Exploring Precision Oncology: From Gene Fusions to lncRNAs

探索精准肿瘤学：从基因融合到 lncRNA

• 批准号: 10219190
• 负责人: ARUL M CHINNAIYAN
• 金额: $ 92.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219190
• 关键词: Achievement; Advanced Malignant Neoplasm; Antisense Oligonucleotides; Area; Award; Biological; Biological Markers; Cancer Intervention; Cancer Patient; Clinical; Communities; Data; Development; Diagnosis; Diagnostic; Disseminated Malignant Neoplasm; ERG gene; Foundations; Gene Fusion; Goals; Human; Individual; Malignant Neoplasms; Malignant neoplasm of prostate; Mission; Modeling; Molecular; Molecular Target; PSA level; Pathogenesis; Patients; Peptides; Prognosis; Prostate; Reporting; Research; Research Personnel; Resources; Role; Sampling; Screening for Prostate Cancer; Serum; TMPRSS2 gene; Therapeutic Intervention; Untranslated RNA; Urine; Validation; Work; bioinformatics resource; cancer type; clinical sequencing; disease diagnosis; efficacious treatment; experience; inhibitor/antagonist; knowledge base; novel marker; peptidomimetics; precision medicine; precision oncology; prognostic; programs; research clinical testing; single cell sequencing; targeted treatment; therapeutic development; therapeutic target; transcriptome; transcriptomics; translational cancer research; tumor progression

Project Summary / Abstract The potential of precision medicine to benefit the lives of cancer patients continues to emerge. The mission of the Chinnaiyan lab is to advance the field of precision oncology, and we aim to achieve this through the discovery and development of molecular targets that will aid in diagnosis, prognosis, or therapeutic intervention of cancers. Over the past several years, we have made a number of significant advancements in these areas. One of these landmark studies found that TMPRSS2-ETS gene fusions exist in the majority of prostate cancers. This discovery led to our development of a non-invasive clinical test (Mi-Prostate Score, MiPS) that combines analysis of urine levels of TMPRSS2-ERG and the long non-coding RNA (lncRNA) PCA3 with serum levels of PSA to detect prostate cancers. Due to its subsequently established roles in prostate cancer pathogenesis, we also reported on the development of peptidomimetic inhibitors (ERG inhibitory peptides, EIPs) of the ERG gene fusion product. A monumental achievement in the field of precision oncology has also been establishment of our comprehensive sequencing program for advanced cancer patients, called Mi-Oncoseq. Mi-Oncoseq has become a model for integrative clinical sequencing and generated several pivotal findings, including our recent report on the integrative sequencing analysis of metastatic cancers. Data from our sequencing program were also included in our report of the lncRNA landscape of the human transcriptome. Studies of individual lncRNAs have additionally emerged in our lab, such as validation of SChLAP1 as a marker for aggressive prostate cancer. This brief description of selected achievements highlights our commitment to advancing precision oncology and our vast foundational experience in this arena. Through the NCI Outstanding Investigator Award, we propose to continue these lines of research to further explore the diagnostic potential of precision oncology, therapeutic targeting of identified markers, and roles of nominated targets in cancer development. The future research program centered on diagnostic potential will include such initiatives as creation of new bioinformatic resources (e.g. “Mi-PANDA”, a compendia of transcriptomic data), high throughput single cell sequencing analysis of patient samples, and creation of cancer-specific lncRNA panels for use with non-invasive clinical isolates. Therapeutic targeting will be explored through the use of antisense oligos to lncRNAs and studies on the efficacy of peptidomimetics for gene fusions and “undruggable” targets. These avenues of research will provide impetus for studying the roles of selected noteworthy targets in cancer development. In particular, we have already discovered two lncRNAs, ARlnc1 and THOR1, which appear to be involved in cancer progression. Overall, this ambitious research program will advance the field of precision oncology by providing new community resources, identifying novel biomarkers, exploring the therapeutic targeting of nominated molecular players, and adding to the knowledge-base of cancer development mechanisms, particularly those of lncRNAs. Importantly, this award and the proposed work would assist our lab in its mission to remain a leader in the field of precision oncology.

项目摘要/摘要 精准医疗造福癌症患者生命的潜力不断显现。的使命 钦奈亚实验室致力于推动精确肿瘤学领域的发展，我们的目标是通过这一发现实现这一目标。 以及分子靶点的开发，这将有助于癌症的诊断、预后或治疗干预。 在过去的几年里，我们在这些领域取得了一些重大进展。这其中的一个 里程碑式的研究发现，TMPRSS2-ETS基因融合存在于大多数前列腺癌中。这一发现 导致我们开发了一种结合尿液分析的非侵入性临床测试(Mi-Protel Score，MIPS) TMPRSS2-ERG和长非编码RNA(LncRNA)PCA3水平与血清PSA水平检测 前列腺癌。由于后来确定了它在前列腺癌发病机制中的作用，我们还报道了 关于ERG基因融合产物的模拟肽抑制剂(ERG抑制肽，EIPs)的开发。 在精确肿瘤学领域的一项不朽成就也是建立了我们的综合 晚期癌症患者的测序计划，称为Mi-ONCOSEQ。MI-ONCOSEQ已成为 综合临床测序并产生了几个关键发现，包括我们最近关于 转移癌的综合测序分析。我们测序计划的数据也包括在 我们关于人类转录组的lncRNA图谱的报告。对单个lncRNA的研究还增加了 例如，SChLAP1被证实为侵袭性前列腺癌的标志物。 这篇对精选成果的简要描述突显了我们对推进精准肿瘤学和 我们在这个领域的丰富基础经验。通过NCI杰出调查员奖，我们建议 继续这些研究方向，以进一步探索精确肿瘤学、治疗学 确定的标记物的靶向，以及被提名的靶标在癌症发展中的作用。未来的研究方向 以诊断潜力为中心的计划将包括创建新的生物信息资源等倡议 (例如：Mi-Panda，转录数据汇编)，高通量单细胞测序分析 患者样本，以及创建癌症特异性LncRNA面板，用于非侵入性临床分离。 将通过使用针对lncRNAs的反义寡核苷酸和研究其疗效来探索治疗的靶向性。 用于基因融合和“无法下药的”靶标的多肽类药物。这些研究途径将提供动力 用于研究选定的值得注意的靶点在癌症发展中的作用。特别是，我们已经 发现了两个似乎与癌症进展有关的lncRNAs，ARlnc1和THOR1。总体而言，这 雄心勃勃的研究计划将通过提供新的社区资源来推动精确肿瘤学领域的发展， 识别新的生物标记物，探索被提名的分子成员的治疗靶点，并添加 癌症发生机制的知识库，特别是lncRNAs的知识库。重要的是，这个奖项 拟议的工作将有助于我们的实验室完成其使命，保持在精确肿瘤学领域的领先地位。