Development of Targeted Therapies

One of the characteristics of the malignant phenotype is the ability of cells to grow in an autonomous manner. Various components of the proliferative and/or survival signaling pathways can become constitutively activated or deregulated in human cancers.1 Many studies have attempted to show that a given molecular change is the key event involved in the pathogenesis of a specific cancer. Such information may not only provide a better understanding of cancer but may allow a novel target to be identified for therapeutic intervention.

With our ever-increasing understanding of the pathogenesis of cancer, there are now a plethora of potential molecular targets in human cancer cells that are being utilized for the development of novel anticancer therapies (Table 5.1). Perhaps the oldest and most established targeted therapy is endocrine treatment for breast and prostate cancer, taking advantage of the estrogen receptor (ER) and androgen receptor (AR) that can readily be detected in many breast and prostate carcinomas, respectively. More recently, peptide growth factor receptors (EGFR and HER2) have become viable targets in human solid epithelial tumors such as lung, head and neck, breast, and colon cancer. The unraveling of the signal transduction cascade within cells has resulted in various small molecule signal transduction inhibitors (STIs) entering clinical development, whereas the complex protein interactions that regulate the cell cycle may allow various modulators to be developed to restore cell-cycle control in aberrantly behaving malignant cells. Likewise the ability to effectively trigger programmed cell death (apoptosis) in cancer cells adapted to prolonged survival is a promising new approach for the future. Finally, the capacity for malignant cells to acquire a blood supply is a key event in the growth of human tumors, and drugs are being developed that target either the endothelial cell or the vascular growth factor pathways. The principles and current status of targeted therapies in each of these six areas are reviewed in this chapter. However, a common theme to all these approaches is the need to confirm that a given molecular target is specifically involved in the pathogenesis of that cancer, to develop an assay to reliably detect the target in tumors, and to show that interrupting its function gives the desired anticancer effect.

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