Targeted bio weapons in the war against gynecologic cancers

October 1, 2006
Angeles Alvarez Secord, MD
Angeles Alvarez Secord, MD

DR. ALVAREZ SECORD is an Assistant Professor, Dept. of OB/GYN, Duke University Medical Center, Durham, N.C.

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Andrew Berchuck, MD
Andrew Berchuck, MD

DR. BERCHUCK is F. Bayard Carter Distinguished Professor of Obstetrics and Gynecology in the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, N.C., and a member of the Contemporary OB/GYN E

Will biological warfare revolutionize the battle against gynecologic cancers? Two experts share the latest molecular tactics using "special" agents. Lethal weapons like Herceptin can throw up some roadblocks, even when they can't always destroy a tumor.

Revolutionary. Stunning. Remarkable. Excited cancer researchers are using adjectives like these to describe the impressive effectiveness of some targeted biological therapies like trastuzumab (better known as Herceptin, Genentech). Trastuzumab, for example, isn't just for fighting breast cancer recurrence in women who overexpress a certain protein anymore; given to this group of women with early breast cancer, it can cut the risk of cancer returning nearly in half.1 But the enthusiasm engendered by some clinical trials is tempered by other disappointing news. Trastuzumab can do little for women with ovarian cancer, since few of them overexpress that certain protein, ErbB-2 (better known as HER-2/neu).

It's one thing to selectively destroy a cancer cell when it can be clearly identified as such. But that's been nearly impossible to do. At least until now. [Advances in understanding the molecular changes that distinguish cancers from nearby normal host tissues have opened up unique opportunities for developing targeted biological therapies.] These novel "special" agents are designed to inhibit or interfere with the function of specific molecular pathways without which the tumor can't grow, invade, and metastasize. The further good news is that because targeted therapies focus on molecular changes that are fairly specific to cancers, they may also be likelier to have fewer side effects than standard chemotherapy.

Our goal here is to discuss several molecular targeted cancer treatments-like the monoclonal antibody Herceptin for breast cancer-that have already received FDA approval, and some of the many others-including small-molecule inhibitors-now being tested in clinical trials.

Monoclonal antibodies (MoAbs) have been developed that bind to the outer part of the growth factor receptors or to the growth factors, and thus prevent the growth factors from binding to their respective receptors. These include cetuximab (Erbitux, ImClone Systems, and Bristol-Myers Squibb), bevacizumab (Avastin, Genentech), and trastuzumab. Alternatively, researchers have also developed small-molecule inhibitors that can penetrate cells, binding to and inactivating the inner part of the growth factor receptors (known as the tyrosine kinase domain)-the part responsible for transmitting signals to stimulate growth. These receptors are also known as tyrosine kinase receptors (TKRs). Among several tyrosine kinase inhibitors (TKIs) previously or currently being evaluated in gynecologic malignancies are gefitinib (Iressa, AstraZenica), erlotinib (Tarceva, Genentech, OSI Oncology), and imatinib (Gleevec, Novartis).

Two types of TKRs that are often activated in cancers are the epidermal growth factor (Erb family) and vascular endothelial growth factor (VEGF) receptor families.

Epidermal growth factor receptor family

The epidermal growth factor receptor (EGFR) family is composed of four similar TKRs: EGFR, ErbB-2 (HER2/neu), ErbB-3, and ErbB-4.4 The binding of growth factors to the receptor spurs tyrosine kinase activity and enables the cell's surface to communicate with its nucleus.

Several MoAbs have been developed against members of the EGFR family. As mentioned earlier, ob/gyns are especially interested in trastuzumab, which targets cancer cells that overexpress the receptor protein. By binding to ErbB-2 receptors, trastuzumab can slow the growth and spread of tumors that overexpress this receptor. [In 1998, trastuzumab received FDA approval for patients with metastatic breast cancer whose tumors overexpress the ErbB-2 protein.] ErbB-2 overexpression (2+/3+), analyzed using immunohistochemistry (IHC), was seen in up to 30% of breast cancers.5,6 Trastuzumab was initially shown to be well tolerated and active in women with heavily pretreated breast cancer.7 It has now been linked to a higher incidence of cardiac dysfunction, however.8 A recent study has shown that cardiac toxicity is reversible in most patients (94%) and additional treatment with trastuzumab can be resumed after recovery of cardiac function.9