Linking molecular diagnostics to molecular therapeutics: targeting the PI3K pathway in breast cancer

Modulation of the signaling pathways that are aberrant in cancer cells has the potential to provide an effective nontoxic approach to patient management in a broad range of cancers. This quest has taken a major leap forward with the demonstration that STI-571 (imatinib mesylate) induces clinical and molecular remissions in the majority of patients with interferon-refractory chronic myelogenous leukemia and gastrointestinal stromal tumors through inhibition of the Bcr/Abl fusion protein required for the initiation and progression of chronic myelogenous leukemia and inhibition of a mutant, activated c-kit present in gastrointestinal stromal tumors. Support for the concept of targeting products of fusion genes found in specific cancers was first provided by the efficacy of all-trans retinoic acid in acute promyelocytic leukemia where the RARalpha all-trans retinoic acid target is the target of multiple different chromosomal rearrangements. In breast cancer, trastuzumab, which alters the function of the HER2 proto-oncogene overexpressed in a portion of breast cancers, provides an additional example of targeting specific molecular aberrations present in cancer cells. Although the target for these signal transduction modulators is functional in normal cells, acceptable therapeutic indices sufficient to prevent tumor growth without unacceptable toxicities have been observed. Whether STI-571 and other signal transduction modulators also target the stroma, and specifically the neovasculature, in addition to the tumor remains an open question. The presence of the target in the cancer cells or in the surrounding stroma appears to be required but not sufficient for the action of molecular therapeutics. Thus, linking molecular diagnostics to identify patients where the target is amplified or activated and driving the pathophysiology of the patients' tumor to effective molecular therapeutics will be necessary to translate these concepts into approaches that will alter the outcome for breast cancer patients. This review will focus on the phosphatidylinositol 3-kinase pathway and novel molecules targeting this pathway to illustrate the questions and challenges underlying the implementation of molecular therapeutics in breast cancer.