Mini-reviewThe insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer
Introduction
Prostate cancer (PCa) is the most common male cancer and the third cause of cancer death among men in European countries [1]. PCa is a heterogeneous disease, ranging from slow-growing indolent tumors to rapidly progressing and highly aggressive carcinomas associated with significant morbidity and mortality. Targeting the androgen receptor (AR) signaling pathway is the current standard treatment for hormone-naïve PCa. After two to three years, however, AR signaling is reactivated leading to castration resistant PCa (CRPC) [2], [3]. Until two years ago, chemotherapy with docetaxel was the standard treatment for this stage of disease. However, next-generation AR targeting agents such as abiraterone acetate or enzalutamide have been developed and are now routinely used in the clinical setting [4], [5], [6]. In addition carbazitaxel, a next-generation taxane, has been approved for CRPC after docetaxel relapse [7]. In 2013 the U.S. Food and Drug Administration (FDA) approved radium-223 chloride (radium-223) for the treatment of metastatic CRPC in patients whose metastases are limited to the bones [8]. Table 1 provides an overview of drugs currently approved for treatment of CRPC [4], [7], [8], [9], [10], [11], [12], [13].
Despite this progress in therapy, not all patients respond to current therapies and in the majority of cases development of therapy resistance is inevitable. There remains therefore a need for new agents selectively targeting anti-cancer pathways. Several new drugs are currently in advanced phases of clinical testing and it is hoped that some may be added to the therapeutic armamentarium in the near future. The insulin-like growth factor (IGF) axis is one of the most investigated targets in cancer and mediates critical physiological processes, including cellular growth, cell differentiation, apoptosis, development as well as glucose and lipid metabolism [14], [15], [16], [17], [18]. Moreover, the IGF axis plays a fundamental role in regulating embryonic growth [19]. IGFs also exert growth stimulating and pro-survival effects on tumor cells and have been shown to mediate carcinogenesis, angiogenesis, malignant cell proliferation and metastatic growth of a variety of tumors [20], [21], [22].
To date, more than 100 agents have been developed that target the receptors of the IGF axis and many are currently being evaluated in preclinical and clinical studies. The present review provides an overview of IGF targeting agents, their mechanisms of action, advantages and disadvantages as well as the current status of their application in the clinical setting of PCa.
Section snippets
Insulin-like growth factor (IGF) axis
The IGF axis is a multicomponent network composed of three ligands, IGF1, IGF2 and insulin, and the receptors IGF1 receptor (IGF1R), IGF2 receptor (IGF2R) and insulin receptor (INSR) [23], [24] (Fig. 1). The biological functions of IGF1 and IGF2 are predominantly mediated by IGF1R, a tyrosine kinase transmembrane receptor that binds IGF1 with higher affinity than IGF2. The IGF2R is a mannose 6-phosphate receptor implicated in targeting lysosomal enzymes. It binds IGF2 with higher affinity than
Preclinical studies demonstrating the role of the IGF axis in prostate cancer
Preclinical studies have demonstrated that the IGF axis modulates the development and progression of PCa. IGF1 signaling is elevated in PCa compared to benign prostate tissue and plays a role in tumor progression [36], [37], [38], [39]. In addition, IGF receptors have been shown to be overexpressed in several cancer entities, including PCa [40], [41], [42], [43], [44]. Data obtained from mouse cells with a disrupted IGF1R gene suggest that this receptor is a prerequisite for cells to undergo
Interaction of the IGF axis with the AR pathway
The AR is a key promoter of PCa growth, tumor progression, therapy and drug resistance. In former studies the AR has been shown to upregulate IGF1R expression via an active AR binding site in the IGF1R gene promoter [96]. Pandini et al. reported that androgens induce a selective up-regulation of IGF1R in PCa cells thereby increasing cell proliferation and invasiveness in response to IGF1 [97]. Moreover, re-expression of wild-type but not mutant AR in an AR-negative PCa cell line significantly
IGF axis components as prostate cancer biomarkers
In the past years a large number of population-based studies have been performed to investigate the suitability of IGF axis components as biomarkers in PCa detection, monitoring and selection of therapy. The conflicting results of these studies are still a matter of debate and are summarized below.
Conclusion
The first results from clinical trials of IGF-based therapies for PCa have been disappointing in comparison to the high promise these agents demonstrated in pre-clinical studies. However, the final results of many of these clinical studies encompassing quite different clinico-pathological settings are yet to be published. A comprehensive understanding of the function of the IGF axis as a whole, as well as redundant and non-redundant functions of IGF and INSR receptors, is mandatory to
Funding
COMET Center Oncotyrol (Project 2.1.4), the Autonomous Province of Bolzano – South Tyrol (Grant 37/40.3), the Austrian Cancer Foundation Tyrol, and the Austrian Science Fund (FWF, V216-B13 and W1101).
Conflict of interest
All authors have no conflict of interest to declare.
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