Precision microRNA medicine in cancer

MicroRNAs(MiRNAs)是调控多种癌症过程的rna分子，包括 增殖/细胞周期、存活、代谢和转移，并在非编码RNA中发挥带头作用 (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 在癌症中既要有信息性，又要有因果关系。这是一种独特的诊断和治疗(治疗) 有机会将基于miRNA的策略用作有效的癌症生物标记物和治疗药物。我的将军 战略是一种独特的三管齐下的方法，它培育和利用了miRNA中的新发现， 再加上HIRM/BIDMC/DFHCC在小鼠模型和临床能力方面的专业知识，包括： A.癌症中miRNA空间的全面发现和功能验证。即使是浩瀚的 大多数人类转录本是非编码的，绝大多数与疾病相关的SNP存在于NC 作为基因组的一部分，我们对它们在人类细胞中的作用知之甚少。在这里，我们将发现密钥 MiRNAs在人类肿瘤及其微环境中的错误表达，并挖掘miRNA和3‘UTRs 新的癌症等位基因的基因组部分。这些将在细胞系分析中进行功能验证，患者 衍生有机体(PDO)和异种移植(PDX)动物模型。B.克服癌症组织的传递障碍 和目标交战。虽然我们在针对这些基于RNA的新型分子方面取得了一些成功 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来实现这一点 更有效，测试肿瘤内和体外给药，并最终实现个性化靶向。C.推进 以miRNA为基础的医学走向临床。在这里，我建议使用患者肿瘤组织的miRNA图谱来指导 基于患者miRNA缺陷、针对免疫检查点等的个性化治疗选项，甚至 设计一种基于miRNA分子的个性化治疗方案，最初在PDO和 PDX型号。此外，我建议利用我接近最好的医生和I期临床的机会 试验单位，以促进将我们的临床前工作转化为临床应用，在诊断和 治疗区域。我希望这些新颖的、个性化的方法将在癌症护理标准上趋同。 未来的病人。虽然这种方法可能与许多难以治疗的肿瘤类型相关，但我提出了我的 从PDAC和NSCLC开始的基本原理，在那里我成功地与临床医生合作 调查人员在这里应用我们的专业知识。 虽然miRNA疗法仍然是一种广泛针对癌症途径的新方法，但我们是第一个 建议进行miRNA筛选，着眼于个性化治疗，并将miRNA整合到 癌症患者的护理标准。作为新的哈佛医学院核糖核酸研究所的主任 医学，我将追求所有这些目标，并尝试利用资源(研究/临床 /知识分子)，并希望将这些进步带给患者。

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.