Preclinical evaluation of a small molecule inhibitor of the IGF-1/insulin receptor kinases in prostate cancer
Authors: Ricardo Attar, Joan Carboni, Janet Dell-John, Ann Greer, Donald Hawken, Warren Hurlburt, Maria Jure-Kunkel, Frank Lee, Liang Schweizer, Marco Gottardis, Becky Penhallow, Cheryl Rizzo, Thomas Spires, Mark Wittman
Journal: Cancer Research (2007)

4471   Prostate cancer is the second leading cause of cancer related death in men in the United States. The androgen receptor (AR) is a transcription factor whose activity is essential for the development and maintenance of the prostate gland. Upon the binding of testosterone or dihydrotestosterone (DHT), the AR regulates the expression of genes involved in proliferation, survival, and differentiation. Based on this, the most common treatment for tumors that recur to the first line treatment, that is, surgical resection or radiotherapy is androgen ablation. In most cases, the disease eventually becomes hormone independent. However these tumors are still AR dependent, the AR is overexpressed and is activated in an androgen independent manner in advanced hormone refractory prostate cancer. One of the proposed mechanisms for the disease progression is the cross talk between the AR and the insulin and insulin-like growth factor (IGF) axis. For example, it has been reported an association between elevated levels of plasma IGF-I and reduced levels of the main serum binding protein, IGF-BP3, with an increased risk of prostate cancer [1]. In addition, several studies have shown that the inhibition of the IGF-1 axis, for example by the use of IGF-IR antisense oligonucleotides, also inhibits the growth and the migration of a human prostate cancer cell line in vitro [2]. Furthermore, multiple laboratories have investigated the functional link between the AR and the PI3K/Akt signaling pathways, particularly in terms of the phosphorylation of the AR. In this study we will describe the effects of BMS-536924, a small molecule inhibitor equipotent for both the type I insulin-like growth factor (IGF1-R), and the insulin (IR) receptor tyrosine kinases (70 and 80 nM respectively), on the IGF-1 and insulin pathways in a panel of prostate cell lines (22rv1, PC3, LNCaP, and MDA PCa 2b).. BMS-536924 inhibits the in vitro proliferation of these cells lines with IC 50  ranging between 0.51 - 1.12 μM. It was also efficacious in preventing the growth of MDA PCa 2b and LuCaP 35 in xenograft models. Surprisingly BMS-536924 induced the expression of the endogenous PSA gene in the presence of DHT in LNCaP cells (androgen dependent) and by itself in 22rv1 and MDA PCa 2b (androgen independent). Moreover, in the presence of BMS-536924 and DHT there was an increase in the phosphorylation of the Ser 213 of the AR and in its recruitment to both the endogenous PSA promoter and enhancer. The possible mechanism of action and the interpretation of these results will be discussed.  1. Djavan, B., et al.,  Insulin-like growth factors and prostate cancer.  World J Urol, 2001.  19 (4): p. 225-33.  2. Grzmil, M., et al.,  Blockade of the type I IGF receptor expression in human prostate cancer cells inhibits proliferation and invasion, up-regulates IGF binding protein-3, and suppresses MMP-2 expression.  J Pathol, 2004.  202 (1): p. 50-9.