Microenvironmental influence on pre-clinical activity of polo-like kinase inhibition in multiple myeloma: implications for clinical translation.
Microenvironmental influence on pre-clinical activity of polo-like kinase inhibition in multiple myeloma: implications for clinical translation.
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DOI：
10.1371/journal.pone.0020226
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Mitsiades CS
中科院分区：
文献类型：
--
作者：
McMillin DW;Delmore J;Negri J;Ooi M;Klippel S;Miduturu CV;Gray NS;Richardson PG;Anderson KC;Kung AL;Mitsiades CS
Polo样激酶（PLKs）在细胞周期进程、检查点控制和有丝分裂中起重要作用。晚期癌症的高有丝分裂指数和染色体不稳定性表明，PLK抑制剂可能是目前无法治愈的全身受累的晚期肿瘤（如多发性骨髓瘤（MM））的一种有吸引力的治疗选择。我们研究了PLK 1，2，3抑制剂BI 2536，并观察到对分离的MM细胞的有效（IC 50 <40 nM）和快速（细胞死亡承诺<24小时）体外活性，以及对传统皮下异种移植小鼠模型的体内活性。然而，MM患者中的肿瘤细胞并不是孤立存在的，而是存在于骨微环境中并与骨微环境相互作用。因此，常规的体外和体内临床前测定没有考虑MM细胞与骨微环境之间的相互作用如何可能赋予耐药性。为了探讨这一问题，我们进行了肿瘤细胞区室特异性生物发光成像试验，以比较存在与不存在基质细胞或破骨细胞时BI 2536的体外临床前抗MM活性。我们观察到这些骨髓非恶性细胞的存在导致BI 2536的抗MM活性降低。我们在弥漫性MM骨病变的原位体内小鼠模型中进一步验证了这些结果，其中肿瘤细胞与骨微环境的非恶性细胞相互作用。我们再次观察到BI 2536在肿瘤-骨微环境相互作用的体内模型中的活性降低，这突出表明，尽管BI 2536在常规测定中具有有希望的活性，但其在微环境模型中缺乏活性引起了对其MM临床开发的担忧。更广泛地说，在不存在相关肿瘤微环境相互作用的情况下进行临床前药物试验可能会高估潜在的临床活性，从而至少部分解释了MM和其他癌症的临床前与临床疗效之间的差距。
Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers.
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影响因子：
45.3
作者：
Decaux, Olivier;Lode, Laurence;Minvielle, Stephane
通讯作者：
Minvielle, Stephane
DOI：
10.1158/1078-0432.ccr-07-4568
发表时间：
2008-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Burington B;Barlogie B;Zhan F;Crowley J;Shaughnessy JD Jr
通讯作者：
Shaughnessy JD Jr
影响因子：
20.3
作者：
Barlogie, B;Desikan, R;Tricot, G
通讯作者：
Tricot, G
影响因子：
8
作者：
Mattioli, M;Agnelli, L;Neri, A
通讯作者：
Neri, A
影响因子：
82.9
作者：
通讯作者：
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