Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancerReportar como inadecuado




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BMC Cancer

, 14:742

Experimental therapeutics and drug development

Abstract

BackgroundCastration resistant prostate cancer CRPC is a leading cause of cancer-related deaths in men. The primary cause of mortality and morbidity in patients is bone metastases and remodeling resulting in osteoblastic and osteolytic lesions. Recently, cabozantinib, a multi-kinase inhibitor VEGFR2 and c-MET inhibitor, was shown to have efficacy on bone lesions in patients. In this study we tested multi-kinase inhibitors: axitinib VEGFR inhibitor and crizotinib c-MET inhibitor in a combination trial in mice models.

MethodsVCaP-Luc cells were grown as subcutaneous implants in intact and castrated NOD-SCID-gamma NSG mice to confirm the androgen dependency. For bone metastasis model two cohorts of NSG mice castrated and intact received orthotopic injection of VCaP-Luc cells into the bone marrow cavity of left tibia. Mice were monitored weekly for tumor growth using bioluminescence imaging. Animals were randomized into 4 groups based on the tumor bioluminescence signal: vehicle, crizotinib alone, axitinib alone, crizotinib and axitinib in combination. Animals were imaged weekly by in vivo 2-D X-ray imaging to monitor bone remodeling. At the end of the study animals were euthanized and both tibias were extracted for ex vivo high-resolution 3-D micro-computed tomography μCT imaging.

ResultsSubcutaneous model showed that androgen stimulation may be helpful but not essential for the growth of VCaP-Luc cells. VCaP-Luc cells grown intra-tibially in intact animals caused extensive remodeling of bone with mixed osteoblastic bone formation and osteolytic bone matrix dissolution lesions. The osteoblastic lesions were predominant and at times extended beyond the tibial shaft into the surrounding tissue. In contrast, only osteolytic lesions were prominent throughout the study in castrated animals. Treatment with crizotinib alone reduced the osteolytic lesions in castrated animals. Axitinib alone reduced the osteoblastic lesions in the intact animals. Combination therapy with axitinib and crizotinib remarkably inhibited the tibial remodeling by VCaP-Luc cells which resulted in a significant reduction of both osteoblastic and osteolytic lesions.

ConclusionOur data show that combined inhibition of c-MET and VEGFR can be beneficial for treatment of metastatic bone disease in CRPC and that the drugs act on two different stages of the disease.

KeywordsCRPC Bone metastasis μCT imaging X-ray BLI Axitinib VEGFR crizotinib c-MET AbbreviationsADTAndrogen deprivation therapy

BLIBioluminescence

BVBone volume

CRPCCastration resistant prostate cancer

μCTMicro-computed tomography

NBFNormal buffered formalin

PCProstate cancer

TVTrabecular volume

SOCStandard of care.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-742 contains supplementary material, which is available to authorized users.

Jeetendra Eswaraka, Anand Giddabasappa and Gang Li contributed equally to this work.

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Autor: Jeetendra Eswaraka - Anand Giddabasappa - Guangzhou Han - Kush Lalwani - Koleen Eisele - Zheng Feng - Timothy Affolter - Ja

Fuente: https://link.springer.com/







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