Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

Koreckij, Theodore D.; Nguyen, Holly M.; Brown, Lisha G.; Yu, Evan Y.; Vessella, Robert L.; Corey, Eva

doi:10.1038/sj.bjc.6605178

Cited by 86 publications

(55 citation statements)

References 29 publications

(33 reference statements)

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“…Separate studies showed that dasatinib treatment reduced lymph node metastasis and also resulted in normalization of bone density in an i.t. bone lysis model (43,44). The agreement among these studies and the results reported here that different classes of Src inhibitors result in antitumor activity in a prostate tumor model setting provides a strong rationale for using Src inhibitors in a prostate cancer patients.…”

Section: Discussionsupporting

confidence: 76%

SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis

Rabbani

Valentino²,

Arakelian³

et al. 2010

Molecular Cancer Therapeutics

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In the current study, we have examined the efficacy of a Src/Abl kinase inhibitor SKI-606 (Bosutinib) for its effect on prostate cancer growth and skeletal metastasis. Treatment of highly invasive human prostate cancer cells PC-3 and DU-145 with different doses of SKI-606 decreased Src activation, cell proliferation, migration, and invasion as determined by Matrigel Boyden chamber invasion assay. For in vivo studies, PC-3 cells were inoculated through s.c. or i.t. route into male BALB/c nu/nu or Fox Chase severe combined immunodeficient mice, respectively. Experimental animals treated with SKI-606 developed tumors of a significantly smaller volume and a significant decrease (50%) in experimental skeletal lesion area. A marked increase (32%) in bone volume to tumor volume ratio was also seen by micro-computed tomography analysis of tibias from control and experimental groups of animals. Western blot analysis showed the ability of SKI-606 to significantly decrease the phosphorylation of signaling molecules (AKT, mitogen-activated protein kinase, focal adhesion kinase) and the expression of tumor progression-associated genes uPAR, MMP-2, MMP-9, N-cadherin, fibronectin, BMP-2 (bone morphogenetic protein 2), BMP-6 (bone morphogenetic protein 6), IL-8 (interleukin 8), and TGF-β (transforming growth factor β) in prostate cancer cells. SKI-606 is currently in clinical trials for breast cancer and chronic myelogenous leukemia. Results from these studies provide convincing evidence for evaluating its efficacy in prostate cancer patients. Mol Cancer Ther; 9(5); 1147-57.

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Section: Discussionsupporting

confidence: 76%

SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis

Rabbani

Valentino²,

Arakelian³

et al. 2010

Molecular Cancer Therapeutics

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“…The latter effect may be related to the bone-protecting characteristic of dasatinib. In fact, in prostate cancer, tumored tibiae show a decrease in bone mineral density and trabecular bone volume (49,50), which can be counteracted by dasatinib (51).…”

Section: Dasatinib Combinations In Solid Tumorsmentioning

confidence: 99%

Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors

Montero

Seoane²,

Ocaña³

et al. 2011

Clinical Cancer Research

248

195

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Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) a and b, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor-positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale. Clin Cancer Res; 17(17); 5546-52. Ó2011 AACR.

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“…There were no significant adverse effects. Dasatinib alone and in combination therapy with docetaxel improved bone mineral density in the LNCaP C4-2B tumor-implanted tibias (43).…”

Section: Discussionmentioning

confidence: 99%

Effect of the Specific Src Family Kinase Inhibitor Saracatinib on Osteolytic Lesions Using the PC-3 Bone Model

Yang

Bai

Yap

et al. 2010

Molecular Cancer Therapeutics

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The hematogenous metastatic spread of prostate cancer is preferentially to bone and can result in significant patient morbidity. Although these metastatic lesions are typically osteoblastic, bone resorption is believed to have a prerequisite role in their development. Src kinase has been identified to contribute to prostate cancer tumor growth and metastasis. In addition, Src is also essential in bone metabolism, especially in bone resorption. We hypothesized that inhibiting Src activity with the specific Src family kinase inhibitor saracatinib (AZD0530) would inhibit tumor cell growth and osteoclast differentiation in the tumor-bone interface, thus providing a new approach for advanced prostate cancer. We found that saracatinib inhibited PC-3 cell growth and invasion in a dose-dependent manner. Phosphorylation of Src, focal adhesion kinase, and P38 kinases was inhibited by saracatinib at the submicromolar range. Saracatinib also inhibited the expression and secretion of invasion-related molecules interlukin-8, urokinase-type plasminogen activator, and matrix metalloprotease-9. Receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and signaling were inhibited by saracatinib in both macrophages and PC-3 cells. In in vivo studies, control mice developed more severe osteolytic lesions compared with the treatment group. Immunohistochemical and biochemical assays of bone metabolites confirmed that saracatinib preserved bone architecture in the presence of prostate cancer tumor cells. In summary, we have shown the inhibition of PC3 cell growth and invasion by saracatinib. Src inhibition also blocked the RANKL stimulatory pathway in osteoclasts and PC3 cells. The inhibition of Src thus targets multiple sites involved in prostate cancer bone metastasis, which may offer a therapeutic advantage in treating advanced prostate cancer. Mol Cancer Ther; 9(6); 1629-37. ©2010 AACR.

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Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

Cited by 86 publications

References 29 publications

SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis

SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis

Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors

Effect of the Specific Src Family Kinase Inhibitor Saracatinib on Osteolytic Lesions Using the PC-3 Bone Model

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