%u25BA Navigating Multiple Pathways: Evolving Strategies and Future Directions in Targeted Therapies
Manuel Hidalgo, MD, PhD, Associate Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD chaired an Amgen-sponsored, continuing medical education–certified, satellite symposium at ASCO. The symposium was designed to provide the clinical community with updated information on advances in targeted agents and the rapidly evolving understanding of molecular biology and cellular pathways in cancer.
The first presentation was a discussion of the clinical evidence for targeting epidermal growth factor receptor (EGFR), led by Louis M. Weiner, MD, Chairman, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
EGFR is a transmembrane glycoprotein that is constitutively expressed in normal epithelial tissues and a variety of solid tumors. It is a member of the ErbB receptor tyrosine kinase family, which consists of four family members, EGFR (ErbB1), ErbB2 (Her2), ErbB3, and ErbB4. Ligand binding to the EGFR induces a conformational change, causing the ErbB family receptors to homodimerize or heterodimerize with each other, resulting in transautophosphorylation, with subsequent initiation of intracellular proliferation and survival signaling pathways. In malignant cells that express EGFR, inappropriate activation of the receptor occurs, which leads to uncontrolled cellular growth. Constitutive signaling in these tumors may be the result of EGFR overexpression, increased production of ligands, heterodimerization with other ErbB receptors, transactivation of heterologous signaling networks, activating mutations, and/or loss of negative regulatory mechanisms for receptor signaling. EGFR activation mediates several tumor-promoting processes, including cell proliferation, inhibition of apoptosis, angiogenesis, enhanced survival, and metastatic tumor spread. In preclinical studies, inhibition of EGFR signaling results in antitumor activity in multiple xenograftmodels of human disease.
Lee S. Rosen, MD, President and Founder, Premier Oncology, California, Santa Monica, CA (affiliated with the John Wayne Cancer Institute and St. John’s Health Center, Santa Monica, CA) led a discussion about multi-targeted tyrosine kinase inhibitors. Dr. Rosen and colleagues are actively pursuing the next generation of targeted therapies that attack tumor cells and tumor stroma. They apply this approach in an extensive research and clinical development program. Current areas of focus are growth regulation, angiogenesis, apoptosis, bone metabolism and metastases, muscle metabolism and cachexia, tissue protection and repair, and hematopoiesis.
Three pathways involved in growth regulation were reviewed: 1) the epidermal growth factor (EGF) pathway, 2) the hepatocyte growth factor (HGF) pathway, and 3) the insulin-like growth factor–1/2 (IGF-1/2) pathway. HGF signaling, through its receptor, the tyrosine kinase c-Met, appears to play an important pathologic role in many types of human cancers. Signaling through the HGF pathway mediates a large number of normal activities in cells of epithelial origin—including proliferation, survival, migration, and invasion. Many of these cellular functions play important roles in cancer-cell dysregulation, tumorigenesis, and tumor metastasis. The ligands IGF-1 and IGF-2 exert pleiotropic effects on cellular behavior via signaling through cell surface receptors. IGF-1 signaling via the type-1 insulinlike growth factor receptor (IGF-1R) influences cellular proliferation, survival, and differentiation. Most human cancers express IGF-1R, and the inhibition of IGF-1R signaling may represent a promising anticancer strategy.
Two pathways relating to angiogenesis were discussed—the angiopoietin–1/2 pathway and the vascular endothelial growth factor (VEGF) pathway. The angiopoietin family— angiopoietin (Ang)-1, Ang-2, Ang-3, and Ang- 4—and their corresponding receptors (Tie-1 and Tie-2)—play an important role in angiogenic as well as lymphangiogenic processes. VEGF receptor–1 (VEGFR-1) and VEGFR-2 are major regulators of angiogenesis. VEGFR-3 is involved in lymphangiogenesis and cancer metastasis via the lymphatic system.
Apoptosis is an evolutionarily conserved process of programmed cell death. Dysregulation of this process contributes to many diseases, including cancer. Apo2L/TRAIL is a member of the tumor necrosis superfamily of cytokines that selectively induces apoptosis in cancer cells. Apo2L/TRAIL binds specifically to distinct cell-surface receptors which are expressed on a wide range of human tumors.
Receptor activator of nuclear factor B ligand— also called RANK ligand (RANKL)—is an essential mediator of osteoclast formation, function, and survival that is expressed by osteoblasts and stromal cells. RANKL is a member of the tumor necrosis factor (TNF) ligand family, which is essential for this process. RANKL binds to RANK, a receptor on the cell surface of osteoclasts and osteoclast precursors, to stimulate proliferation and differentiation of cells to form the osteoclast phenotype and inhibit apoptosis. In metastatic disease, RANKL is thought to contribute to a vicious cycle of bone destruction and tumor growth.