Targeting the" vicious cycle" of cancer-induced bone disease with TRAIL and bisphosphonates

对于患有多种形式实体瘤的患者来说，最严重的临床问题是转移到骨骼，这会导致潜在的衰弱性并发症，从而影响患者的生活质量，最终导致死亡。不幸的是，骨转移通常发生在预防性治疗之前。我们最近的研究表明，重组可溶性TRAIL是一种有效的抗癌剂，通过直接靶向骨内的癌细胞，在小鼠模型中防止癌症引起的骨破坏，并且没有证据表明对正常组织有毒副作用。TRAIL和双膦酸盐通过不同但重叠的信号通路诱导癌细胞凋亡。因此，两种方法的结合可能有助于通过其中一种途径杀死抵抗死亡诱导的肿瘤细胞。联合治疗也可以减少对任何一种治疗产生获得性耐药的可能性。我们提出一种组合方法，使用双膦酸盐选择性靶向破骨细胞和TRAIL选择性靶向癌细胞，将是一种理想的治疗和安全的方法，可以延迟、减缓或完全消除骨内癌症的生长。

The most serious clinical problem with patients with many forms of solid tumours is metastasis to bone, which leads to potentially debilitating complications that can cause erosion of the patient's quality of life, and eventually death. Unfortunately, bony metastases usually occur before pre-emptive treatments can be applied to prevent it. We have recently shown that recombinant soluble TRAIL is a potent anticancer agent that prevents cancer-induced bone destruction in a mouse model by directly targeting cancer cells within bone, and with no evidence of toxic side effects to normal tissues. Death receptor targeting by TRAIL, and bisphosphonates induce cancer cell apoptosis through different but overlapping signaling pathways. Therefore, combination of the two approaches may facilitate killing of tumour cells that resist death induction through either one of the pathways. Combination therapy may also reduce the probability of acquired resistance to either therapy. We propose that a combinatorial approach, using bisphosphonates to selectively target osteoclasts and TRAIL to selectively target cancer cells, would be an ideal therapeutic and safe approach to delay, slow or completely eliminate growth of cancer within bone.