Influence of bone microenvironment on drug resistance in prostate cancer bone metastasis

在美国，超过80%的前列腺癌患者死于骨转移。 二线激素疗法，如苯扎鲁胺，只会改善整体患者 大约50%的患者存活几个月，而且几乎所有的患者都出现 抗药性。因此，迫切需要确定药物的作用机制。 并制定新的方法来克服这种阻力和 更好地治疗前列腺癌骨转移。 苯扎鲁胺是雄激素受体(AR)的小分子抑制剂。我们的 初步研究表明，尽管苯扎鲁胺对小鼠肿瘤生长有抑制作用 抗去势前列腺癌C4-2B细胞异种原位移植或 皮下注射对C4-2B肿瘤生长无明显影响。 骨损伤的发展。这一数据突出了微环境的关键作用 在前列腺癌骨转移中对苯扎鲁胺耐药。有趣的是，我们发现 苯扎鲁胺显著且特异地降低转化生长因子-βII型受体 成骨细胞中的(TGFBR2)蛋白。这一观察结果在前列腺中也得到了证实。 接受过二线激素治疗的癌症患者，如 苯扎鲁胺。TGFBR2在成骨细胞成骨过程中的作用 转移，我们使用了一种小鼠模型(Tgfbr2Col1CreERT KO)，该模型具有诱导的TGFBR2基因敲除 尤其是在成骨细胞中。我们发现TGFBR2 KO在成骨细胞中显著 促进前列腺癌骨转移。基于这些结果，我们假设 苯扎鲁胺导致成骨细胞中TGFBR2的减少导致对 该药用于前列腺癌的骨转移。这项建议的目标是 确定苯扎鲁胺如何降低成骨细胞TGFBR2，从而促进前列腺 癌症骨转移，并找出新的方法来对抗 对苯扎鲁胺耐药。

In the United States, over 80% of prostate cancer patients die with bone metastases. Second line hormonal therapies such as enzalutamide only improve overall patient survival by a few months in about 50% of the patients, and almost all patients develop drug resistance. Thus, there is an urgent need to determine the mechanisms of drug resistance and to develop new approaches for overcoming such resistance and for better treatment of prostate cancer bone metastasis. Enzalutamide is a small-molecule inhibitor of the androgen receptor (AR). Our preliminary study demonstrated that although enzalutamide inhibited the tumor growth of castration-resistant prostate cancer C4-2B cells when xenografted orthotopically or subcutaneously, it had no effect on the growth of C4-2B tumors in the bone and the development of bone lesions. This data highlights a crucial role of the microenvironment in enzalutamide resistance in prostate cancer bone metastasis. Interestingly, we found that enzalutamide significantly and specifically reduced the TGF-β type II receptor (TGFBR2) protein in osteoblasts. This observation was also confirmed in prostate cancer patients who had undergone the second line hormonal therapies such as enzalutamide. To determine the role of TGFBR2 in the osteoblasts during bone metastasis, we used a mouse model (Tgfbr2Col1CreERT KO) with inducible Tgfbr2 knockout specifically in the osteoblasts. We found that Tgfbr2 KO in osteoblasts significantly promoted prostate cancer bone metastasis. Based on these results, we hypothesize that reduction of TGFBR2 in osteoblasts caused by enzalutamide results in resistance to the drug in prostate cancer bone metastasis. The objectives of this proposal are to determine how enzalutamide decreases osteoblast TGFBR2 and thus promotes prostate cancer bone metastasis and to identify novel approaches to counteracting the enzalutamide resistance.