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: 10680474
• 负责人: ARUL M CHINNAIYAN
• 金额: $ 91.01万
• 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/10680474
• 关键词: Achievement; Advanced Malignant Neoplasm; Antisense Oligonucleotides; Area; Award; Biological; Cancer Intervention; Cancer Patient; Clinical; Communities; Data; Development; Diagnosis; Diagnostic; Disseminated Malignant Neoplasm; ERG gene; 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; biomarker identification; cancer type; clinical sequencing; disease diagnosis; efficacious treatment; experience; inhibitor; knowledgebase; 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.

项目总结/摘要 精准医疗造福癌症患者生命的潜力不断显现。的使命 Chinnaiyan实验室是为了推进精确肿瘤学领域，我们的目标是通过发现 以及有助于癌症诊断、预后或治疗干预的分子靶点的开发。 在过去的几年里，我们在这些领域取得了许多重大进展。其中一 具有里程碑意义的研究发现，TMPRSS 2-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-Prostate Score，MiPS） TMPRSS 2-ERG水平和长链非编码RNA（lncRNA）PCA 3与血清PSA水平检测 前列腺癌由于其在前列腺癌发病机制中的作用，我们还报道了 对ERG基因融合产物的拟肽抑制剂（ERG抑制肽，EIP）的开发。 精准肿瘤学领域的一项里程碑式的成就也是建立了我们的全面的 一个针对晚期癌症患者的测序项目，名为Mi-Oncoseq。Mi-Oncoseq已成为 综合临床测序，并产生了几个关键的发现，包括我们最近的报告， 转移性癌症的整合测序分析。来自我们测序程序的数据也包括在 我们对人类转录组lncRNA景观的报告。对单个lncRNA的研究还 例如，SChLAP 1作为侵袭性前列腺癌的标志物的验证。 对所选成就的简要描述突出了我们对推进精准肿瘤学的承诺， 我们在这个竞技场的丰富基础经验。通过NCI杰出研究者奖，我们建议 继续这些研究领域，进一步探索精准肿瘤学、治疗学的诊断潜力 确定的标记物的靶向，以及指定靶点在癌症发展中的作用。今后的研究 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举措 (e.g.“Mi-PANDA”，转录组学数据的纲要），高通量单细胞测序分析， 患者样本，以及创建用于非侵入性临床分离株的癌症特异性lncRNA组。 将通过使用lncRNA的反义寡核苷酸和研究其疗效来探索治疗靶向 用于基因融合和“非药物性”靶点的肽模拟物。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 发现了两种lncRNA，ARlnc 1和THOR 1，它们似乎与癌症进展有关。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， 确定新的生物标志物，探索指定分子参与者的治疗靶向，并增加 癌症发展机制的知识基础，特别是lncRNA。重要的是，这个奖项 并且所提出的工作将有助于我们的实验室在其使命中保持在精确肿瘤学领域的领导地位。

项目成果

Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve.

• DOI: 10.1021/acs.jmedchem.3c00912
• 发表时间: 2023-09-14
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Li, Chungen;Qiao, Yuanyuan;Jiang, Xia;Liu, Lianchao;Zheng, Yang;Qiu, Yudi;Cheng, Caleb;Zhou, Fengtao;Zhou, Yang;Huang, Weixue;Ren, Xiaomei;Wang, Yuzhuo;Wang, Zhen;Chinnaiyan, Arul M.;Ding, Ke
• 通讯作者: Ding, Ke

The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma.

• DOI: 10.1038/s41467-022-31430-0
• 发表时间: 2022-06-29
• 期刊: Nature communications
• 影响因子: 16.6

Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response.

• DOI: 10.1073/pnas.2103240118
• 发表时间: 2021-06-15
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Zhang Y;Narayanan SP;Mannan R;Raskind G;Wang X;Vats P;Su F;Hosseini N;Cao X;Kumar-Sinha C;Ellison SJ;Giordano TJ;Morgan TM;Pitchiaya S;Alva A;Mehra R;Cieslik M;Dhanasekaran SM;Chinnaiyan AM
• 通讯作者: Chinnaiyan AM

Argonaute 2 modulates EGFR-RAS signaling to promote mutant HRAS and NRAS-driven malignancies.

• DOI: 10.1093/pnasnexus/pgac084
• 发表时间: 2022-07
• 期刊: PNAS NEXUS
• 作者: Siebenaler, Ronald F.;Chugh, Seema;Waninger, Jessica J.;Dommeti, Vijaya L.;Kenum, Carson;Mody, Malay;Gautam, Anudeeta;Patel, Nidhi;Chu, Alec;Bawa, Pushpinder;Hon, Jennifer;Smith, Richard D.;Carlson, Heather;Cao, Xuhong;Tesmer, John J. G.;Shankar, Sunita;Chinnaiyan, Arul M.
• 通讯作者: Chinnaiyan, Arul M.

Genomics driven precision oncology in advanced biliary tract cancer improves survival.

• DOI: 10.1016/j.neo.2023.100910
• 发表时间: 2023-08
• 期刊: NEOPLASIA
• 影响因子: 4.8
• 作者: Kumar-Sinha, Chandan;Vats, Pankaj;Tran, Nguyen;Robinson, Dan R.;Gunchick, Valerie;Wu, Yi-Mi;Cao, Xuhong;Ning, Yu;Wang, Rui;Rabban, Erica;Bell, Janice;Shankar, Sunita;Mannan, Rahul;Zhang, Yuping;Zalupski, Mark M.;Chinnaiyan, Arul M.;Sahai, Vaibhav
• 通讯作者: Sahai, Vaibhav