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。 二线激素治疗（如Enzalutamide）仅改善总体患者 大约50%的患者存活了几个月，几乎所有的患者都发展为 耐药性因此，迫切需要确定药物的作用机制。 并开发新的方法来克服这种阻力， 更好的治疗前列腺癌骨转移。 Enzalutamide是一种雄激素受体（AR）的小分子抑制剂。我们 初步研究表明，尽管Enzalutamide抑制了 去势抵抗性前列腺癌C4-2B细胞，当异种原位移植时， 皮下注射时，它对骨中C4-2B肿瘤的生长没有影响， 骨病变的发展。这些数据突出了微环境的关键作用 恩杂鲁胺耐药前列腺癌骨转移。有趣的是，我们发现 Enzalutamide显著特异性降低TGF-β II型受体 成骨细胞中的TGF-β R 2蛋白。这一观察结果也在前列腺中得到证实 接受过二线激素治疗的癌症患者， 恩杂鲁胺。为了确定成骨细胞中TGF β R 2在骨形成过程中的作用， 转移，我们使用了诱导型Tgfbr 2基因敲除的小鼠模型（Tgfbr 2Col 1CreERT KO 特别是在成骨细胞中。我们发现成骨细胞中的Tgfbr 2基因敲除显著地 促进前列腺癌骨转移。基于这些结果，我们假设 恩杂鲁胺引起的成骨细胞中TGFBR 2的减少导致对 前列腺癌骨转移的药物。本提案的目标是 确定Enzalutamide如何降低成骨细胞TGFBR 2，从而促进前列腺 癌症骨转移，并确定新的方法来抵消 恩杂鲁胺耐药。

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.