Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-017-9848-8) contains supplementary material, which is available to authorized users.

Role of the runt‐related transcription factor (RUNX) family in prostate cancer

“…Moreover, RUNX2 is upregulated in osteoblasts in response to PCa cells in the bone microenvironment [65]. In PC3 cells, RUNX2 promotes invasion of PCa cells and increases expression of metastatic genes, as previously discussed [19].…”

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

“…As yet, there is no clinical evidence to support the use of IGF-targeted therapies as specific treatments for bone metastasis, and there are differences in IGF production between human and rodent bone cells (70) that may impact clinical relevance. Nevertheless, given the known involvement of the IGF axis in bone metastasis (6,60,61), and initial preclinical data supporting the utility of IGF blockade in this context (23,60,62,64), we suggest that exploration of the potential benefits of IGF inhibition may be warranted in patients with bone metastases, particularly for breast and prostate cancers.…”

“…The IGF axis plays an important role in bone development and remodeling (18), and is implicated in metastasis of primary tumors to bone. Preclinical data demonstrate that inhibition of IGF axis signaling can suppress metastasis and tumor cell proliferation in bone (23,60,62,64). Most evidence related to the value of targeting IGF comes from the models of breast and prostate cancer bone metastases, probably because these cancers are commonly associated with metastatic spread to the bone (5).…”

“…Several preclinical studies have investigated the effects of antibodies or tyrosine kinase inhibitors (TKI) directed at IGF-1R, the results of which suggest that IGF axis inhibition can at least partially prevent the establishment and progression of bone tumors (Table 1). Furthermore, whole-genome expression analysis of bone metastasis biopsies from patients with prostate cancer suggested an inverse relationship between IGF-1R expression and immune cell function, (64) suggesting that IGF-1R inhibition has the potential to stimulate an antitumor response from endogenous immune cells, a concept that is also supported by models of other tumor types (65)(66)(67)(68).…”

Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy

“…IGF-IR phosphorylation is elevated in prostate cancer cells and residual resistant tumors after treatment with abiraterone [114]. Accordingly, IGF-IR inhibition can enhance the efficacy of castration and abiraterone on prostate cancer [114,115].…”