Inhibition of Protein Kinase c-Src as a Therapeutic Approach for Cancer and Bone Metastases (original) (raw)
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Src Inhibitors in Metastatic Bone Disease
Clinical Cancer Research, 2006
Src tyrosine kinase was the first gene product shown to have an essential function in bone using recombinant DNA technology after its expression was knocked out in mice f15 years ago. Since then, our understanding of the regulation of bone catabolism has advanced significantly with the identification of other key enzymes that regulate osteoclast formation, activation, and survival after their knockout in mice or recognition of mutations in them in humans. This led to the discovery or development of specific inhibitors of some of these key enzymes, including Src, as proof-of-concept lead compounds or potential clinical candidates for the prevention of diseases associated with increased bone resorption, such as osteoporosis and metastatic bone disease. Although bisphosphonates have been prescribed with proven and improving efficacy for the prevention of bone loss for >30 years, adverse effects, such as upper gastrointestinal tract
Bone-Targeted Therapies in Cancer-Induced Bone Disease
Calcified tissue international, 2017
Cancer-induced bone disease is a major source of morbidity and mortality in cancer patients. Thus, effective bone-targeted therapies are essential to improve disease-free, overall survival and quality of life of cancer patients with bone metastases. Depending of the cancer-type, bone metastases mainly involve the modulation of osteoclast and/or osteoblast activity by tumour cells. To inhibit metastatic bone disease effectively, it is imperative to understand its underlying mechanisms and identify the target cells for therapy. If the aim is to prevent bone metastasis, it is essential to target not only bone metastatic features in the tumour cells, but also tumour-nurturing bone microenvironment properties. The currently available bone-targeted agents mainly affect osteoclasts, inhibiting bone resorption (e.g. bisphosphonates, denosumab). Some agents targeting osteoblasts begin to emerge which target osteoblasts (e.g. romosozumab), activating bone formation. Moreover, certain drugs in...
New molecular targets in bone metastases
Cancer Treatment Reviews, 2010
s u m m a r y Bone metastases have a major impact on morbidity and on mortality in cancer patients. Despite its clinical relevance, metastasis remains the most poorly elucidated aspect of carcinogenesis. The biological mechanisms leading to bone metastasis establishment have been referred as "vicious circle", a complex network between cancer cells and the bone microenvironment. This review is aimed to underline the new molecular targets in bone metastases management other than bisphosphonates. Different pathways or molecules such as RANK/RANKL/OPG, cathepsin K, endothelin-1, Wnt/DKK1, Src have recently emerged as potential targets and nowadays preclinical and clinical trials are underway. The results from those in the advanced clinical phases are encouraging and underlined the need to design large randomised clinical trials to validate these results in the next future.
Current Medicinal Chemistry, 2011
Solid tumors such as breast, prostate, thyroid, lung and renal cell cancer exhibit significant osteotropism and often metastasize in the skeleton . Bone metastasis is a major cause of morbidity and mortality of several carcinomas. The tendency of certain solid tumors to colonize bone tissue is currently explained by the concept of organ-specific metastasis, introduced by the -seed and soil‖ hypothesis, initially proposed by Dr. Steven Paget, more than one hundred years ago . Dr. Paget proposed that a receptive microenvironment (soil) is present in certain organs, and this is the prerequisite for circulating cancer cells (seeds) to colonize it and develop metastases. This microenvironment offers the fertile ‗‗soil'' where neoplastic cells can reside, grow and develop. Bone metastasis usually occurs during the late stages of cancer progression, and involves a complex multistep process, which involves alterations in the structure and/or expression of specific genes, resulting in the acquisition of an advanced malignant phenotype by the cell . Cancer cells must express the appropriate phenotype to successfully leave the primary tumor, grow in the adjacent mesenchyme, survive in the blood-stream, attach to the endothelial cells, transverse them, and finally invade and proliferate at secondary sites. Metastatic bone disease is classified as either osteolytic or osteblastic. Osteolytic-type metastases are more common and are characterized by significant bone disruption due to enhanced osteoclastic activity. In contrast, osteoblastic metastases are less common, and are characterized by over-production of osseous tissue by activated osteoblasts. These two types of bone destruction represent the two extremes of a continuum of metastasis-associated bone pathology since in the majority of the cases both, the osteolytic and the osteoblastic component co-exist. Metastases of breast and lung 4 cancer are predominantly osteolytic. On the other hand, prostate cancer typically develops osteoblastic metastases . Bone disease is also developed in multiple myeloma, a B-cell neoplasm, characterized by expansion within the bone marrow of a malignant plasma cell clone, which leads to the formation of typical osteolytic lesions . Bone disease is often associated with various skeletal events such as bone pain, pathological fractures, hypercalcemia, various nerve compression syndromes, paralysis and bone marrow aplasia . Occasionlly, bone destruction can also be observed in other hematological malignancies of lymphoid (non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lympocytic leukemia) and of nonlymphoid origin (acute myelogenous leukemia, Langerhans-and non-Langerhans cell's histiocytosis, etc.).
Advances in Treating Metastatic Bone Cancer: Summary Statement for the First Cambridge Conference
Clinical Cancer Research, 2006
The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.
Effects of Bone-Targeted Agents on Cancer Progression and Mortality
JNCI Journal of the National Cancer Institute, 2012
Bone-targeted treatments with bisphosphonates and denosumab, which reduce bone resorption, are known to reduce the risk of skeletal complications and prevent treatment-induced bone loss in patients with malignant bone disease. Additionally, these drugs may modify the course of bone destruction via inhibitory effects on the "vicious cycle" of growth factor and cytokine signaling between tumor and bone cells within the bone marrow microenvironment. Effects of the drugs on the stem cell niche, direct effects on the cancer cells, and immune modulation may also contribute. In early-stage (stages I, II, and III) breast cancer, treatment with the bisphosphonate zoledronic acid has shown improvements in disease-free and overall survival. Improved survival was particularly notable in women with established menopause at diagnosis and in premenopausal women with endocrine-responsive disease who received treatment with goserelin, which suppresses ovarian function by inhibiting the production of ovarian hormones. Additionally, in castrate-resistant prostate cancer, treatment with denosumab delays the development of bone metastases. These results strongly support the adjuvant use of bone-targeted treatments but suggest that reproductive hormones are an important treatment modifier to take into account. In advanced-stage (stage IV, ie, metastatic) cancers, survival benefits have been observed in patients with multiple myeloma and in patients with other solid tumors with rapid rates of bone destruction who received treatment with zoledronic acid. Here, we have critically reviewed the increasing evidence to support a disease-modifying effect of bone-targeted treatment and discussed the impact on clinical management.
Therapeutic strategies for treating osteolytic bone metastases
Drug Discovery Today, 2014
The recent progress in oncologic management of patients with localized cancer or metastatic disease has permitted a significant improvement in life expectancy. Nevertheless, bone metastases and their consequent skeletal-related events (SREs) are still associated with unfavorable prognosis and greatly affect quality of life. Global management of these bone metastases includes traditional local approaches (surgery, radiotherapy, etc.) and systemic administration of chemotherapeutic agents. This review focuses on treatments specific for bone metastases and, in particular, on inhibitors of bone resorption that are effective for preventing and delaying the development of SREs.
New trends in the treatment of bone metastasis
Journal of Cellular Biochemistry, 2007
Bone metastasis is often the penultimate harbinger of death for many cancer patients. Bone metastases are often associated with fractures and severe pain resulting in decreased quality of life. Accordingly, effective therapies to inhibit the development or progression of bone metastases will have important clinical benefits. To achieve this goal understanding the mechanisms through which bone metastases develop and progress may provide targets to inhibit the metastases. In the past few years, there have been advances in both understanding the mechanisms through which bone metastases develop and how they impact bone remodeling. Additionally, gains in promising clinical strategies to target bone metastases have been developed. In this prospectus, we will discuss some of these advances.
Osteogenic Effects of a Potent Src-over-Abl-Selective Kinase Inhibitor in the Mouse
Journal of Pharmacology and Experimental Therapeutics, 2011
Src-null mice have higher bone mass because of decreased bone resorption and increased bone formation, whereas Ablnull mice are osteopenic, because of decreased bone formation. Compound I, a potent inhibitor of Src in an isolated enzyme assay (IC 50 0.55 nM) and a Src-dependent cell growth assay, with lower activity on equivalent Abl-based assays, potently, but biphasically, accelerated differentiation of human mesenchymal stem cells to an osteoblast phenotype (1-10 nM). Compound I (Ն0.1 nM) also activated osteoblasts and induced bone formation in isolated neonatal mouse calvariae. Compound I required higher concentrations (100 nM) to inhibit differentiation and activity of osteoclasts. Transcriptional profiling (TxP) of calvaria treated with 1 M compound I revealed downregulation of osteoclastic genes and up-regulation of matrix genes and genes associated with the osteoblast phenotype, confirming compound I's dual effects on bone resorption and formation. In addition, calvarial TxP implicated calcitonin-related polypeptide,  (-CGRP) as a potential mediator of compound I's osteogenic effect. In vivo, compound I (1 mg/kg s.c.) increased vertebral trabecular bone volume 21% (microcomputed tomography) in intact female mice. Increased trabecular volume was also detected histologically in a separate bone, the femur, particularly in the secondary spongiosa (100% increase), which underwent a 171% increase in bone formation rate, a 73% increase in mineralizing surface, and a 59% increase in mineral apposition rate. Similar effects were observed in ovariectomized mice with established osteopenia. We conclude that the Src inhibitor compound I is osteogenic, presumably because of its potent stimulation of osteoblast differentiation and activation, possibly mediated by -CGRP.
Translational Strategies to Target Metastatic Bone Disease
Cells
Metastatic bone disease is a common and devastating complication to cancer, confounding treatments and recovery efforts and presenting a significant barrier to de-escalating the adverse outcomes associated with disease progression. Despite significant advances in the field, bone metastases remain presently incurable and contribute heavily to cancer-associated morbidity and mortality. Mechanisms associated with metastatic bone disease perpetuation and paralleled disruption of bone remodeling are highlighted to convey how they provide the foundation for therapeutic targets to stem disease escalation. The focus of this review aims to describe the preclinical modeling and diagnostic evaluation of metastatic bone disease as well as discuss the range of therapeutic modalities used clinically and how they may impact skeletal tissue.