Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors that progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long-term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432–41. ©2017 AACR.

中文翻译：

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mTOR 激酶抑制有效地降低了在 rapalog 治疗中进展并延迟心脏损伤的神经内分泌肿瘤亚组的进展

使用 rapalog 依维莫司抑制 mTOR 信号传导是 FDA 批准的针对肺和胃肠胰腺神经内分泌肿瘤 (NET) 患者的靶向疗法。然而，患者最终会在治疗上取得进展，这突显了对额外治疗的需求。我们专注于胰腺 NETs (pNET) 并推断这些肿瘤在 rapalog 治疗进展时使用 mTOR 激酶抑制剂 (mTORKi)，例如 CC-223，可以克服肿瘤中的许多耐药机制并延迟心​​脏类癌. 我们在体外使用人类 pNET 细胞进行了临床前研究，并将它们皮下或原位注射，以确定单独用雷帕霉素治疗或在进展时改用 CC-223 治疗的小鼠的肿瘤进展和心脏功能。对 mTOR 治疗敏感或进展的肿瘤进行了详细的信号传导和 RNA 测序分析。在接受 rapalog 治疗后进展的 pNET 肿瘤小鼠中，大约 57% 的小鼠在切换到 CC-223 后显示肿瘤体积显着减少。此外，与仅用安慰剂或雷帕霉素治疗的小鼠相比，用 mTORKi 治疗的小鼠心脏扩张和心脏瓣膜增厚减少。总之，在大多数在 rapalogs 上取得进展的 pNET 中，使用 mTORKi（例如 CC-223）可以减少疾病进展。此外，与安慰剂或rapalog 治疗的小鼠相比，CC-223 对瓣膜纤维化具有额外的瞬时心脏益处。这些结果为在 rapalog 治疗进展后在临床上进一步开发 mTORKi 并进一步测试它们在那些易患类癌综合征的 NET 患者中的长期心脏保护作用提供了临床前基本原理。摩尔癌症治疗; 16(11); 2432-41。©2017 AACR。