Differentiation Therapy of Cancer: Journey from the Laboratory into the Clinic

Cancer is a progressive process characterized by uncontrolled cell proliferation and de-differentiation and clinical protocols involving cytotoxic agents remain a mainstay of conventional cancer therapies despite many non-specific adverse side effects. An alternative approach to potentially reduce the toxicity of anti-cancer therapy employs the induction of cancer cells to undergo terminal differentiation leading to irreversible inhibition of growth and induction of programmed cell death (apoptosis). The concept of ‘differentiation therapy of cancer’ has been validated using cell culture and animal models including leukemia, neuroblastoma and melanoma supporting its potential for translation into the clinic. By inducing terminal differentiation of metastatic human melanoma cells in combination with subtraction hybridization, we have identified and cloned novel genes that participate in critical cellular processes including genes involved in cell cycle and growth control, differentiation, metastasis, innate immune response, apoptosis, inflammation and senescence. One originally novel gene, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a member of the IL-10 gene family of cytokines and is a cancer cell-specific inducer of apoptosis. This review discusses the concept of ‘differentiation therapy of cancer’ in a historical context and highlights important findings from the melanoma model system with an emphasis on the translation of basic research findings to the clinical treatment of cancer patients. _____________________________________________________________________________________________________________