Abstract
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-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. 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 significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.
Highlights
Prostate cancer (PCa) is one of the most common malignancies among men world-wide
To evaluate the fraction of patients who may benefit from receiving anti-insulin-like growth factors (IGFs)-1R therapy in combination with androgen deprivation therapy (ADT), or at later stages in combination with therapies given for castration-resistant prostate cancer (CRPCa), a series of bone metastasis biopsies from treatment-naïve (n = 14) and castration-resistant (n = 47) patients were evaluated for IGF-1R immunoreactivity
To confirm that the insulin-like growth factor 1 (IGF-1) induced increase in viability could be blocked by the IGF-1R inhibitor NVP-AEW541, cells were stimulated with DHT and 100 ng/ml IGF-1 in the presence of various concentrations of NVP-AEW541
Summary
Prostate cancer (PCa) is one of the most common malignancies among men world-wide It shows a wide clinical diversity, ranging from slow tumor growth and very low risk of dying from the disease to a highly progressive fatal disease that frequently metastasize to the skeleton [1]. In a mouse model of breast cancer, local bone resorption was shown to stimulate bone metastasis to that site, while disruption of IGF-1R signaling completely abolished this effect [4]. The IGF-1R has been considered a possible therapeutic target in cancer for a long time and many clinical trials have started, and are still ongoing, were IGF-1R signaling is disrupted, either by monoclonal antibodies or by small tyrosine kinase inhibitors given as single agents or in combinations with conventional cancer therapies The possibility of giving anti-IGF-1R therapy in combination with standard therapies for advanced disease, raises the question if acute therapeutic effects could be potentiated by providing IGF-1R inhibition to selected patients during a limited time-period and, without the risk of introducing adverse effects by long-term IGF-1R inhibition
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