M J Morris1, H I Scher. 1. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. MorrisM@MSKCC.org
Abstract
BACKGROUND: An increased understanding of the biology of prostate carcinoma has led to the clinical evaluation of mechanism-based and targeted therapies. Modulating the immune system has been pursued through the use of both active and passive immunity as well as the ex vivo genetic manipulation of effector cells. A variety of gene therapies has been proposed not only to replace defective genes but to localize activation of prodrugs. Angiogenesis and tumor invasion also have been targeted, as have cell cycling and signal transduction. Strategies promoting apoptosis and augmenting differentiation are also under study. METHODS: This study is a review of current clinical strategies using biologic, immunologic, and genetic approaches for the treatment of prostate carcinoma. RESULTS: The clinical development of therapy targeting differentiation, apoptosis, cell signaling, angiogenesis, metastasis, immune surveillance, and others are in various stages of clinical development. A disease states model is used to discuss treatment groups, outcome measures, and other trial design elements in relation to specific therapeutic strategies. CONCLUSIONS: Development of novel agents requires consideration of where in the natural history of the disease they should be applied. In addition, understanding the genetic and molecular alterations that occur as the disease progresses from a localized to a metastatic state, and from androgen dependence to independence, is necessary. Clinical trial design will require consideration of cytostatic and cytotoxic effects, the status of pathways not directly targeted, and potentially unexpected influences on prostate specific antigen expression by these agents. Copyright 2000 American Cancer Society.
BACKGROUND: An increased understanding of the biology of prostate carcinoma has led to the clinical evaluation of mechanism-based and targeted therapies. Modulating the immune system has been pursued through the use of both active and passive immunity as well as the ex vivo genetic manipulation of effector cells. A variety of gene therapies has been proposed not only to replace defective genes but to localize activation of prodrugs. Angiogenesis and tumor invasion also have been targeted, as have cell cycling and signal transduction. Strategies promoting apoptosis and augmenting differentiation are also under study. METHODS: This study is a review of current clinical strategies using biologic, immunologic, and genetic approaches for the treatment of prostate carcinoma. RESULTS: The clinical development of therapy targeting differentiation, apoptosis, cell signaling, angiogenesis, metastasis, immune surveillance, and others are in various stages of clinical development. A disease states model is used to discuss treatment groups, outcome measures, and other trial design elements in relation to specific therapeutic strategies. CONCLUSIONS: Development of novel agents requires consideration of where in the natural history of the disease they should be applied. In addition, understanding the genetic and molecular alterations that occur as the disease progresses from a localized to a metastatic state, and from androgen dependence to independence, is necessary. Clinical trial design will require consideration of cytostatic and cytotoxic effects, the status of pathways not directly targeted, and potentially unexpected influences on prostate specific antigen expression by these agents. Copyright 2000 American Cancer Society.