Using a stem cell-based signature to guide therapeutic selection in cancer.
Using a stem cell-based signature to guide therapeutic selection in cancer.
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DOI：
10.1158/0008-5472.can-10-1735
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Nevins JR
中科院分区：
文献类型：
--
作者：
Shats I;Gatza ML;Chang JT;Mori S;Wang J;Rich J;Nevins JR
鉴于大多数人类癌症的异质性很大，很可能大多数癌症治疗方法只对任何患者群体中的一小部分有效。因此，开发新的治疗方法，再加上将治疗与个体患者相匹配的方法，将是实现疾病结果显著增长的关键。其中一个机会是使用表达签名来识别关键的致癌表型，这些表型不仅可以作为生物标记物，而且可以作为识别可能专门针对这些表型的治疗性化合物的一种手段。考虑到针对表现为干细胞样表型的肿瘤的潜在重要性，我们开发了一种表达特征，它反映了各种干细胞样特征的共同生物学方面。共识干细胞排名(CSR)标记在肿瘤晚期的肿瘤干细胞富集型样本中上调，并与多种癌症类型的不良预后有关。使用两种独立的计算方法，我们利用CSR签名来识别可以针对CSR表型的临床有用的化合物。体外试验证实，包括拓扑异构酶抑制剂和白藜芦醇在内的几种预测化合物对表现出高CSR表型的乳腺癌细胞株具有选择性。重要的是，CSR标记可以预测乳腺癌患者对包括CSR特异性药物的新辅助方案的临床反应。总而言之，这些结果提示了在相关的癌症患者队列中针对CSR表型的治疗机会。
Given the very substantial heterogeneity of most human cancers, it is likely that most cancer therapeutics will be active in only a small fraction of any population of patients. As such, the development of new therapeutics, coupled with methods to match a therapy with the individual patient, will be critical to achieving significant gains in disease outcome. One such opportunity is the use of expression signatures to identify key oncogenic phenotypes that can serve not only as biomarkers but also as a means of identifying therapeutic compounds that might specifically target these phenotypes. Given the potential importance of targeting tumors exhibiting a stem-like phenotype, we have developed an expression signature that reflects common biological aspects of various stem-like characteristics. The Consensus Stemness Ranking (CSR) signature is upregulated in cancer stem cell enriched samples, at advanced tumor stages and is associated with poor prognosis in multiple cancer types. Using two independent computational approaches we utilized the CSR signature to identify clinically useful compounds that could target the CSR phenotype. In vitro assays confirmed selectivity of several predicted compounds including topoisomerase inhibitors and resveratrol towards breast cancer cell lines that exhibit a high-CSR phenotype. Importantly, the CSR signature could predict clinical response of breast cancer patients to a neoadjuvant regimen that included a CSR-specific agent. Collectively, these results suggest therapeutic opportunities to target the CSR phenotype in a relevant cohort of cancer patients.