Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5 cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow. Here we describe the development of a synergistic combination treatment strategy that may be applicable in both soft tissue sarcomas as well as sarcomas of bone that takes advantage of targeting the cell cycle. We show that Rb-positive cell lines treated with the CDK4/6 inhibitor palbociclib reversibly arrest in the G1 phase of the cell cycle, and upon drug removal cells progress through the cell cycle as expected within 6–24 hours. Using a long-term high-throughput assay that allows us to examine drugs in different sequences or concurrently, we found that palbociclib-induced cell-cycle arrest poises Rb-positive sarcoma cells (SK-LMS1 and HT-1080) to be more sensitive to agents that work preferentially in S–G2 phase such as doxorubicin and Wee1 kinase inhibitors (AZD1775). The synergy between palbociclib and AZD1775 was also validated in vivo using SK-LMS1 xenografts as well as Rb-positive patient-derived xenografts (PDX) developed from leiomyosarcoma patients. This work provides the necessary preclinical data in support of a clinical trial utilizing this treatment strategy. Mol Cancer Ther; 16(9); 1751–64. ©2017 AACR .

中文翻译：

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CDK4 / 6抑制剂通过可逆的细胞周期逮捕使Rb阳性肉瘤细胞对Wee1激酶抑制。

对软组织肉瘤生物学的研究发现很少有有效的治疗策略可以改善当前的护理标准，该标准通常涉及手术，放射线和化学疗法。许多大（> 5厘米）高级别肉瘤患者会复发，并且此时可用的治疗选择有限。挑战之一是肉瘤遗传驱动因子的异质性，其中许多未经验证的靶标。即使这些基因是易于治疗的靶标，每种肉瘤亚型的稀有性也使研究进展缓慢。在这里，我们描述了一种协同联合治疗策略的发展，该策略可能适用于软组织肉瘤以及利用靶向细胞周期优势的骨肉瘤。我们显示，用CDK4 / 6抑制剂palbociclib处理的Rb阳性细胞系可逆地停滞在细胞周期的G1期，并且在去除药物后，细胞会如预期的那样在6-24小时内通过整个细胞周期。通过长期的高通量检测，我们可以检查不同序列或同时检测药物，我们发现palbociclib诱导的细胞周期停滞使Rb阳性肉瘤细胞（SK-LMS1和HT-1080）更加敏感适用于优先在S–G2期工作的药物，例如阿霉素和Wee1激酶抑制剂（AZD1775）。还使用SK-LMS1异种移植物以及平滑肌肉瘤患者开发的Rb阳性患者来源异种移植物（PDX）在体内验证了palbociclib和AZD1775之间的协同作用。这项工作提供了必要的临床前数据，以支持利用这种治疗策略的临床试验。分子癌疗法；16（9）; 1751–64。©2017 AACR。