The future of cytotoxic therapy: selective cytotoxicity based on biology is the key

Abstract

Although mortality from breast cancer is decreasing, 15% or more of all patients ultimately develop incurable metastatic disease. It is hoped that new classes of target-based cytotoxic therapeutics will significantly improve the outcome for these patients. Many of these novel agents have displayed cytotoxic activity in preclinical and clinical evaluations, with little toxicity. Such preferential cytotoxicity against malignant tissues will remain tantamount to the Holy Grail in oncologic therapeutics because this portends improved patient tolerance and overall quality of life, and the capacity to deliver combination therapy. Combinations of such rationally designed target-based therapies are likely to be increasingly important in treating patients with breast carcinoma. The anticancer efficacy of these agents will, however, remain dependent on the involvement of the targets of these agents in the biology of the individual patient's disease. Results of DNA microarray analyses have raised high hopes that the analyses of RNA expression levels can successfully predict patient prognosis, and indicate that the ability to rapidly 'fingerprint' the oncogenic profile of a patient's tumor is now possible. It is hoped that these studies will support the identification of the molecules driving a tumor's growth, and the selection of the appropriate combination of targeted agents in the near future.

Figure 1

Clinical trials evaluating combinations of trastuzumab and other signal transduction inhibitors targeting erbB growth factor receptor tyrosine kinases (for example OSI-774, ZD-1839, GW572016, CI-1033) or downstream kinases (R115,777, BAY 43-9006, CI-1040) are needed to enhance the anticancer activity of trastuzumab and reverse trastuzumab resistance in HER2-positive disease. Erk, extracellular signal-regulated protein kinase; MEKK, MAP kinase/Erk kinase kinase; PI3-kinase, phosphoinositide 3-kinase.

Figure 2

Estrogen receptor-α (ERα) can be directly activated, by serine phosphorylation at Ser-118 and Ser-167, by mitogen-activated protein kinase (MAPK) and Akt respectively, through growth factor signaling. This can result in the ligandless activation of ERα and hormone resistance. Clinical trials of combinations of signaling inhibitors and hormonal agents are needed to investigate whether signaling blockade can enhance hormone resistance.