Emerging molecular therapies in breast cancer.
Authors: Baselga J , Di Cosimo S , Cortes J 
Published: December 2010

Abstract #ES-6

The cellular and molecular processes that lead to cancer, include self-sufficiency in growth signals, insensivity to anti-growth factor signals, evasion of apoptosis, lack of senescence, invasion and metastasis, and sustained angiogenesis. All these processes can be potentially targeted with a variety of therapeutic strategies that include, in addition to anti-HER2 therapies, the following classes of agents:&#x2028; 1. Growth factor receptor signaling pathways&#x2028; 1.1. Inhibitors of PI3K/Akt pathway&#x2028; The frequent dysregulation of the PI3K/Akt/mTOR pathway in human breast cancer has made components of this pathway attractive for therapeutic targeting. Clinical trials are currently underway with mTOR, PI3K, and Akt inhibitors.&#x2028; 1.2. Src-family Tyrosine Kinases Inhibitors&#x2028; Src is a non-receptor signaling kinase that functions at the hub of a vast array of signal transduction pathways that influence cellular proliferation, differentiation, motility, and survival. In addition, Src activity also mediates epithelial-to-mesenchymal transition. Src inhibitors are in clinical development either given alone or in combination with other therapies. As with other kinase inhibitors, src inhibitors differ among themselves by their specificity.&#x2028; 1.3. RAF/MEK/MAPK(ERK) Pathway Inhibitors&#x2028; The RAS proteins are members of a large superfamily of GTP-binding proteins that play a complex role in the normal transduction of growth factor receptor-induced signals. Different agents have been developed to target the Ras/Raf/MAPK(ERK) pathway due to the aberrant activation of this pathway in a large number of human tumors. These agents include farnesyltransferase inhibitors, Raf inhibitors, and MEK/MAPK inhibitors.&#x2028; 1.4. Heat Shock Protein (Hsp) 90 Inhibitors&#x2028; Hsp90 is a molecular chaperone that is required for the refolding of proteins under conditions of environmental stress and for the conformational maturation of a subset of key signaling proteins. Many of these client proteins such as AKT, HER2, c-KIT, EGFR and PDGFR-α are oncoproteins and important cell-signaling proteins deregulated in cancer. In the clinic, initial studies with HSP90 inhibitors have demonstrated anti-tumor activity and tolerability in patients with trastuzumab-refractory HER2-positive metastatic breast cancer patients.&#x2028; 2. DNA-repair interfering agents. PARP-1 Inhibitors&#x2028; PARP inhibitors have been shown to enhance, in human cancer cell models, the antitumor activity of DNA-methylating agents and to restore sensitivity of tumors resistant to methylating agents or topoisomerase I inhibitors, two classes of agents being used for the treatment of breast cancer. Initial phase I studies with the PARP inhibitors have shown to be safety and clinical activity in patients with an inherited mutation in one of the cancer genes, BRCA1 or BRCA2.&#x2028; 3. Targeting Programmed Cell Death (Apoptosis)&#x2028; Evasion of apoptosis is associated with many human cancers and is one of the hallmarks of the malignant phenotype and may play a role in the observed chemoradioresistance that occurs in many tumors. TRAIL receptor agonists are currently entering clinical trials in patients with breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr ES-6.