less severe and debilitating side effects?

With the advent of several remarkable discoveries over the past decade, these challenges are being addressed, and the answers are profoundly altering the way we look at and treat cancer.


Chemotherapy damages or kills cancer cells by disrupting the mechanisms responsible for cell division—cancer cells are particularly vulnerable to chemotherapy because, unlike most normal cells, they tend to be in a constant state of rapid and uncontrolled division.

However, several types of normal cells also divide rapidly, most notably the cells of the bone marrow, the linings of the mouth and intestines, and hair follicles.

Therefore, chemotherapy characteristically damages these cells along with cancer cells, causing the classic chemotherapy-associated side effects of myelosuppression (reduced levels of red blood cells, white blood cells, and/or platelets produced by the bone marrow), mucositis (inflammation of the mucosal cells that line the mouth and intestines), and alopecia (hair loss).

Depending on the specific agent, chemotherapy may also cause a wide range of other debilitating side effects, including severe nausea and vomiting, neuropathy (nerve damage), nephropathy (kidney damage), and cardiotoxicity (heart damage).


Carcinogenesis can be defined simply as the transformation of a normal cell into a cancer cell. For some time, researchers have known that this transformation was initiated by genetic mutations (alterations to a cell's DNA). Once a sufficient number of mutations has occurred, a cell that once functioned normally transforms into a cell that functions abnormally, no longer following the biological rules that govern cell division, growth, and death. But only recently, with the aid of new discoveries and techniques in molecular biology, have researchers actually begun to understand the specific molecular mechanisms behind this carcinogenic transformation.

What they've discovered is that most cancers are associated with mistakes in the genetic code. Such mutations have been found in more than 120 genes¹. These genes control the synthesis of proteins that carry out the biochemical reactions (referred to as molecular signaling pathways) that regulate cell division, growth, and death. Mutations to one or more of these genes may cause a cell to produce too much or too little of a key protein or produce a defective protein that does not respond appropriately to the molecular signals. Carcinogenesis is initiated when these mutations are sufficiently severe to disrupt the molecular pathways that control cell division and other related cellular properties, resulting in the formation of a tumor, invasion of surrounding tissues, and metastasis. Learn more about oncogenes and tumor suppressor genes.

Each cancer has its own unique genetic and molecular signature. This explains why individuals with the same type and stage of cancer may experience dramatic differences in their responses to chemotherapy. Researchers now have the means to rapidly analyze the unique signature of a patient's tumor based on the expression of the genes involved in its carcinogenesis. This capability has opened the door to more accurately predicting the outcome of a patient's cancer and individualizing his or her treatment to match the molecular characteristics of the tumor.

Today, researchers are discovering other facets of cancer biology involving cancer stem cells, epigenetics, microRNA, metabolism and inflammation, which they hope will yield more avenues to attack the disease. Keeping up with these discoveries, and what they mean for patients, will create ever-greater challenges for physicians in the era of personalized medicine.

¹Welsh SJ and Powis G. Toward Personalized Therapy for Cancer. From Current Clinical Oncology: Targeted Cancer Therapy. Edited by R Kurzrock and M. Markman. Humana Press, Totowa, NJ, 2008.


Normal cell division is regulated by both positive and negative forces. The positive forces are controlled by oncogenes, which produce proteins that stimulate cell division. In a normal cell, oncogenes are biochemically "switched on" at the appropriate times to stimulate cell division when it is required. Mutations to oncogenes may cause them to get "stuck" in the on position, resulting in continuous and uncontrolled cell division (a hallmark of cancer). The negative factors governing cell division are controlled by tumor suppressor genes, which produce proteins that inhibit the cell's ability to divide. In a normal cell, tumor suppressor genes are biochemically switched on at the appropriate times to stop cell division when it is no longer required. Mutations to tumor suppressor genes may prevent them from switching on, resulting once again in continuous and uncontrolled cell division.


Once researchers have the knowledge and technology to identify the genetic and molecular signature of tumor cells, they can begin to design drugs that specifically target the defective molecular pathways responsible for the cancer cell's abnormal properties. This revolutionary treatment approach is referred to as molecular targeted therapy (MTT), or targeted therapy, because it targets only the specific molecular defects responsible for a cancer cell's uncontrolled division, invasion into surrounding tissues, and metastasis. (Contrast this approach with the nonspecific broad brushstroke of conventional chemotherapy, which attacks the general mechanisms of cell division in all cells whether they are normal or cancerous.) This new treatment approach is also referred to as individualized, or personalized, cancer therapy because it is based on the genetic and molecular signature of an individual patient's tumor cells rather than on general categorizations of the cancer based solely on its organ of origin (e.g., the lungs or colon).

The molecules and pathways currently targeted by molecular targeted therapy are those that provide the cancer cell with the ability to divide continuously, resist cell death (apoptosis), invade surrounding tissues, and metastasize to distant sites. Although there are hundreds of potential target molecules, the following three examples have been the focus of several recently approved molecular targeted therapies:

  • EGFR (Epidermal Growth Factor Receptor): EGFR is a type of protein, called a receptor, that is overexpressed (produced in excessive quantities) in many types of cancer cells. When a signal molecule (growth factor) binds to EGFR, it activates a biochemical pathway that stimulates the cell to divide.
  • VEGF (Vascular Endothelial Growth Factor): VEGF is a type of protein, called a growth factor, that is secreted in large quantities by tumor cells. When VEGF binds to a receptor on blood vessels, it initiates and promotes angiogenesis (the formation of new blood vessels), which is required to supply nutrients and oxygen to growing tumors.
  • HER2/neu: HER2/neu is a type of protein, called a receptor, that is overexpressed in some types of breast cancer cells. When a signal molecule (growth factor) binds to HER2/neu, it activates a biochemical pathway involved in the pathogenesis of breast cancer.

Drugs targeting these molecules are now an important component of therapy for several different types of solid tumors, including breast cancer, lung cancer, colorectal cancer, and pancreatic cancer.

Learn more about examples of currently approved molecular targeted therapies for solid tumors.


Drug Molecular Target Approved Indications
Avastin (bevacizumab)
Tykerb (lapatinib)
Company: Genentech
colorectal cancer, non-small-cell lung cancer (nonsquamous), breast cancer
Erbitux (cetuximab)
Company: Imclone
EGFR colorectal cancer, head and neck cancers
Iressa (gefitinib)
Company: AstraZeneca
EGFR non-small-cell lung cancer
Tarceva (erlotinib)
Company: Genentech
EGFR non-small cell lung cancer, pancreatic cancer
Herceptin (trastuzumab)
Company: Genentech
HER2/neu breast cancer
Gleevec (imatinib)
Company: Gleevec (imatinib)
c-kit, abl, PDGF-R chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST)


Although not yet fully integrated into the mainstream standard of care for most types of cancer, molecular targeted therapy is slowly shifting the treatment paradigm for cancer in several profound ways. One key shift is from a focus on clinical results obtained from the study of large populations of patients (an "n" of many), to clinical results based on diagnosis, treatment and observation tailored to each individual (an "n" of one). This involves the molecular analysis of a patient's tumor early in the diagnostic process to determine what molecular defect is fueling the cancer. (Drugs that exert their effects by aiming at a particular molecular target will only be effective in patients whose cancer cells rely on that target or its associated pathway for their survival, growth, or metastasis.) Therefore, a key component of molecular targeted therapy is the identification of molecular biomarkers that predict which patients are most likely to benefit from a particular targeted therapy. Because of the speed with which advanced cancer can progress, it's critical to initiate the most effective and least toxic molecular targeted therapy and/or chemotherapy as quickly as possible based on the molecular signature of the tumor.

Another important paradigm shift relates to viewing advanced cancer as a chronic disease to be managed over the long term rather than as a terminal disease that must be completely eradicated by any means necessary to prevent the death of the patient. The goal of conventional chemotherapy is to either destroy the cancer entirely (cure the patient) or disrupt the carcinogenic process sufficiently to induce a pause (remission) in the cancer's growth and metastasis. However, in the treatment of most advanced cancers with chemotherapy, cures are rare, remission periods short, and side effects extremely harsh. In contrast, molecular targeted therapy controls cancer by blocking its ability to wreak havoc on the body through uncontrolled growth, invasion of surrounding tissues, and metastasis to vital organs. Because molecular targeted therapy typically causes fewer side effects than conventional chemotherapy, it has the potential to be administered continually over a long period of time without significantly diminishing a patient's quality of life. The drug Gleevec has led this transformation. Used to treat chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST),Gleevec became the first approved drug to target the underlying cause of cancer. Many patients now take Gleevec for long-term maintenance of their health.

Learn more about the long-term management of once-terminal diseases.


Many diseases that are now managed long-term as chronic conditions were once considered untreatable and terminal. For example, before the availability of synthetically derived insulin, Type 1 diabetes was rapidly fatal. Before the advent of cholesterol-lowering drugs, anti-hypertensive medications, and angioplasties, many currently manageable chronic heart disorders were fatal or severely debilitating. Before the discovery of antiretroviral drugs, HIV infection almost always progressed to AIDS and the patient invariably died shortly thereafter from its myriad of complications. Today, millions of patients with these conditions, and many others, are now able to manage their disease and live full lives thanks to new discoveries and developments in medicine. It is the hope of patients, oncologists, and researchers worldwide that this type of paradigm shift—from a terminal disease to a manageable chronic disease—can be provided by molecular targeted therapy in the treatment of cancer.