Attacking Cancer Where It Counts

Targeted therapies make important inroads against several types of cancer.

By Kari Bohlke, ScD

Targeted cancer therapies have been in the news a great deal recently, but you may not be exactly sure what they are. In short, targeted therapies are drugs that interfere with specific pathways involved in cancer cell growth or survival. Some targeted therapies block growth signals from reaching cancer cells; others reduce the blood supply to cancer cells; and still others stimulate the immune system to recognize and attack the cancer cell. Depending on the specific “target,” targeted therapies may slow cancer cell growth or increase cancer cell death, often with fewer side effects than traditional chemotherapy.

These therapies are often (though not always) used in combination with conventional cancer treatments such as surgery, chemotherapy, and/or radiation therapy. And although targeted therapies have been shown to improve outcomes in several types of cancer, the extent of the benefit varies by drug, by cancer type, and often by the specific characteristics of the cancer cells. To determine whether your cancer is likely to respond to a particular targeted therapy, it may be necessary to test a sample of the cancer before treatment begins. The goal? More-personalized and more-effective cancer therapy.

The following are several ways in which targeted cancer therapies are making a difference for cancer patients.

Chronic Myeloid Leukemia

One of the most successful examples of a targeted therapy is Gleevec® (imatinib) in the treatment of chronic myeloid leukemia (CML). Most cases of CML are characterized by a chromosomal abnormality—the Philadelphia chromosome—in which genetic material is exchanged between chromosome 9 and chromosome 22. This exchange brings together two genes: BCR and ABL. The combination of these two genes into the single BCR-ABL gene results in the production of a protein (Bcr-Abl) that contributes to uncontrolled cell growth.

Recognition of the pivotal role of the Bcr-Abl protein in CML led to the development of Gleevec, which blocks the activity of this protein. Gleevec produces high rates of remission among patients with chronic-phase CML, often with few side effects, and has dramatically changed the treatment of this disease.[1] Newer drugs that target the Bcr-Abl protein include Tasigna® (nilotinib) and Sprycel® (dasatinib).

Non-Hodgkin’s Lymphoma

A majority of non-Hodgkin’s lymphomas (NHLs) involve abnormal B cells. B cells often express a molecule known as the CD20 antigen, and drugs that target CD20—such as Rituxan® (rituximab)—have improved outcomes for many patients with B-cell NHL. When Rituxan binds to CD20, it prompts the body’s immune system to recognize and destroy the B cell. It may also have direct cell-killing effects. Often used in combination with chemotherapy, Rituxan has improved NHL treatment response rates and survival.[2]

Two other targeted therapies are Bexxar® (tositumomab and iodine I 131 tositumomab) and Zevalin® (ibritumomab tiuxetan). These drugs, which provide a type of treatment known as radioimmunotherapy (RIT), kill B cells by delivering radiation directly to CD20-positive cells.

Colorectal Cancer

Targeted therapies that may be used in the treatment of metastatic colorectal cancer include Avastin® (bevacizumab), Erbitux® (cetuximab), and Vectibix® (panitumumab). Avastin reduces the blood supply to tumors by targeting a protein known as the vascular endothelial growth factor (VEGF). In combination with chemotherapy, Avastin can delay cancer progression of metastatic colorectal cancer.[3]

Erbitux and Vectibix reduce cancer cell growth and increase cancer cell death by targeting the epidermal growth factor receptor (EGFR), a protein that is overexpressed in several types of cancer. These drugs illustrate how information about specific tumor characteristics can help individualize cancer treatment. An estimated 40 to 50 percent of metastatic colorectal cancers contain a mutation in a gene known as KRAS. Colorectal cancers with this mutation do not appear to respond to drugs such as Erbitux and Vectibix.[4],[5] It’s therefore important to test a sample of the tumor for KRAS status before deciding whether to use these drugs.

Breast Cancer

Approximately 20 to 25 percent of breast cancers overexpress (make too much of) a protein known as HER2. Overexpression of this protein leads to increased growth of cancer cells. Fortunately, the development of drugs that specifically target HER2-positive cells has improved outcomes among women with HER2-positive breast cancer. These drugs include Herceptin® (trastuzumab) and Tykerb® (lapatinib). These two drugs target HER2 in different ways, and ongoing research is assessing whether they can or should be used together.[6]

Avastin, mentioned previously for the treatment of colorectal cancer, may also be used in selected patients to delay the progression of metastatic breast cancer. Thus far studies have not found that Avastin improves overall survival among women with breast cancer.[7]

Finally, hormonal therapies such as tamoxifen (Nolvadex®), Femara® (letrozole), Arimidex® (anastrozole), and Aromasin® (exemestane) are also examples of targeted therapies and are commonly used in the treatment of hormone receptor–positive breast cancer. These drugs block the activity or production of estrogen.

Kidney Cancer

Prior to the recent introduction of several targeted therapies for the treatment of advanced kidney cancer, treatment options were few.[8] The most common type of kidney cancer—renal cell carcinoma (RCC)—does not respond well to traditional chemotherapy and instead was often treated with immunotherapy drugs such as interferon or interleukin. These drugs are only modestly effective and can produce severe side effects. When studies demonstrated that targeted therapies could delay cancer progression, it dramatically changed the treatment of this disease. Targeted drugs that may be used in the treatment of advanced RCC include Avastin, Sutent® (sunitinib), Nexavar® (sorafenib), Votrient® (pazopanib), Torisel® (temsirolimus), and Afinitor® (everolimus). Among other anticancer effects, several of these drugs deprive the cancer of the blood supply that it needs to grow. Two of the drugs (Torisel and Afinitor) inhibit cancer cell growth by targeting a protein known as mTOR.

Research Is Ongoing

Although these and other targeted therapies have provided important benefits to many patients, research in this field continues. Questions remain, for example, about how best to use these drugs in combination with one another and with conventional cancer treatments such as chemotherapy. Researchers also continue to search for additional cancer characteristics that predict response to treatment and that can be used to further individualize treatment decisions. As new targets are identified and new drugs are developed, there is also hope that outcomes can be further improved, for both patients with early-stage cancer and those with advanced disease. The need for continued progress, however, should not detract from the progress that has already been made. Every step counts.

Additional Progress Will Come from Clinical Trials

A clinical trial is a research study designed to evaluate potential new treatment options. Clinical trials test the safety and the effectiveness of new or modified cancer drugs, new drug doses, unique approaches to surgery or radiation therapy, and varied combinations of treatments. In the United States, all new cancer treatment products must proceed through an orderly clinical trials evaluation process to ensure that they have an acceptable level of safety and that they demonstrate benefit to helping patients with a specific cancer before they become commercially available to other patients.

Several ongoing clinical trials are investigating targeted cancer therapies and other promising new approaches to cancer treatment. If you think you may be interested in participating in a clinical trial, talk with your doctor about the potential risks and benefits. You can learn more about ongoing clinical trials through the National Cancer Institute (www.cancer.gov/clinicaltrials) and eCancerTrials.com.

References

[1]. Pinilla-Ibarz J, Quintas-Cardama A. New agents in the treatment of chronic myelogenous leukemia. Journal of the National Comprehensive Cancer Network. 2009;7(9):1028-37.

[2]. Winter MC, Hancock BW. Ten years of rituximab in NHL. Expert Opinion on Drug Safety. 2009;8(2):223-35.

[3]. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized Phase III study. Journal of Clinical Oncology. 2008;26(12):2013-19.

[4]. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. KRAS mutations and benefit from cetuximab in advanced colorectal cancer. New England Journal of Medicine. 2008;359(17):1757-65.

[5]. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008;26(10):1626-34.

[6]. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. The Oncologist. 2009;14(4):320-68.

[7]. Miles DW. Final overall survival (OS) results from the randomised, double-blind, placebo-controlled, Phase III AVADO study of bevacizumab (BV) plus docetaxel (D) compared with placebo (PL) plus D for the first-line treatment of locally recurrent (LR) or metastatic breast cancer (mBC). Paper presented at: 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas. Abstract 41.

[7]. Saylor PJ, Michaelson MD. New treatments for renal cell carcinoma: targeted therapies. Journal of the National Comprehensive Cancer Network. 2009;7(6):645-56.