Darolutamide in Combination with Radium-223 Exhibits Synergistic Antitumor Efficacy in LNCaP Prostate Cancer Models.

Despite treatment, prostate cancer commonly progresses into castration-resistant prostate cancer (CRPC), which remains largely incurable, requiring the development of new interventions. Darolutamide is an orally administered second-generation androgen receptor inhibitor indicated for patients with non-metastatic CRPC or metastatic hormone-sensitive prostate cancer. Here, we evaluated the effect of androgen receptor (AR) inhibition by darolutamide in combination with DNA double-strand-break-inducing targeted radium-223 alpha therapy in vitro and in an intratibial LNCaP xenograft model mimicking prostate cancer metastasized to bone.

Zoledronic Acid Prevents Bone Resorption Caused by the Combination of Radium-223, Abiraterone Acetate, and Prednisone in an Intratibial Prostate Cancer Mouse Model.

An increased risk of non-pathological fractures in patients with prostate cancer and bone metastases has been associated with combination treatment with radium-223, abiraterone, and prednisone/prednisolone in the absence of bone-protecting agents. Here, we investigated possible mechanisms leading to this outcome using an intratibial LNCaP model mimicking prostate cancer bone metastases. Male NOD.

Enhanced Antitumor Efficacy of Radium-223 and Enzalutamide in the Intratibial LNCaP Prostate Cancer Model.

Radium-223 dichloride and enzalutamide are indicated for metastatic castration-resistant prostate cancer and their combination is currently being investigated in a large phase 3 clinical trial. Here, we evaluated the antitumor efficacy of radium-223, enzalutamide, and their combination in the intratibial LNCaP model mimicking prostate cancer metastasized to bone. experiments revealed that the combination of radium-223 and enzalutamide inhibited LNCaP cell proliferation and showed synergistic efficacy.

Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model.

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis.

The Mode-of-Action of Targeted Alpha Therapy Radium-223 as an Enabler for Novel Combinations to Treat Patients with Bone Metastasis.

Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. The vicious cycle is characterized by cancer cells residing in bone releasing signal molecules that promote the differentiation of osteoclasts and osteoblasts either directly or indirectly.

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models.

Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models. Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups ( = 12-17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals.

Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis.

Background: Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis.

Methods: We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and osteoblast cultures as well as a mouse model of breast cancer bone metastasis.

Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.

Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction.

Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis.

TGF-β regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-β is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for TGF-β-induced IL-11 production in highly bone metastatic MDA-MB-231(SA) breast cancer cells.

D-18F-fluoromethyl tyrosine imaging of bone metastases in a mouse model.

Unlabelled: The presence and localization of metastatic bone lesions is important for the staging of the disease and subsequent treatment decisions. Detecting tumor cells would have additional value over the current indirect bone scintigraphy method for detecting areas of elevated skeletal metabolic activity. d-(18)F-fluoromethyl tyrosine (d-(18)F-FMT) has recently shown good uptake and fast elimination, resulting in good tumor-to-background ratios.

Characterization of a new renal cell carcinoma bone metastasis mouse model.

Metastatic bone disease caused by renal cell carcinoma (RCC) occurs frequently and becomes more and more prevalent presumably because survival times among patients with disseminated cancers are increasing. Patients with bone metastases from renal cell carcinoma suffer from severe pain, nerve compression syndromes and pathologic fractures. Very little is known about the mechanisms of skeletal metastases of RCC.

Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis.

Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, an understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidences for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice.

Luminescent imaging technology as an opportunity to reduce and refine animal experiments: Light at the end of the tunnel?

In vivo luminescent imaging technology was introduced in experimental life science research several years ago and has rapidly gained wide acceptance. By making use of this technology substantially more information can be gained from animal experiments than was previously possible. The concept of the 3Rs describes the aim to Refine, Reduce and Replace animal models in research.

Sagopilone inhibits breast cancer bone metastasis and bone destruction due to simultaneous inhibition of both tumor growth and bone resorption.

Purpose: Bone metastases have a considerable impact on quality of life in patients with breast and other cancers. Tumors produce osteoclast-activating factors, whereas bone resorption promotes the growth of tumor cells, thus leading to a "vicious cycle" of bone metastasis. Sagopilone, a novel, fully synthetic epothilone, inhibits the growth of breast cancer cells in vitro and in vivo, and here we report its activity in the MDA-MB-231(SA) breast cancer bone metastasis mouse model.

Urinary osteocalcin as a marker of bone metabolism.

Background: Osteocalcin (OC) is produced by osteoblasts during bone formation, and circulating OC has been used in clinical investigations as a marker of bone metabolism. OC is excreted into urine by glomerular filtration and can be found in urine as midmolecule fragments.

Methods: We developed and evaluated three immunoassays (U-MidOC, U-LongOC, and U-TotalOC) for the detection of various molecular forms of urine OC (U-OC).

Fracture-induced changes in bone turnover: a potential confounder in the use of biochemical markers in osteoporosis.

To examine the short- and long-term bone metabolic effects of fracture assessed by biochemical markers, we utilized a clinical fracture model-proximal tibial osteotomy-and prospectively followed 14 patients. This model of an induced fracture of a major bone gives the advantage of assessing baseline levels prior to fracture. Follow-up occurred at 6-9 weeks, 4-7 months, 9-13 months, and 14-17 months after fracture.

Identification of novel proteolytic forms of osteocalcin in human urine.

In this study, we report the isolation and characterization of osteocalcin in human urine using mass spectrometry and N-terminal sequencing. Multiple proteolytic forms of osteocalcin were found, which consisted of 16-27 residues from the middle region of the molecule. Several fragments had residue Gly7 at the N-terminus and the most predominant was fragment 7-31.

Mechanisms of osteolytic bone metastases in breast carcinoma.

Osteolytic and osteoblastic metastases are often the cause of considerable morbidity in patients with advanced prostate and breast carcinoma. Breast carcinoma metastasis to bone occurs because bone provides a favorable site for aggressive behavior of metastatic cancer cells. A vicious cycle arises between cancer cells and the bone microenvironment, which is mediated by the production of growth factors such as transforming growth factor beta and insulin growth factor from bone and parathyroid hormone-related protein (PTHrP) produced by tumor cells.

Characteristics and composition of the vitamin K-dependent gamma-glutamyl carboxylase-binding domain on osteocalcin.

Two different sites on vitamin K-dependent gamma-glutamyl carboxylase (VKC) are involved in enzyme-substrate interaction: the propeptide-binding site required for high-affinity substrate binding and the active site for glutamate carboxylation. Synthetic descarboxy osteocalcin (d-OC) is a low-K(m) substrate for the VKC, but unique since it possesses a high-affinity recognition site for the VKC, distinct from the propeptide which is essential as a binding site for VKC. However, the exact location and composition of this VKC-recognition domain on d-OC has remained unclear until now.

Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways.

Transforming growth factor (TGF)-beta promotes breast cancer metastasis to bone. To determine whether the osteolytic factor parathyroid hormone-related protein (PTHrP) is the primary mediator of the tumor response to TGF-beta, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitutively active TGF-beta type I receptor. Treatment of the mice with a PTHrP-neutralizing antibody greatly decreased osteolytic bone metastases.

Serum osteocalcin in relation to calcaneal bone mineral density in elderly men and women: a 5-year follow-up.

A 5-year follow-up study investigated serum concentrations of total (tOC) and intact (iOC) osteocalcin in relation to calcaneal bone mineral density (BMD). The study comprised two cohorts, 75- and 80-year-olds, both resident in the city of Jyväskylä, Finland. Baseline OC and BMD were obtained for 161 men and 233 women, of whom 83 men and 189 women participated in follow-up bone measurements.