Precision microRNA medicine in cancer

微小RNA（miRNAs）是调控RNA分子，其控制多种癌症过程，包括 增殖/细胞周期，存活，代谢和转移，并已导致非编码RNA的收费 （ncRNA）革命。我的实验室已经证明，它们调节关键的癌症基因，它们的错误表达可以 在癌症中既有信息性又有因果性。这提出了一个独特的诊断和治疗（治疗诊断学） 有机会使用基于miRNA的策略作为有效的癌症生物标志物和治疗方法。我的一般 策略是一种独特的三管齐下的方法，它可以培养和利用miRNA中的新发现， 再加上在小鼠模型和临床能力的专业知识，在HALCOST/BIDMC/DFHCC，包括： a.癌症中miRNA空间的全面发现和功能验证。尽管绝 大多数人类转录物是非编码的，并且绝大多数疾病相关的SNP位于nc 尽管它们是基因组的一部分，但我们对它们在人类细胞中的作用知之甚少。在这里我们将发现 在人类肿瘤及其微环境中错误表达的miRNA，并挖掘miRNA和3 'UTR 新癌症等位基因的基因组部分。这些将在细胞系试验中进行功能验证，患者 衍生的类器官（PDO）和异种移植（PDX）动物模型。B.克服癌组织的输送障碍 和目标交战虽然我们已经成功地将这些新的基于RNA的分子靶向 癌症组织，目前的方法在很大程度上是非组织特异性的，我们提出了一个计划，使这一点 更有效，测试肿瘤内和离体递送，并最终个性化靶向。C.推进 基于miRNA的药物应用于临床。在这里，我建议使用患者肿瘤组织的miRNA谱来指导 基于患者miRNA缺陷、靶向免疫检查点等的个性化治疗选择，甚至 设计一种基于miRNA的分子治疗的个性化方案，最初在PDO中测试这一想法， PDX模型。此外，我建议利用我接近最好的医生和I期临床 试验单位，以促进我们的临床前工作转化为临床应用，在诊断和 治疗领域。我希望这些新颖的、个体化的方法能成为癌症治疗的标准 患者在未来虽然这种方法可能与许多难以治疗的肿瘤类型有关，但我提出了我的 从PDAC和NSCLC开始的理由，我已经成功地与临床合作， 调查人员在这里运用我们的专业知识。 虽然miRNA疗法仍然是广泛靶向癌症途径的新方法，但我们是第一个 提出了针对个性化治疗的miRNA筛选，并将miRNA整合到 癌症患者的护理标准。作为新成立的哈佛医学院RNA研究所的主任 医学，我将追求所有这些目标，以及试图利用资源（研究/临床 /知识分子）的哈佛社区在这些努力，并希望提供这些进步的病人。

MicroRNAs (miRNAs) are regulatory RNA molecules that control a large variety of cancer processes including proliferation/cell cycle, survival, metabolism and metastasis, and have led the charge in the non-coding RNA (ncRNA) revolution. My lab has shown that they regulate key cancer genes and that their mis-expression can be both informational AND causal in cancer. This presents a unique diagnostic and therapeutic (theranostic) opportunity to use miRNA-based strategies as effective cancer biomarkers AND therapeutics. My general strategy is a unique three-pronged approach that grows and harnesses the new discoveries in miRNAs, coupled with the expertise in mouse models and clinical capabilities at HIRM/BIDMC/DFHCC, including: a. Comprehensive discovery and functional validation in the miRNA space in cancer. Even though the vast majority of human transcripts are non-coding and the vast majority of disease associated SNP lie in the nc portion of the genome, we understand very little of their roles in human cells. Here we will discover the key miRNAs mis-expressed in human cancers and their microenvironment, and mine the miRNA and 3’UTR portions of the genome for novel cancer alleles. These will be functionally validated in cell line assays, patient derived organoid (PDO) and xenograft (PDX) animal models. b. Overcoming delivery barriers to cancer tissue and target engagement. While we have had some success in targeting these novel RNA-based molecules to cancer tissues, the current approaches are largely non-tissue specific and we propose a program to make this more effective, testing intratumoral and ex vivo delivery and to ultimately personalize targeting. c. Advancing miRNA-based medicine to the clinic. Here I propose to use the miRNA profiles of patient tumor tissue to guide personalized treatment options based on patient miRNA deficiencies, targeting immune checkpoints etc., even to design a personalized regimen of miRNA-based molecules for therapy, initially testing the idea in PDO and PDX models. In addition, I propose to capitalize on my proximity to the best physicians and Phase I clinical trials units to facilitate the translation of our preclinical work to clinical applications, in both diagnostic and therapeutic areas. I hope these novel, individualized methods will converge on standard of care for cancer patients in the future. While this approach could be relevant to many difficult-to-treat tumor types, I present my rationale for starting in PDAC and NSCLC, where I have been successful in collaborating with clinical investigators to apply our expertise here. While miRNA therapeutics are still a novel approach to broadly target cancer pathways, we are the first to propose miRNA screening with an eye towards personalized therapeutics and integrating miRNAs into standard of care for cancer patients. As the Director of the new Harvard Medical School Institute for RNA Medicine, I will pursue all of these goals as well as attempt to harness the resources (research /clinical /intellectual) of the Harvard community in these efforts, and hope to deliver these advancements to patients.