Human cancer results from genetic and epigenetic changes that affect key cellular processes. Most of these processes, including excessive cell division and attraction of blood vessels to growing tumors, are normally regulated by binding of hormones called growth factors and angiogenic factors to receptors at the cell surface. Activation of the receptors by the hormones, and the resulting cascade of changes inside the cells that determine whether the cells will divide or commit suicide, and also whether growing tumors are likely to invade other tissues and disseminate to form metastases, is called signal transduction. Not surprisingly, the majority of mutations and chromosomal changes that contribute to cancer development affect these same pathways and processes. Thus, elucidation of signal transduction is vital for understanding how cancer arises in each individual, and the features that distinguish benign from aggressive cancers. Most importantly, components of the cellular machinery that mediates receptor-regulated growth processes are among the best rational cancer therapeutic targets in cancer.
The first drug targeting a cancer gene, Herceptin, is helpful for many breast cancer patients with tumors driven by the target hormone receptor, HER2. Chronic myelogenous leukemia (CML) is caused by activation of the signaling protein Abl, and is treated successfully with the drug Gleevec. Gleevec is also effective for the treatment of gastrointestinal stromal tumors (GIST) because it blocks the hormone receptor Kit that often causes this disease. Other drugs in clinical use include Tarceva, Erbitux, and Sutent (SU11248), which block hormone receptors, and a growing number of drugs including Velcade and Sorafenib that target the molecular machinery that responds to these hormones.
Despite continuing success in this area, much remains to be learned. Laboratories in the Signal Transduction Program are investigating how these signaling systems regulate cancer stem cells, communication of cancer cells with their tissue environment, and how they affect cancer invasion and survival of metastatic cells in foreign tissues. An important practical goal is the development of the best methods for matching patients with the appropriate cancer drugs for “personalized medicine.” Each cancer develops in its own idiosyncratic manner, so that different signaling pathways are dysregulated in each cancer. The challenge is to match patients to the drugs that will have the greatest impact on the pathways affected in their own disease.