Dataset Information

Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancer.

ABSTRACT:

Background

Castration 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.

Methods

VCaP-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 (?CT) imaging.

Results

Subcutaneous 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.

Conclusion

Our 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.

SUBMITTER: Eswaraka J

PROVIDER: S-EPMC4190397 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Publications

Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancer.

Eswaraka Jeetendra J Giddabasappa Anand A Han Guangzhou G Lalwani Kush K Eisele Koleen K Feng Zheng Z Affolter Timothy T Christensen James J Li Gang G

BMC cancer 20141002

<h4>Background</h4>Castration 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) ...[more]

PMID: 25277255

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Project description:BACKGROUND:It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone. OBJECTIVE:To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC). DESIGN, SETTING, AND PARTICIPANTS:This open-label, single-centre interventional study was conducted in bmCRPC patients. INTERVENTION:Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and Cmin plasma concentrations were evaluated. RESULTS AND LIMITATIONS:Sixty patients were enrolled. Common AEs independent of grade/causality included fatigue (72%), hyperglycaemia (67%), alkaline phosphatase (ALP) elevation (53%), and hot flush (43%). Grade 3 AEs included hypertension (17%), alanine aminotransferase elevation (12%), ALP elevation (5%), and arthralgia (5%). No treatment-related grade 4 AEs or deaths were reported. Median treatment-discontinuation time was 312d (95% confidence interval [CI] 196.0-483.0). Maximal PSA decline ?50% and ?90% occurred in 46 (77%) and 29 (48%) patients, respectively. Median PFS was 251d (95% CI 147-337). At week 9, median tumour microenvironment androgens, precursors, and nuclear AR expression decreased (p<0.001). The baseline tumour AR C/N terminal ratio of ?80% was associated with treatment benefit. At enzalutamide steady state, abiraterone acetate Cmin was ?23% lower (range 14.05-200.5ng/ml) than when given alone. CONCLUSIONS:Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC. PATIENT SUMMARY:This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.

Project description:BackgroundProstate cancer is poorly responsive to immune checkpoint inhibition, yet a combination with radiotherapy may enhance the immune response. In this study, we combined radiotherapy with immune checkpoint inhibition (iRT) in a castration-resistant prostate cancer (CRPC) preclinical model.MethodsTwo Myc-CaP tumor grafts were established in each castrated FVB mouse. Anti-PD-1 or anti-PD-L1 antibodies were given and one graft was irradiated 20 Gy in 2 fractions.ResultsIn CRPC, a significant increase in survival was found for radiation treatment combined with either anti-PD-1 or anti-PD-L1 compared to monotherapy. The median survival for anti-PD-L1 alone was 13 days compared to 30 days for iRT (p = 0.0003), and for anti-PD-1 alone was 21 days compared to 36 days for iRT (p = 0.0009). Additional treatment with anti-CD8 antibody blocked the survival effect. An abscopal treatment effect was observed for iRT in which the unirradiated graft responded similarly to the irradiated graft in the same mouse. At 21 days, the mean graft volume for anti-PD-1 alone was 2094 mm3 compared to iRT irradiated grafts 726 mm3 (p = 0.04) and unirradiated grafts 343 mm3 (p = 0.0066). At 17 days, the mean graft volume for anti-PD-L1 alone was 1754 mm3 compared to iRT irradiated grafts 284 mm3 (p = 0.04) and unirradiated grafts 556 mm3 (p = 0.21). Flow cytometry and immunohistochemistry identified CD8+ immune cell populations altered by combination treatment in grafts harvested at the peak effect of immunotherapy, 2-3 weeks after starting treatment.ConclusionsThese data provide preclinical evidence for the use of iRT targeting PD-1 and PD-L1 in the treatment of CRPC. Immune checkpoint inhibition combined with radiotherapy treats CPRC with significant increases in median survival compared to drug alone: 70% longer for anti-PD-1 and 130% for anti-PD-L1, and with an abscopal treatment effect.PrecisCastration-resistant prostate cancer in a wild-type mouse model is successfully treated by X-ray radiotherapy combined with PD-1 or PD-L1 immune checkpoint inhibition, demonstrating significantly increased median overall survival and robust local and abscopal treatment responses, in part mediated by CD8 T-cells.

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Dataset Information

Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancer.

Background

Methods

Results

Conclusion

Publications

Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancer.

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