The discovery of microRNAs that predict chemotherapeutic responsiveness of cancer

描述(由申请人提供) 摘要：绝大多数癌症死亡是由癌细胞向远端器官转移造成的。全身化疗可以通过杀死全身微小的肿瘤细胞来防止某些患者的转移。化疗还可以极大地减少一些晚期患者的转移灶。有趣的是，这些标准的化疗方案是在事先不知道个别患者的敏感性的情况下对数十万患者进行的。对癌细胞进行这样的治疗。如果我们能够在诊断时识别患者的化疗反应和耐药亚群，无数的患者将免于无效化疗的风险、副作用和费用，而是在预先设置的基础上提供替代和实验性治疗。此外，这些生物标志物的识别可以为化疗耐药的分子基础提供机械性的见解。在乳腺癌的研究中，我们最近发现了一组人类microRNAs，在一个强大的乳腺癌小鼠模型中，它们可以强烈地抑制转移。这些microRNAs作为生物标记物，因为它们在原发肿瘤中的表达水平预测未来的转移复发，从而指导临床决策。结直肠癌是一种高度流行和侵袭性的疾病，其治疗选择比乳腺癌少得多。我们建议应用一种概念和技术创新、系统和多学科的方法来发现化疗反应预测microRNAs。通过一种结合了分子、体外、体内和人类临床见解的实验方法。我们将通过前瞻性的活体人体研究来验证这些microRNA生物标记物的效力。如果成功，我们设想这种强大的方法也适用于其他常见的癌症。此类microRNA的鉴定不仅将具有巨大的临床价值，而且将为未来旨在产生基于microRNA的新型治疗药物以预防和治疗癌症转移的机制和合成努力奠定基础。 公共卫生相关性：结直肠癌是一种高度流行和侵袭性的疾病实体。尽管手术切除了原发肿瘤，但数以万计的患者会将他们的癌症转移到肝脏或肺等器官，从而死于他们的疾病。通过一种多学科、协作和高度创新的方法，整合了分子、体外、体内和人类临床分析，我们建议发现特定的microRNA生物标志物，使临床医生能够识别其肿瘤将对结直肠癌标准化疗产生耐药性的患者。这种生物标志物的识别每年将使成千上万的患者免于无效的治疗，并使他们有资格接受替代和实验性治疗。这些miRNA生物标志物的鉴定不仅将具有巨大的临床诊断价值，而且将为未来旨在开发基于microRNA的新型治疗药物预防和治疗结直肠癌转移奠定基础。

DESCRIPTION (Provided by the applicant) Abstract: The vast majority of cancer deaths result from the metastatic spread of cancer cells to distal organs. Systemic chemotherapy can prevent metastasis in some patients by killing microscopic tumor cells throughout the body. Chemotherapy can also dramatically reduce the size of metastases in some advanced stage patients. Interestingly, these standard chemotherapeutic regimens are administered to hundreds of thousands of patients without prior knowledge of the sensitivity of individual patients. cancer cells to such treatments. If we could identify the chemotherapeutic responsive and resistant subsets of patients at diagnosis, innumerable patients would be spared from the risks, side effects, and expense of ineffective chemotherapy and instead offered alternative and experimental therapies in the upfront setting. Furthermore, the identification of such biomarkers could provide mechanistic insights into the molecular underpinnings of chemotherapeutic resistance. Working in breast cancer, we recently discovered a set of human microRNAs that strongly suppress metastasis in a robust mouse model of breast cancer. These microRNAs act as biomarkers since their expression levels in primary tumors predict future metastatic relapse, thus guiding clinical decision-making. Colorectal cancer is a highly prevalent and aggressive disease entity with significantly fewer treatment options than breast cancer. We propose to apply a conceptually and technically innovative, systematic, and multi-disciplinary approach to discover .chemotherapeutic-response predictive microRNAs. through an experimental approach that integrates molecular, in vitro, in vivo, and human clinical insights. We will validate the power of these microRNA biomarkers through prospective in vivo human studies. If successful, we envision this powerful approach applied to other common cancers. The identification of such microRNAs will not only be of tremendous clinical value now, it will also lay the foundation for future mechanistic and synthetic efforts aimed at generation of novel microRNA-based therapeutic agents for the prevention and treatment of cancer metastasis. Public Health Relevance: Colorectal cancer is a highly prevalent and aggressive disease entity. Despite surgical resection of primary tumors, tens of thousands of patients will develop metastatic spread of their cancers to organs such as the liver or lung and will consequently die of their disease. Through a multi-disciplinary, collaborative, and highly innovative approach that integrates molecular, in vitro, in vivo, and human clinical analyses, we propose to discover specific microRNA biomarkers that will empower clinicians to identify patients whose tumors will display resistance to standard chemotherapy for colorectal cancer. The identification of such biomarkers will save thousands of patients annually from ineffective treatment and make them eligible for alternative and experimental therapies. The identification of such miRNA biomarkers will not only be of tremendous clinical diagnostic value now, but will lay the foundation for future efforts aimed at generating novel microRNA-based therapeutic agents for the prevention and treatment of colorectal cancer metastasis.