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. The increased activity of osteoclasts and osteoblasts then increases bone turnover, which releases growth factors that benefit metastatic cancer cells. In order to improve the prognosis of patients with bone metastases this cycle must be broken. Radium-223 dichloride (radium-223), the first targeted alpha therapy (TAT) approved, is an osteomimetic radionuclide that is incorporated into bone metastases where its high-linear energy transfer alpha radiation disrupts both the activity of bone cells and cancer cells. Therefore, radium-223 treatment has been shown preclinically to directly affect cancer cells in both osteolytic breast cancer and osteoblastic prostate cancer bone metastases as well as to inhibit the differentiation of osteoblasts and osteoclasts. Clinical studies have demonstrated an increase in survival in patients with metastatic castration-resistant prostate cancer. Due to the effectiveness and low toxicity of radium-223, several novel combination treatment strategies are currently eliciting considerable research interest

Identification of MicroRNAs Inhibiting TGF-beta-Induced IL-11 Production in Bone Metastatic Breast Cancer Cells

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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. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor-bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease

Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

This article has an erratum: http://dx.doi.org/10.1007/s10549-011-1654-4Since 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. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian tissues. Consistently, we observed that the proliferation of MDAMB- 231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L-serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions.Peer reviewe

Sequential treatment with doxorubicin and zoledronic acid has no additive effects in an aggressive model of established bone metastases

Aim: Bisphosphonates are used as an adjuvant treatment in breast cancer bone metastasis patients, often simultaneously with chemotherapeutic agents. Interestingly, their sequential combination has been reported to have synergistic anti-tumor effects on bone metastases in preclinical models. We studied the effects of doxorubicin (DOX) and zoledronic acid (ZOL) and their combination on established bone metastases in the MDA-MB-231(SA)GFP bone metastasis model.Methods: Tumor burden and osteolytic bone lesions were quantitated by fluorescence imaging and radiography, respectively. The mice were randomized in four groups receiving vehicle, DOX, ZOL or both DOX and ZOL in a sequential combination on day 14. Serum marker of osteoclast number was followed weekly, and blood ionized calcium was measured at sacrifice. Bone and tumor area, apoptosis and proliferation of tumor cells were analyzed from histological sections.Results: ZOL prevented hypercalcemia and osteolytic lesion progression, whereas DOX induced apoptosis in the MDA-MB-231(SA)GFP cells. However, neither of the treatments alone nor in sequential combination were able to reduce tumor burden in bone. Furthermore, no additive effects on tumor cell apoptosis were observed in the combination group.Conclusion: No additive effects in combination of DOX and ZOL were observed in this aggressive model of breast cancer bone metastasis

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

This is the final, accepted and revised manuscript of the article "Fracture-induced changes in bone turnover: a potential confounder in the use of biochemical markers in osteoporosis." Use alternative location to go to the published article. Requires subscription

Effects of miR-204, -211, and -379 on Smad signaling.

<p>Smad signaling was quantified using a luciferase construct which encodes the firefly luciferase reporter gene under the control of a minimal (m)CMV promoter and tandem repeats of the Smad transcriptional response element. The luciferase reporter construct and miRNA precursors were co-transfected into MDA-MB-231(SA) cells (n = 3), and the medium was replaced with serum-free medium 16 hours after transfection. TGF-β was added 8 hours later. Activity of the firefly luciferase reporter and Renilla luciferase was measured after 16 hour TGF-β induction. * p<0.05, ** p<0.01, as compared to the Pre-miR negative control and Smad reporter-transfected cells.</p