Efficacy of targeted therapy in patients with renal cell carcinoma with pre-existing or new bone metastases

Żołnierek, Jakub; Nurzyński, Paweł; Langiewicz, Przemysław; Oborska, Sylwia; Waśko-Grabowska, Anna; Kuszatal, Ewa; Obrocka, Beata; Szczylik, Cezary

doi:10.1007/s00432-009-0664-7

Cited by 29 publications

(15 citation statements)

References 26 publications

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“…One retrospective study suggested that targeted agents appeared slightly more effective than cytokine therapy at extending mean time to progression of pre-existing bone lesions [23]. On the other hand, in prospective clinical trials, interestingly, the efficacy of targeted agents was apparently not affected by prior cytokine treatment.…”

Section: Discussionmentioning

confidence: 97%

Treatment outcome and prognostic factors in renal cell cancer patients with bone metastasis

Yuasa

Urakami

Yamamoto

et al. 2011

Clin Exp Metastasis

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We retrospectively analyzed treatment outcomes and factors for poor prognosis for patients with renal cell cancer (RCC) bone metastases. Patients with bone metastases at initial diagnosis of metastasis secondary from RCC, treated at our hospital between 1984 and 2009, were retrospectively reviewed and statistically analyzed. Among 214 RCC patients with metastasis, 71 patients (33%) were found to have bone metastases at initial diagnosis of metastasis. The median follow-up was 21.1 months (intra-quartile range: IQR, 9.1-47.4 months). The estimated median overall survival time from the diagnosis of bone metastasis was 27.7 months. The probability of patients surviving at 1, 2, and 5 years was 63.7, 52.2, and 19.3%, respectively. When they were stratified by MSKCC scores, the probability of the median overall survival of the populations classified as favorable, intermediate, and poor was not reached, 32.9, and 10.5 months, respectively (P = 0.002). In addition, poor performance status (PS) (hazard ratio [HR]: 1.938, P = 0.035) and no prior nephrectomy (HR: 3.008, P = 0.004) were extracted as independent poor prognostic factors by multivariate analysis. All treatment modalities-including radical en bloc surgery, radiation therapy, cytokine therapy, molecular targeted therapy, and administration of zoledronic acid-seemed to contribute to favorable survival. More than half of the patients with bone metastases secondary from RCC were predicted to survive more than 24 months. In this population, MSKCC scores were valid predictors of survival. With increased treatment options, RCC patients with bone metastasis may benefit further from subsequent modalities and/or agents.

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Section: Discussionmentioning

confidence: 97%

Treatment outcome and prognostic factors in renal cell cancer patients with bone metastasis

Yuasa

Urakami

Yamamoto

et al. 2011

Clin Exp Metastasis

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“…The bone marrow microenvironment possesses extensive hypoxic regions [42, 43] that are characterized by abundant HIF-1α staining and HIF target proteins including MCT4 and Glut1 [44]. It’s notable that the hypoxic microenvironment of the bone marrow is conductive to subsequent bone colonization of cancer cells, and therapies targeting HIF/HIF targets has potential value in the prevention of bone colonization [60–62]. Furthermore, accumulating studies revealed that miRNAs are emerging as a novel class targets of hypoxia-responsive molecules [63, 64].…”

Section: Discussionmentioning

confidence: 99%

Oncogenic miR-210-3p promotes prostate cancer cell EMT and bone metastasis via NF-κB signaling pathway

et al. 2017

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BackgroundThe primary issue arising from prostate cancer (PCa) is its high prevalence to metastasize to bone, which severely affects the quality of life and survival time of PCa patients. miR-210-3p is a well-documented oncogenic miRNA implicated in various aspects of cancer development, progression and metastasis. However, the clinical significance and biological roles of miR-210-3p in PCa bone metastasis remain obscure.MethodsmiR-210-3p expression was evaluated by real-time PCR in 68 bone metastatic and 81 non-bone metastatic PCa tissues. The biological roles of miR-210-3p in the bone metastasis of PCa were investigated both in vitro by EMT and Transwell assays, and in vivo using a mouse model of left cardiac ventricle inoculation. Bioinformatics analysis, real-time PCR, western blot and luciferase reporter analysis were applied to discern and examine the relationship between miR-210-3p and its potential targets. RT-PCR was performed to identify the underlying mechanism of miR-210-3p overexpression in bone metastasis of PCa. Clinical correlation of miR-210-3p with its targets was examined in human PCa and metastatic bone tissues.ResultsmiR-210-3p expression is elevated in bone metastatic PCa tissues compared with non-bone metastatic PCa tissues. Overexpression of miR-210-3p positively correlates with serum PSA levels, Gleason grade and bone metastasis status in PCa patients. Upregulating miR-210-3p enhances, while silencing miR-210-3p represses the EMT, invasion and migration of PCa cells in vitro. Importantly, silencing miR-210-3p significantly inhibits bone metastasis of PC-3 cells in vivo. Our results further demonstrate that miR-210-3p maintains the sustained activation of NF-κB signaling via targeting negative regulators of NF-κB signaling (TNF-α Induced Protein 3 Interacting Protein 1) TNIP1 and (Suppressor Of Cytokine Signaling 1) SOCS1, resulting in EMT, invasion, migration and bone metastasis of PCa cells. Moreover, our results further indicate that recurrent gains (amplification) contribute to miR-210-3p overexpression in a small number of PCa patients. The clinical correlation of miR-210-3p with SOCS1, TNIP1 and NF-κB signaling activity is verified in PCa tissues.ConclusionOur findings unravel a novel mechanism for constitutive activation of NF-κB signaling pathway in the bone metastasis of PCa, supporting a functional and clinical significance of epigenetic events in bone metastasis of PCa.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0688-6) contains supplementary material, which is available to authorized users.

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“…Sunitinib, a small molecule inhibitor targeting VEGF receptor (VEGFR) and platelet-derived growth factor receptor β (PDGFRβ), is more effective than interferon-α or sorafenib, a chemical kinase inhibitor that targets VEGFR and PDGFRβ, at blocking the formation and time to occurrence of osteolytic lesions in bone metastatic renal cell carcinoma (RCC) patients (Zolnierek et al, 2010), likely due to the high extent of vascularization observed in RCC bone metastases. A retrospective study reported that the RCC patient long-term responders to sunitinib had lower odds of having a bone metastasis (Molina et al, 2013), and thus these patients already had a better prognosis and less aggressive disease.…”

Section: Therapeutic Potential Of Hif Targets In Bone Metastasismentioning

confidence: 99%

HIF targets in bone remodeling and metastatic disease

Johnson

Schipani

Giaccia

2015

Pharmacology & Therapeutics

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The bone marrow isa hypoxic microenvironment that is rich in growth factors and blood vessels and is readily colonized by tumor cells disseminated from numerous cancers including tumors of the breast, prostate, lung, and skin. The origin of metastatic growth promoting factors for tumor cells disseminated to the bone marrow is derived from multiple sources: the bone matrix, which is a reservoir for growth factors, and cells residing in the marrow and along bone surfaces, such as osteoblasts, osteoclasts, macrophages, and T cells, which secrete cytokines and chemokines. Low oxygen levels within the bone marrow induce hypoxia signaling pathways such as hypoxia inducible factor (HIF), which is regulated by oxygen requiring prolyl hydroxylases (PHDs) and von Hippel–Lindau (VHL) tumor suppressor. These hypoxia signaling pathways have profound effects on bone development and homeostasis. Likewise, hypoxic conditions observed in local breast and prostate tumors point to a role for hypoxia-inducible genes in metastasis to and colonization of the bone marrow. This review will explore the role of hypoxia-regulated factors in bone development and remodeling, and how these elements may contribute to solid tumor metastasis to the bone.

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Efficacy of targeted therapy in patients with renal cell carcinoma with pre-existing or new bone metastases

Abstract: Further evaluation of the effect of these therapies on bone metastases in RCC is warranted.

Cited by 29 publications

References 26 publications

Treatment outcome and prognostic factors in renal cell cancer patients with bone metastasis

Treatment outcome and prognostic factors in renal cell cancer patients with bone metastasis

Oncogenic miR-210-3p promotes prostate cancer cell EMT and bone metastasis via NF-κB signaling pathway

HIF targets in bone remodeling and metastatic disease

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