Solid Tumor Differentiation Therapy - Is It Possible?

Filemon Dela Cruz 1 and Igor Matushansky 2 1 Division of Pediatric Oncology, Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY 2 Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY Received : May 19, 2012, Accepted: May 23, 2012, Published: May 24, 2012 Keywords: Differentiation therapy, soft tissue sarcoma, retinoids, histone deacetylase inhibitor, PPAR-gamma agonist, trabectedin. Correspondence: Igor Matushansky , email: // // Abstract Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells. The promise of differentiation-based therapy as a viable treatment modality is perhaps best characterized by the addition of retinoids in the treatment of acute promyelocytic leukemia (APML) revolutionizing the management of APML and dramatically improving survival. However, interest and application of differentiation-based therapy for the treatment of solid malignancies have lagged due to deficiencies in our understanding of differentiation pathways in solid malignancies. Over the past decade, a differentiation-based developmental model for solid tumors has emerged providing insights into the biology of various solid tumors as well as identification of targetable pathways capable of re-activating blocked terminal differentiation programs. Furthermore, a variety of agents including retinoids, histone deacetylase inhibitors (HDACI), PPARγ agonists, and others, currently in use for a variety of malignancies, have been shown to induce differentiation in solid tumors. Herein we discuss the relevancy of differentiation-based therapies in solid tumors, using soft tissue sarcomas (STS) as a biologic and clinical model, and review the preclinical data to support its role as a promising modality of therapy for the treatment of solid tumors.