Cancer Discovery：Everolimus 可用于治疗Myc驱动的淋巴瘤

根据发表在美国癌症研究协会周刊《Cancer Discovery》上的预临床试验数据，临床中通过抑制信号分子mTORC1 来治疗几种乳腺癌和肾癌的药物，对那些由于Myc基因突变而引起的癌症（占人类总癌症15%以上）进行治疗可能也同样有效。

澳大利亚墨尔本Peter MacCallum 癌症中心，转化研究教授Grant A. McArthur博士说：“每年有超过一百万人被查出由Myc改变而引发的肿瘤，然而，开发以Myc为靶点的药物已经被证明是不可能的。”

“Myc基因的一项功能就是调节细胞生长。由于mTORC1 也是一种细胞生长调节因子，所以我们假设使用everolimus 来抑制mTORC1 ，或许可以抑制Myc驱动的肿瘤的产生和生长。”

McArthur 和他的同事在Myc驱动的淋巴瘤的模型小鼠上检验了他们的假设，他们发现使用everolimus 治疗为实验模型对抗疾病提供了强有力的保护。使用everolimus 治疗的33只小鼠只有四分之一产生了淋巴瘤，相对的使用安慰剂治疗的34只小鼠有22只得了淋巴瘤。

此外，在患上淋巴瘤的小鼠中，相对于安慰剂使用everolimus治疗使得肿瘤萎缩并且生存率有显着的提高。然而，所有这些经治疗存活的小鼠由于淋巴瘤细胞对everolimus效果的抵抗而最终复发。

McArthur说：“这些治疗证实了我们的假设，mTORC1抑制能够抑制Myc驱动的肿瘤的发生和生长，最惊讶的发现是在mTORC1 抑制如何导致肿瘤萎缩过程中。我们预期其将会通过细胞的有丝分裂来使癌细胞死亡，但是我们发现实际不是这样的。”

仔细研究这些肿瘤后表明everolimus 通过诱导细胞衰老来使肿瘤萎缩。根据McArthur的研究，当癌症驱动基因被启动，正常细胞通过进入一个称为衰老的阶段来保护他们自己。当癌症产生，癌症细胞就会找到方法克服这种保护措施。McArthur说：“我们的研究表明癌细胞饿可通过mTORC1信号通路而绕过细胞衰老途径，尤其是Myc诱导的细胞衰老途径。患有淋巴瘤的小鼠对everolimus 治疗产生抵抗与p53失去功能有关系， 众所周之p53有助于抑制肿瘤形成和生长。

McArthur说：“everolimus在治疗p53 功能不全的淋巴瘤时失去作用，具有很重要的临床意义。Everolimus 将成为临床治疗Myc驱动的癌症（特别是B细胞淋巴瘤）的一种新的有利武器，但是其只有对那些具有p53功能的病人有帮助。

与淋巴瘤相关的拓展阅读：

• 疟疾患者得Burkitt淋巴瘤风险增高
• JAMA：儿童霍奇金淋巴瘤放疗效果好
• JCO:ABVD仍是进展期霍奇金淋巴瘤的标准治疗方案
• J Clin Invest：发现淋巴瘤细胞逃避程序性死亡新途径
• ACR 2012：TNF抑制剂似乎不增加淋巴瘤风险
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doi: 10.1158/2159-8290.CD-12-0404
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The mTORC1 Inhibitor Everolimus Prevents and Treats Eμ-Myc Lymphoma by Restoring Oncogene-Induced Senescence

Meaghan Wall1,3,4, Gretchen Poortinga1,3, Kym L. Stanley1, Ralph K. Lindemann1,13, Michael Bots1, Christopher J. Chan1,9, Megan J. Bywater1, Kathryn M. Kinross1, Megan V. Astle1, Kelly Waldeck1, Katherine M. Hannan1, Jake Shortt1,3, Mark J. Smyth1,6,7, Scott W. Lowe11,12, Ross D. Hannan1,5,7,8,10, Richard B. Pearson1,5,7,8, Ricky W. Johnstone1,6,7 and Grant A. McArthur1,2,3,6,7

MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in Eμ-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of Eμ-Myc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established Eμ-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes. SIGNIFICANCE: This work provides novel insights into the requirements for MYC-induced oncogenesis by showing that mTORC1 activity is necessary to bypass senescence during transformation of B lymphocytes. Furthermore, tumor eradication through senescence elicited by targeted inhibition of mTORC1 identifies a previously uncharacterized mechanism responsible for significant anticancer activity of rapamycin analogues and serves as proof-of-concept that senescence can be harnessed for therapeutic benefit.