Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone
(English)Manuscript (preprint) (Other academic)
Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1R inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In co-culture with mouse calvarial explants, tumor cells induced a sclerotic bone response, as determined from gene expression profiles and release of bone formation/resorption markers. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was induced 2.7-fold outside, but unaffected inside, the tibial bone when castration and NVP-AEW541 were combined. Proliferation was significantly reduced by both therapies, independent of growth site, with the maximum decrease (24%) observed after combined treatment. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases, and positive staining was observed in most patients (74%, n=61). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, although diverse responses could be anticipated depending on metastasis site.
Cancer and Oncology
Research subject Oncology
IdentifiersURN: urn:nbn:se:umu:diva-131804OAI: oai:DiVA.org:umu-131804DiVA: diva2:1076166