Mammalian target of rapamycin

Targeted molecular therapeutics are tailored toward the genetic abnormalities that cause tumor progression. Modulation of certain signaling pathways that are aberrant in cancer cells has the potential to provide an effective, nontoxic approach to therapy in a broad range of cancers. Agents targeting BCR-ABL (imatinib mesylate [formerly known as STI-571], Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ), retinoid receptor fusion proteins (all-trans retinoic acid), ErbB-2 or HER2/neu (trastuzumab, Herceptin; Genentech, Inc, South San Francisco, CA), epidermal growth factor receptor (IMC-C225 and ZD1839), and the phosphatidylinositol 3-kinase pathway (CCI-779) have all induced remarkable, nontoxic responses in a subset of patients with cancer and abnormalities in the corresponding signal transduction cascades. To achieve successful individualized therapy, the specific components within the aberrant signaling pathways that are driving the pathophysiology of the tumors must be identified in each patient. Molecular diagnostics can identify patients in whom the target is aberrant; linking molecular diagnostics with effective molecular therapeutics will be necessary to translate these concepts into approaches that will alter the outcome for patients with cancer. In addition, intermediary markers and/or molecular imaging techniques must be used to identify the biologically relevant dose that is sufficient to inhibit the target of interest. This review focuses on the PI3K pathway, and novel molecules targeting this pathway, to illustrate the questions and challenges underlying the implementation of molecular therapeutics in breast and ovarian cancer. © 2004 Elsevier Inc. All rights reserved.