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

2019 ◽  
Vol 20 (16) ◽  
pp. 3899 ◽  
Author(s):  
Mari I. Suominen ◽  
Timothy Wilson ◽  
Sanna-Maria Käkönen ◽  
Arne Scholz
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Cancer Cells ◽  
Bone Cells ◽  
Metastatic Cancer ◽  
Signal Molecules ◽  
Targeted Alpha Therapy ◽  
Radium 223 ◽  
Alpha Therapy

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.

scholarly journals Systemic Targeted Alpha Radiotherapy for Cancer - A Review

2014 ◽  
Vol 6 (1) ◽  
pp. 21-38 ◽  
Author(s):  
Barry J Allen
Keyword(s):  
Glioblastoma Multiforme ◽  
Cancer Cells ◽  
Medical Physics ◽  
Metastatic Cancer ◽  
External Beam Radiotherapy ◽  
Palliative Therapy ◽  
Experimental Therapy ◽  
Alpha Radiation ◽  
Targeted Alpha Therapy ◽  
Alpha Therapy

The fundamental principles of internal targeted alpha therapy for cancer were established many decades ago. The high linear energy transfer (LET) of alpha radiation to the targeted cancer cells causes double strand breaks in DNA. At the same time, the short range of alpha- radiation spares adjacent normal tissues. This targeted approach complements conventional external beam radiotherapy and chemotherapy. Such therapies fail on several fronts, such as lack of control of some primary cancers (eg glioblastoma multiforme) and inhibition of the development of lethal metastatic cancer after successful treatment of the primary cancer. This review charts the developing role of systemic high LET in internal radiation therapy. Targeted alpha therapy is a rapidly advancing experimental therapy that holds promise to deliver high cytotoxicity to targeted cancer cells. Initially thought to be indicated for leukaemia and micrometastases, there is now evidence that solid tumours can also be regressed. Alpha therapy may be molecular or physiological in its targeting. Alpha emitting radioisotopes such as Bi-212, Bi-213, At-211 and Ac-225 are used to label monoclonal antibodies or proteins that target specific cancer cells. Alternatively, radium-233 is used for palliative therapy of breast and prostate cancers because of its bone seeking properties. In this review, preclinical studies and clinical trials of alpha therapy are discussed for leukaemia, lymphoma, melanoma, glioblastoma multiforme, bone metastases, ovarian cancer, pancreatic cancer and other cancers.   DOI: http://dx.doi.org/10.3329/bjmp.v6i1.19755 Bangladesh Journal of Medical Physics Vol.6 No.1 2013 21-38

Effects of ALK1Fc treatment on prostate cancer cells interacting with bone and bone cells in bone metastasis models.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16576-e16576
Author(s):  
Marianna Kruithof-de Julio ◽  
Letizia Astrologo ◽  
Eugenio Zoni ◽  
Sofia Karkampouna ◽  
Peter C Gray ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Bone Cells ◽  
Critical Role ◽  
Prostate Cancer Cells ◽  
Primary Prostate Cancer ◽  
The Impact

e16576 Background: Prostate cancer is the second most common cancer in men worldwide. Lethality is normally associated with the consequences of metastasis rather than the primary tumor. In particular, bone is the most frequent site of metastasis and once prostate tumor cells are engrafted in the skeleton, curative therapy is no longer possible. Bone morphogenetic proteins (BMPs) play a critical role in bone physiology and pathology. However, little is known about the role of BMP9 and its signaling receptors, ALK1 and ALK2, in prostate cancer and bone metastasis. In this context, we investigate the impact of BMP9 on primary prostate cancer and derived bone metastasis. Methods: The human ALK1 extracellular domain (ECD) binds BMP9 and BMP10 with high affinity. In order to study the effect of BMP9 in vitro and in vivo we use a soluble chimeric protein, consisting of ALK1 ECD fused to human Fc (ALK1Fc), for preventing the activation of endogenous signaling. ALK1Fc sequesters BMP9 and BMP10, preserving the activation of ALK1 through other ligands. Results: We show that ALK1Fc reduces BMP9-mediated signaling and decreases proliferation of highly metastatic and tumor initiating human prostate cancer cells in vitro. In line with these observations, we demonstrate that ALK1Fc reduces tumor growth in vivo in an orthotopic transplantation model. The propensity of the primary prostate cancer to metastasize to the bone is also investigated. In particular, we report how the ALK1Fc influences the prostate cancer cells in vitro and in vivo when these are probed in different bone settings (co-culture with bone cells and intraosseous transplantation in mice). Conclusions: Our study provides the first demonstration that ALK1Fc inhibits prostate cancer cells growth identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. All together, these findings justify the ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.

Synergistic antitumor efficacy of radium-223 and enzalutamide in the intratibial LNCaP prostate cancer xenograft model.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 105-105
Author(s):  
Mari I Suominen ◽  
Matias Knuuttila ◽  
Jukka Vääräniemi ◽  
Birgitta Sjöholm ◽  
Esa Alhoniemi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Cancer Cells ◽  
Combination Treatment ◽  
Bone Structure ◽  
Antitumor Efficacy ◽  
Antitumor Effects ◽  
Tumor Bearing ◽  
Radium 223 ◽  
Pre Treatment

105 Background: Radium-223 dichloride (Ra-223) is a targeted alpha therapy that binds to newly formed bone matrix in bone metastases and induces DNA double-strand breaks in cancer cells, osteoblasts and osteoclasts. It is used for treating men with castration-resistant prostate cancer (CRPC) and bone metastases. Enzalutamide (enza) is a second-generation androgen receptor inhibitor also used for treating the same patient population, and the combination of Ra-223 and enza is currently being investigated in clinical trials. We evaluated the antitumor efficacy of Ra-223 and enza in the LNCaP intratibial model mimicking prostate cancer metastasized to bone. Previously, additive or synergistic antitumor effects were not observed when Ra-223 was combined with abiraterone and prednisone in the LNCaP model (Suominen et al., AACR 2020). Methods: LNCaP prostate cancer cells were inoculated into the right tibia of male NOD.scid mice. The mice were randomized (n = 9/group) based on serum PSA and treated with vehicle, Ra-223 (330 kBq/kg, i.v., Q4W x 2), enza (30 mg/kg, p.o., QD) or with a combination treatment of Ra-223 and enza, for 28 days. Serum PSA levels were analyzed at the end of the study and compared to the pre-treatment levels. Serum bone formation and resorption biomarkers, PINP and CTX, respectively, were measured during the study. Tumor-induced abnormal bone area and Ra-223 uptake were determined by X-ray and gamma counter, respectively. The healthy tibiae were evaluated by microCT. Results: Combination treatment showed synergistic antitumor efficacy as observed by lower PSA levels when compared to the vehicle, Ra-223 or enza monotherapies (p = 0.04, p = 0.008 and p = 0.002, respectively). A statistical interaction between Ra-223 and enza treatments was found (p = 0.003), confirming the synergistic effect. In combination treatment, the serum PSA change relative to pre-treatment levels was 18% of the vehicle. Accordingly, a decreasing trend (p = 0.08) in tumor-induced abnormal bone changes was associated with the combination treatment in the tumor-bearing tibiae (46% of the vehicle), whereas no changes in total bone structure/quality were observed in the healthy tibiae. Compared to monotherapies, the combination treatment had the most prominent lowering effect on the bone metabolism biomarkers PINP and CTX during the study. Concurrent administration of enza with Ra-223 did not affect Ra-223 uptake in tumor-bearing tibiae. Conclusions: Compared to Ra-223 and enza monotherapies, the combination treatment demonstrated synergistic antitumor efficacy by decreasing PSA levels in the LNCaP intratibial model. Despite of prominent effects on tumor growth, the combination treatment was not observed to compromise bone health in the healthy tibiae. In conclusion, these preclinical results support the ongoing phase 3 trials PEACE III (NCT02194842) & ESCALATE (NCT04237584) of this combination.

scholarly journals Overexpression of Interferon Regulatory Factor 7 (IRF7) Reduces Bone Metastasis of Prostate Cancer Cells in Mice

2017 ◽  
Vol 25 (4) ◽  
pp. 511-522 ◽  
Author(s):  
Yang Zhao ◽  
Wenxia Chen ◽  
Weiliang Zhu ◽  
Hui Meng ◽  
Jie Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Nk Cells ◽  
Cancer Cells ◽  
Interferon Regulatory Factor ◽  
Target Cells ◽  
Regulatory Factor ◽  
Prostate Cancer Cells ◽  
Interferon Regulatory Factor 7

The purpose of this study was to identify the role of interferon regulatory factor 7 (IRF7) in the bone metastasis of prostate cancer. Herein we demonstrated the lower expression of IRF7 in bone metastases of prostate cancer. Overexpression of IRF7 in prostate cancer cells had a marked effect on inhibiting bone metastases but not on tumor growth in xenograft nude mice. While in vitro, upregulation of IRF7 had little effect on the malignant phenotype of prostate cancer cells including proliferation, apoptosis, migration, and invasion. However, prostate cancer cells overexpressing IRF7 significantly enhanced the activity of NK cells, which resulted in the cytolysis of prostate cancer target cells. The underlying mechanism may be relevant to the increasing expression of IFN-β induced by IRF7, as the downregulation of which could inversely inhibit the activity of NK cells. In conclusion, our findings indicate that IRF7 plays a role in reducing bone metastasis of prostate cancer by IFN-β-mediated NK activity.

scholarly journals Bone, a Secondary Growth Site of Breast and Prostate Carcinomas: Role of Osteocytes

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1812
Author(s):  
Paola Maroni ◽  
Paola Bendinelli
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Cancer Cells ◽  
Bone Tissue ◽  
Fibroblast Growth Factor 23 ◽  
Secondary Growth ◽  
New Therapeutic Approaches ◽  
Breast And Prostate Cancer ◽  
Prostate Cancers

Bone is the primarily preferred site for breast and prostate cancer to metastasize. Bone metastases are responsible for most deaths related to breast and prostate cancer. The bone’s particular microenvironment makes it conducive for the growth of cancer cells. Studies on bone metastasis have focused on the interaction between cancer cells and the bone microenvironment. Osteocytes, the most common cell type of bone tissue, have received little attention in bone metastasis, although they are master signal sensors, integrators, and skeleton transducers. They play an important role in regulating bone mass by acting on both osteoblasts and osteoclasts, through the release of proteins such as sclerostin, Dickkopf-1 (DKK-1), and fibroblast growth factor 23 (FGF23). Osteocytes have been extensively re-evaluated, in light of their multiple functions: with different experimental approaches, it has been shown that, indeed, osteocytes are actively involved in the colonization of bone tissue by cancer cells. The present review focuses on recent research on the role that osteocytes play in bone metastasis of breast and prostate cancers. Moreover, the studies here summarized open up perspectives for new therapeutic approaches focused on modulating the activity of osteocytes to improve the condition of the bone metastatic patients. A better understanding of the complex interactions between cancer cells and bone-resident cells is indispensable for identifying potential therapeutic targets to stop tumor progression and prevent bone metastases.

scholarly journals β2AR-HIF-1α-CXCL12 signaling of osteoblasts activated by isoproterenol promotes migration and invasion of prostate cancer cells

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhibin Huang ◽  
Guihuan Li ◽  
Zhishuai Zhang ◽  
Ruonan Gu ◽  
Wenyang Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Chronic Stress ◽  
Metastatic Cancer ◽  
Migration And Invasion ◽  
Prostate Cancer Cells ◽  
Mesenchymal Transition ◽  
Du145 Cells ◽  
Emt Markers

Abstract Background Chronic stress is well known to promote tumor progression, however, little is known whether chronic stress-mediated regulation of osteoblasts contributes to the migration and invasion of metastatic cancer cells. Methods The proliferation, migration and invasion of prostate cancer cells were assessed by CCK-8 and transwell assay. HIF-1α expression of osteoblasts and epithelial-mesenchymal transition (EMT) markers of prostate cancer cells were examined by Western blot. The mRNA level of cytokines associated with bone metastasis in osteoblasts and EMT markers in PC-3 and DU145 cells were performed by qRT-PCR. Functional rescue experiment of cells were performed by using siRNA, plasmid transfection and inhibitor treatment. Results Isoproterenol (ISO), a pharmacological surrogate of sympathetic nerve activation induced by chronic stress, exhibited no direct effect on migration and invasion of PC-3 and DU145 prostate cancer cells. Whereas, osteoblasts pretreated with ISO promoted EMT, migration and invasion of PC-3 and DU145 cells, which could be inhibited by β2AR inhibitor. Mechanistically, ISO increased the secretion of CXCL12 via the β2AR-HIF-1α signaling in osteoblasts. Moreover, overexpression of HIF-1α osteoblasts promoted migration and invasion of PC-3 and DU145 cells, which was inhibited by addition of recombinant knockdown of CXCR4 in PC-3 and DU145 cells, and inhibiting CXCL12-CXCR4 signaling with LY2510924 blunted the effects of osteoblasts in response to ISO on EMT and migration as well as invasion of PC-3 and DU145 cells. Conclusions These findings demonstrated that β2AR-HIF-1α-CXCL12 signaling in osteoblasts facilitates migration and invasion as well as EMT of prostate cancer cells, and may play a potential role in affecting bone metastasis of prostate cancer.

scholarly journals Inhibition of glypican-1 expression induces an activated fibroblast phenotype in a human bone marrow-derived stromal cell-line

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sukhneeraj P. Kaur ◽  
Arti Verma ◽  
Hee. K. Lee ◽  
Lillie M. Barnett ◽  
Payaningal R. Somanath ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Stromal Cell ◽  
Prostate Cancer Cell ◽  
Bone Cells ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Prostate Cancer Cells

AbstractCancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in the tumor microenvironment. CAFs orchestrate tumor-stromal interactions, and contribute to cancer cell growth, metastasis, extracellular matrix (ECM) remodeling, angiogenesis, immunomodulation, and chemoresistance. However, CAFs have not been successfully targeted for the treatment of cancer. The current study elucidates the significance of glypican-1 (GPC-1), a heparan sulfate proteoglycan, in regulating the activation of human bone marrow-derived stromal cells (BSCs) of fibroblast lineage (HS-5). GPC-1 inhibition changed HS-5 cellular and nuclear morphology, and increased cell migration and contractility. GPC-1 inhibition also increased pro-inflammatory signaling and CAF marker expression. GPC-1 induced an activated fibroblast phenotype when HS-5 cells were exposed to prostate cancer cell conditioned media (CCM). Further, treatment of human bone-derived prostate cancer cells (PC-3) with CCM from HS-5 cells exhibiting GPC-1 loss increased prostate cancer cell aggressiveness. Finally, GPC-1 was expressed in mouse tibia bone cells and present during bone loss induced by mouse prostate cancer cells in a murine prostate cancer bone model. These data demonstrate that GPC-1 partially regulates the intrinsic and extrinsic phenotype of human BSCs and transformation into activated fibroblasts, identify novel functions of GPC-1, and suggest that GPC-1 expression in BSCs exerts inhibitory paracrine effects on the prostate cancer cells. This supports the hypothesis that GPC-1 may be a novel pharmacological target for developing anti-CAF therapeutics to control cancer.

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