- Email: [email protected]
The Evolution of Bone-Targeted Therapies: Introduction
The Evolution of Bone-Targeted Therapies: Introduction
C
ertain tumor types, including breast cancer, prostate cancer, and lung cancer, show a predilection to metastasize to bone. Bone lesions due to metastatic disease are associated with a dismal prognosis and deleterious clinical consequences, including severe bone pain, pathologic fractures, spinal cord compression, bone deformity, and hypercalcemia, all of which have a devastating impact on patients’ quality of life. Until the advent of bisphosphonates, treatment strategies for the management of skeletal complications due to bone metastasis were primarily palliative in nature. In the current era of personalized medicine, there is great interest in developing rational treatment strategies that are specific to the pathobiology of bone metastasis, and in the last decade or so, we have taken great strides towards that goal. This supplement provides an overview of the mechanisms of bone metastasis and currently available treatment approaches for management, and reviews emerging and provocative data in support of an antitumor role for bisphosphonates. Several puzzling questions pertinent to the pathophysiology of metastasis have captured the attention of researchers and clinicians alike, including what drives some cancers to metastasize to bone, what unique aspects of bone makes it a preferential target site of metastasis, and how certain cancers colonize in bone. In the first article, Theresa Guise from Indiana University outlines our current molecular understanding of the apparent proclivity of certain malignancies to metastasize to bone and discusses the molecular basis of myeloma bone disease. The therapeutic opportunities that such understanding has provided us are also touched upon. Bisphosphonates are analogs of pyrophosphates that bind avidly to metabolizing bone and inhibit several components of the bone resorptive process, thus of-
Publication of this article was supported by an educational grant from Novartis Pharmaceuticals Corporation. Statement of Conflict of Interest: M. Gnant discloses the following potential conflicts of interest: Salary: MerckDarmstadt. Consulting fees: Amgen Inc, AstraZeneca, Novartis Pharmaceuticals Corporation, F. Hoffmann-La Roche Ltd, and SanofiAventis. Speaker’s bureau: AstraZeneca, Novartis Pharmaceuticals Corporation. Contracted research: AstraZeneca, Novartis Pharmaceuticals Corporation, Pfizer Inc, and F. Hoffmann-La Roche Ltd. 0270-9295/ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2010.10.003
Seminars in Oncology, Vol 37, No 5, Suppl 2, October 2010, p S1
fering a rational strategy to target dysfunctional processes underlying the pathobiology of bone metastasis, thereby reducing or even preventing skeletal complications. Based on their proven efficacy in delaying the onset and reducing the risk of skeletal complications from malignant bone disease, bisphosphonates are now the cornerstone of treatment of skeletal complications related to metastatic bone disease. Moreover, our increased understanding of the pathophysiology of metastasis unique to different cancer types has revealed molecular factors in the bone and cancer niche alike that can serve as promising targets for therapeutic intervention; several such agents are in varying stages of clinical development. In the second article, Allan Lipton from Penn State Hershey Cancer Institute comprehensively reviews clinical evidence in favor of the efficacy and safety of currently available and investigational bone-targeted therapies. An accumulating wealth of preclinical evidence strongly suggests an antitumor role for bisphosphonates via both direct and indirect mechanisms. While clinical evidence in support of the potential role of bisphosphonates as anticancer treatment has surfaced only very recently, several prospective studies are ongoing to evaluate this question in many cancer types. Targeting early disease at its hiding place, the bone marrow, is a fascinating vision that could come true, since preliminary data from many of these trials are exciting, and it is expected that mature data will provide important insights into the utility of bisphosphonates in this setting. In the third article, Gareth Morgan from the Royal Marsden Hospital and Allan Lipton assess current preclinical and clinical evidence in support of a potential antitumor role for bisphosphonate therapy in different cancers. Although many questions remain, the potential clinical implications of these exciting advances are far-reaching, and might pave the way for a future of personalized bone-targeted cancer therapy.
Michael Gnant Department of Surgery Comprehensive Cancer Center Vienna Medical University of Vienna Department of Surgery Austria
S1
C
ertain tumor types, including breast cancer, prostate cancer, and lung cancer, show a predilection to metastasize to bone. Bone lesions due to metastatic disease are associated with a dismal prognosis and deleterious clinical consequences, including severe bone pain, pathologic fractures, spinal cord compression, bone deformity, and hypercalcemia, all of which have a devastating impact on patients’ quality of life. Until the advent of bisphosphonates, treatment strategies for the management of skeletal complications due to bone metastasis were primarily palliative in nature. In the current era of personalized medicine, there is great interest in developing rational treatment strategies that are specific to the pathobiology of bone metastasis, and in the last decade or so, we have taken great strides towards that goal. This supplement provides an overview of the mechanisms of bone metastasis and currently available treatment approaches for management, and reviews emerging and provocative data in support of an antitumor role for bisphosphonates. Several puzzling questions pertinent to the pathophysiology of metastasis have captured the attention of researchers and clinicians alike, including what drives some cancers to metastasize to bone, what unique aspects of bone makes it a preferential target site of metastasis, and how certain cancers colonize in bone. In the first article, Theresa Guise from Indiana University outlines our current molecular understanding of the apparent proclivity of certain malignancies to metastasize to bone and discusses the molecular basis of myeloma bone disease. The therapeutic opportunities that such understanding has provided us are also touched upon. Bisphosphonates are analogs of pyrophosphates that bind avidly to metabolizing bone and inhibit several components of the bone resorptive process, thus of-
Publication of this article was supported by an educational grant from Novartis Pharmaceuticals Corporation. Statement of Conflict of Interest: M. Gnant discloses the following potential conflicts of interest: Salary: MerckDarmstadt. Consulting fees: Amgen Inc, AstraZeneca, Novartis Pharmaceuticals Corporation, F. Hoffmann-La Roche Ltd, and SanofiAventis. Speaker’s bureau: AstraZeneca, Novartis Pharmaceuticals Corporation. Contracted research: AstraZeneca, Novartis Pharmaceuticals Corporation, Pfizer Inc, and F. Hoffmann-La Roche Ltd. 0270-9295/ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2010.10.003
Seminars in Oncology, Vol 37, No 5, Suppl 2, October 2010, p S1
fering a rational strategy to target dysfunctional processes underlying the pathobiology of bone metastasis, thereby reducing or even preventing skeletal complications. Based on their proven efficacy in delaying the onset and reducing the risk of skeletal complications from malignant bone disease, bisphosphonates are now the cornerstone of treatment of skeletal complications related to metastatic bone disease. Moreover, our increased understanding of the pathophysiology of metastasis unique to different cancer types has revealed molecular factors in the bone and cancer niche alike that can serve as promising targets for therapeutic intervention; several such agents are in varying stages of clinical development. In the second article, Allan Lipton from Penn State Hershey Cancer Institute comprehensively reviews clinical evidence in favor of the efficacy and safety of currently available and investigational bone-targeted therapies. An accumulating wealth of preclinical evidence strongly suggests an antitumor role for bisphosphonates via both direct and indirect mechanisms. While clinical evidence in support of the potential role of bisphosphonates as anticancer treatment has surfaced only very recently, several prospective studies are ongoing to evaluate this question in many cancer types. Targeting early disease at its hiding place, the bone marrow, is a fascinating vision that could come true, since preliminary data from many of these trials are exciting, and it is expected that mature data will provide important insights into the utility of bisphosphonates in this setting. In the third article, Gareth Morgan from the Royal Marsden Hospital and Allan Lipton assess current preclinical and clinical evidence in support of a potential antitumor role for bisphosphonate therapy in different cancers. Although many questions remain, the potential clinical implications of these exciting advances are far-reaching, and might pave the way for a future of personalized bone-targeted cancer therapy.
Michael Gnant Department of Surgery Comprehensive Cancer Center Vienna Medical University of Vienna Department of Surgery Austria
S1