Emerging targeted therapies in cancer.

The development of target-based therapies has dramatically changed the outlook of cancer treatment and increased the expectations for patients with cancer. Cancers that contain multiple genetic and epigenetic abnormalities are addicted to genes that promote their malignant behavior and cell survival. Targeted cancer therapies with monoclonal antibodies or small-molecule inhibitors interfere with cell proliferation and tumor spread to distant organs. Many of these therapies target proteins that are involved in cell signaling pathways, which form an intricate communication system that controls basic cellular functions, such as cell division, motility, responses to specific extracellular signals, and cell death. Effective target-based drug design, therefore, is based on the concept of discovering genetic alterations and the signaling pathways altered in cancer and requires the identification of effective targets that are known to play key roles in cancer cell growth and survival. Although improvements seen in the trials are modest, the hope is that more biomarkers will be available in the near future to help clinicians predict which patients are most likely to benefit from such therapies. Since 1990, when tamoxifen was the first molecularly targeted drug approved by the US Food and Drug Administration, 38 agents have been introduced in the United States for treatment of various cancers, but the clinical benefit obtained from targeted therapies varies greatly. With the discovery of additional targeted agents, pathologists are required to identify the ‘‘target’’ population or the subset of patients who have cancers with druggable molecular abnormalities. The challenge relies on identifying the most appropriate molecular biomarker that will triage the patient to a ‘‘personalized’’ therapeutic regimen with the highest probability of eradicating the tumor. This task becomes increasingly complex because a higher number of markers are tested on smaller pathology specimens, and tissue availability and allocation for molecular testing becomes a crucial decision in managing patients with cancer. Furthermore, because many targets can be evaluated by multiple laboratory methods, like sequence analysis, fluorescence or chromogenic in situ hybridization, or immunohistochemistry, it is critical that pathology organizations develop standardizing methodologies for marker testing in the clinical laboratory. The special section in this issue of the ARCHIVES focuses on emerging targeted therapies in common cancers and the molecular biomarkers that help identify patients who will benefit from those therapies. First, Olga Pozdnyakova, Jeffery Kutok, and Scott Rodig review the development of select, novel therapies for lymphoid malignancies and examine 4 major regulatory pathways: tyrosine kinase activation, transcription factor activity, apoptotic signaling, and histone acetylation in both preclinical models and early phase clinical trials. Andrea Marrari, Andrew Wagner, and Jason Hornick provide a summary of the biologic predictors of gastrointestinal stromal tumor behavior and response to targeted therapies that currently help guide clinical decision making. Laurie Eisengart, Gary MacVicar, and Ximing Yang explain the molecular basis for targeted therapy against vascular endothelial growth factor and mTOR pathways in renal cell carcinoma, summarize the clinical trials demonstrating the effectiveness of these drugs, and describe the biomarkers clinically significant in patients treated with targeted therapy. The current targeted therapies for colorectal and gastric cancers and their applicability and efficacy in clinical practice are reviewed by Maria McIntire and Mark Redston. In the last article of the series, Philip Cagle and I address the current knowledge about molecular biomarkers that identify patients who will benefit from US Food and Drug Administration–approved and novel promising targeted agents in lung cancer and describe the diagnostic techniques and the pathologic features correlated with tumor response. Molecular testing of cancers expands the expertise of the pathologists, who, in addition to conventional analysis of surgical specimens, will determine the tumor markers that are predictive of sensitivity or resistance to various targeted therapies and that allow patients with cancer to be selected for unique, less-toxic, and highly effective therapies. Accepted for publication January 17, 2012. From the Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, and Harvard Medical School, Boston. The author has no relevant financial interest in the products or companies described in this article. doi: 10.5858/arpa.2012-0684-ED Reprints: Lucian R. Chirieac, MD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (e-mail: lchirieac@partners.org). Special Section—Perspectives on Targeted Therapies for Treatment of Human Cancers