Novel Anti-cancer Compounds for Developing Combinatorial Therapies to Target Anoikis-Resistant Tumors

Abstract

Anoikis, a cell death pathway induced by loss of normal cell-matrix attachment or upon adhesion to a non-native matrix, ensures the balance between proliferative potential of normal cells and maintenance of tissue integrity. Thereby, anoikis serves as a potential molecular barrier against oncogenic transformation of normal cells. Cancer cells acquire anoikis resistance for survival and distant metastatic progression. During the acquisition of anoikis resistance, tumors modulate multiple cell signaling parameters through changes in the expression of up-stream receptors and by dynamically calibrating the dependency on down-stream signaling cascades. Many compounds that target the tumor-acquired switches in integrins, tumor antigens, growth factors, metabolic pathways, oxidative and osmotic-stress signaling are in various phases of pre-clinical and clinical development. Combinatorial approaches maximize the therapeutic efficacy and minimize the activation of alternate signaling pathways, which will otherwise contribute to drug resistance. In this regard, an integrated analysis of the mechanisms of action of potential drugs and lead compounds that can target significant nodes of anoikis signaling networks will provide a rational frame-work for further development and clinical use of respective agents, by formulating more effective combinatorial therapies, in patients with distinct drug-sensitivity profiles.