- Email: [email protected]
New anabolic approaches to treating myeloma bone disease
Abstracts / Bone 48 (2011) S4–S12
standing of the molecular mechanisms by which tyrosine kinases promote the malignant phenotype, especially metastasis, and how the biological properties they perturb may be targeted for therapy. Conflict of interest statement: None declared.
doi:10.1016/j.bone.2010.10.023
S-14 Challenges of research on circulating tumour cells in carcinoma patients S. Riethdorf, K. Pantel Institute of Tumour Biology, University Medical Center HamburgEppendorf, Germany Early dissemination from the primary tumour, circulation in blood as well as homing of single tumour cells in bone marrow (BM) or other organs is usually undetectable at primary diagnosis even by high resolution imaging technologies. However, ultrasensitive immunological and molecular approaches now enable the specific detection of these ‘occult’ tumour cells and provide the potential to track systemic tumour cell spread. This information might support clinicians to assess individual prognosis, stratify patients at risk to systemic adjuvant anti-cancer therapies, and monitor therapeutic efficacy thus contributing to the development of individual therapies. BM appears to be a common homing organ for disseminated tumour cells derived from different carcinomas; however, sequential blood analyses are more convenient for patients than BM analyses. Therefore, many research groups are currently evaluating the clinical utility of circulating tumour cells (CTC) detectable in the peripheral blood. Several publications have described that the presence of CTC in patients with metastatic cancer is associated with worse prognosis and seems to allow early response evaluation. However, evidence has emerged that most currently used CTC detection methods still lack sensitivity or specificity to track all CTC especially those that have lost characteristic epithelial features. Therefore new developments in this field of research are of utmost interest and the potential and limitations of the currently available methods will be presented. Moreover, improvements of approaches enabling further phenotypical and molecular characterisation of CTC, e.g., analyses of single cell whole genomes, gene mutations and gene expression patterns are pivotal in view of the development of personalized targeting anticancer therapies. In this context, it is notable that detection and characterisation of CTC already has entered clinical trials and is of particular importance especially for studies involving patients with metastatic cancer. Furthermore, first results of clinical studies on CTC detection in patients with non-metastatic disease especially in treatment regimens including targeted therapy, e.g., trastuzumab directed against HER2 in breast cancer patients receiving neoadjuvant or adjuvant therapy will be discussed. Conflict of interest statement: None declared. doi:10.1016/j.bone.2010.10.024
S-15 New anabolic approaches to treating myeloma bone disease G. Roodman Veterans Affairs Pittsburgh Healthcare System, Research and Development, Pittsburgh, PA, USA University of Pittsburgh, Department of Medicine/Hematology–Oncology, Pittsburgh, PA, USA
S9
Bone involvement occurs in more than 80% of myeloma (MM) patients and is responsible for some of the most catastrophic effects of the disease. At presentation, 70% of patients have lytic lesions, approximately 20% have a pathologic fracture and 60% have osteopenia. Within one year of diagnosis, 40% of patients sustain a pathologic fracture. Myeloma bone disease is so catastrophic because the normal bone remodeling process is uncoupled with marked suppression of osteoblast (OBL) activity. The suppressed OBL activity results from tumor derived inhibitory factors that block OBL differentiation and activity. These include Wnt signaling antagonists (DKK1 and soluble fizzle related protein 2), IL-3 and IL-7. Pre-clinical studies have suggested that anabolic factors may reverse OBL suppression in MM. Yaccoby et al. reported that an antibody to DKK1 increased bone formation and decreased tumor burden in a murine model of MM. Edwards et al. showed that enhancing Wnt signaling with LiCl enhanced bone formation and decreased tumor burden in bone in the 5TGM1 model of myeloma. Based on these results, a Phase I/II study of an anti-DKK1 human monoclonal antibody is ongoing in MM patients. An Activin A receptor antagonist is also in clinical trials for MM. Activin A inhibits bone formation and increases osteoclast activity, and Activin A levels are increased in the marrow of MM patients. Studies in the 5T2MM model and Valet et al. in the SCID-hu model of MM showed that an Activin A receptor antagonist enhanced new bone formation and decreased tumor burden. A Phase II study of a human Activin receptor 2A antagonist is ongoing in MM patients with osteolytic bone disease. Finally, bortezomib, a proteasome antagonist used to treat MM patients, also has bone anabolic activity in myeloma. Patients who respond to bortezomib have increased alkaline phosphase and bone specific alkaline phosphase levels in their sera. Further, Giuliani et al. reported that bortezomib increases new bone formation in responding patients with myeloma. These results suggest that novel anabolic agents may have the potential to heal bone lesions and improve the quality of life for MM patients. Conflict of interest statement: Amgen: Consultant; Celgene: Consultant; Acceleron: Consultant; Millennium: Consultant. doi:10.1016/j.bone.2010.10.025
S-16 New therapies for cancer-induced bone disease: Preclinical perspective T. Guise Department of Medicine, Division of Endocrinology, Indiana University, IN, USA Bone metastases cause significant morbidity and once housed in bone, the tumors are incurable. Tumors produce factors which stimulate osteoclasts and osteoblasts to dysregulate normal bone remodeling. The bone microenvironment alters the behavior of metastatic tumor cells, driving a feed-forward cycle that makes skeletal metastases refractory to treatment and cure. Many different tumor and host factors are implicated to disrupt bone remodeling and are targets for therapy. Transforming growth factor beta (TGFβ) is a central regulator of many of these factors. It is deposited into mineralized bone matrix by osteoblasts, is released and activated by osteoclastic bone resorption, and changes the phenotype of tumor cells. In mouse models, TGFβ blockade inhibits osteolytic bone metastases due to breast cancer, prostate cancer and melanomas by blocking tumor-produced osteolytic and prometastatic factors (PTHrP, IL-11, CTGF). It also increases bone mass, independent of effects on cancer cells, by increasing osteoblast activity and reducing osteoclast activity. These effects are potentiated with the use of a
standing of the molecular mechanisms by which tyrosine kinases promote the malignant phenotype, especially metastasis, and how the biological properties they perturb may be targeted for therapy. Conflict of interest statement: None declared.
doi:10.1016/j.bone.2010.10.023
S-14 Challenges of research on circulating tumour cells in carcinoma patients S. Riethdorf, K. Pantel Institute of Tumour Biology, University Medical Center HamburgEppendorf, Germany Early dissemination from the primary tumour, circulation in blood as well as homing of single tumour cells in bone marrow (BM) or other organs is usually undetectable at primary diagnosis even by high resolution imaging technologies. However, ultrasensitive immunological and molecular approaches now enable the specific detection of these ‘occult’ tumour cells and provide the potential to track systemic tumour cell spread. This information might support clinicians to assess individual prognosis, stratify patients at risk to systemic adjuvant anti-cancer therapies, and monitor therapeutic efficacy thus contributing to the development of individual therapies. BM appears to be a common homing organ for disseminated tumour cells derived from different carcinomas; however, sequential blood analyses are more convenient for patients than BM analyses. Therefore, many research groups are currently evaluating the clinical utility of circulating tumour cells (CTC) detectable in the peripheral blood. Several publications have described that the presence of CTC in patients with metastatic cancer is associated with worse prognosis and seems to allow early response evaluation. However, evidence has emerged that most currently used CTC detection methods still lack sensitivity or specificity to track all CTC especially those that have lost characteristic epithelial features. Therefore new developments in this field of research are of utmost interest and the potential and limitations of the currently available methods will be presented. Moreover, improvements of approaches enabling further phenotypical and molecular characterisation of CTC, e.g., analyses of single cell whole genomes, gene mutations and gene expression patterns are pivotal in view of the development of personalized targeting anticancer therapies. In this context, it is notable that detection and characterisation of CTC already has entered clinical trials and is of particular importance especially for studies involving patients with metastatic cancer. Furthermore, first results of clinical studies on CTC detection in patients with non-metastatic disease especially in treatment regimens including targeted therapy, e.g., trastuzumab directed against HER2 in breast cancer patients receiving neoadjuvant or adjuvant therapy will be discussed. Conflict of interest statement: None declared. doi:10.1016/j.bone.2010.10.024
S-15 New anabolic approaches to treating myeloma bone disease G. Roodman Veterans Affairs Pittsburgh Healthcare System, Research and Development, Pittsburgh, PA, USA University of Pittsburgh, Department of Medicine/Hematology–Oncology, Pittsburgh, PA, USA
S9
Bone involvement occurs in more than 80% of myeloma (MM) patients and is responsible for some of the most catastrophic effects of the disease. At presentation, 70% of patients have lytic lesions, approximately 20% have a pathologic fracture and 60% have osteopenia. Within one year of diagnosis, 40% of patients sustain a pathologic fracture. Myeloma bone disease is so catastrophic because the normal bone remodeling process is uncoupled with marked suppression of osteoblast (OBL) activity. The suppressed OBL activity results from tumor derived inhibitory factors that block OBL differentiation and activity. These include Wnt signaling antagonists (DKK1 and soluble fizzle related protein 2), IL-3 and IL-7. Pre-clinical studies have suggested that anabolic factors may reverse OBL suppression in MM. Yaccoby et al. reported that an antibody to DKK1 increased bone formation and decreased tumor burden in a murine model of MM. Edwards et al. showed that enhancing Wnt signaling with LiCl enhanced bone formation and decreased tumor burden in bone in the 5TGM1 model of myeloma. Based on these results, a Phase I/II study of an anti-DKK1 human monoclonal antibody is ongoing in MM patients. An Activin A receptor antagonist is also in clinical trials for MM. Activin A inhibits bone formation and increases osteoclast activity, and Activin A levels are increased in the marrow of MM patients. Studies in the 5T2MM model and Valet et al. in the SCID-hu model of MM showed that an Activin A receptor antagonist enhanced new bone formation and decreased tumor burden. A Phase II study of a human Activin receptor 2A antagonist is ongoing in MM patients with osteolytic bone disease. Finally, bortezomib, a proteasome antagonist used to treat MM patients, also has bone anabolic activity in myeloma. Patients who respond to bortezomib have increased alkaline phosphase and bone specific alkaline phosphase levels in their sera. Further, Giuliani et al. reported that bortezomib increases new bone formation in responding patients with myeloma. These results suggest that novel anabolic agents may have the potential to heal bone lesions and improve the quality of life for MM patients. Conflict of interest statement: Amgen: Consultant; Celgene: Consultant; Acceleron: Consultant; Millennium: Consultant. doi:10.1016/j.bone.2010.10.025
S-16 New therapies for cancer-induced bone disease: Preclinical perspective T. Guise Department of Medicine, Division of Endocrinology, Indiana University, IN, USA Bone metastases cause significant morbidity and once housed in bone, the tumors are incurable. Tumors produce factors which stimulate osteoclasts and osteoblasts to dysregulate normal bone remodeling. The bone microenvironment alters the behavior of metastatic tumor cells, driving a feed-forward cycle that makes skeletal metastases refractory to treatment and cure. Many different tumor and host factors are implicated to disrupt bone remodeling and are targets for therapy. Transforming growth factor beta (TGFβ) is a central regulator of many of these factors. It is deposited into mineralized bone matrix by osteoblasts, is released and activated by osteoclastic bone resorption, and changes the phenotype of tumor cells. In mouse models, TGFβ blockade inhibits osteolytic bone metastases due to breast cancer, prostate cancer and melanomas by blocking tumor-produced osteolytic and prometastatic factors (PTHrP, IL-11, CTGF). It also increases bone mass, independent of effects on cancer cells, by increasing osteoblast activity and reducing osteoclast activity. These effects are potentiated with the use of a