Getting More from Less: Multi-omic Capture and Analysis from Patient Samples

事半功倍：从患者样本中进行多组学捕获和分析

基本信息

批准号：
9545010
负责人：
Scott M Berry
金额：
$ 53.38万
依托单位：
SALUS DISCOVERY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9545010
关键词：
Address Adopted Advanced Malignant Neoplasm Agreement Androgen Receptor Automation Biological Assay Biological Markers Biological Models Blood CLIA certified Cancer Center Cancer Diagnostics Cancer Patient Caring Cell Nucleus Cells Cellular Assay Clinic Clinical Clinical Trials Companions Complement Cyclic GMP Cytoplasm DNA Data Development Devices Diagnosis Disease Documentation Drug Targeting Exclusion Foundations Funding Gene Expression Genetic Transcription Genomics Glean Goals Image Industrialization Industry Laboratories Letters Licensing Ligand Binding Malignant Neoplasms Malignant neoplasm of prostate Manuals Measurement Measures Medicine Messenger RNA Methods Modeling Monitor Mutation Neoplasm Circulating Cells Nuclear Translocation Nucleic Acids Patients Pharmaceutical Preparations Phase Population Positioning Attribute Precision therapeutics Preparation Progressive Disease Protein translocation Proteins RNA RNA Splicing Receptor Signaling Recovery Regulation Resistance Resistance development Resources Sampling Small Business Innovation Research Grant Stains TACSTD1 gene Techniques Technology Testing Time Tube Universities Validation Variant Wisconsin abiraterone base cancer therapy carbonate dehydratase clinical diagnostics clinical efficacy clinical practice clinically actionable cohort commercialization design effective therapy improved individual patient inhibitor/antagonist innovation instrumentation manufacturability molecular marker multiple omics next generation sequencing patient biomarkers personalized medicine predictive marker prevent programs prospective protein function public health relevance resistance mechanism success targeted treatment therapy resistant treatment choice tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Personalized medicine is predicated on having sufficient patient specific information to provide a diagnosis specific to that patient. Genomics (e.g. next generation sequencing) is now being adopted into clinical practice and is enabling improvements in patient specific care particularly in cancer. However, sequence information alone will not be sufficient to realize the full potential of personalized medicine. If we examine prostate cancer, more than half of patients do not benefit from new anti-cancer therapies such as Abiraterone and Enzalutamide and nearly all patients who initially benefit develop resistance within 1-2 years. Yet, for the clinician the treatment decisions are largely guesswork as he/she has little quantitative mechanistic data to guide treatment choices. Importantly, prostate cancer is driven in large part by the Androgen Receptor (AR) including ligand binding and translocation from the cytoplasm to the nucleus activating a transcriptional program critical to tumorigenesis. Multiple drugs are currently available that prevent nuclear translocation of the AR via different mechanisms, but sequencing alone will be insufficient to accurately guide therapy choice and to monitor the development of resistance (similar scenarios exist in other cancers and other diseases). Predicting and monitoring targeted therapies requires orthogonal multi-omic (i.e., protein, genomic, gene expression) endpoints. Circulating tumor cells (CTCs) have great potential as an accessible sample and many technologies are being developed for CTC analysis, but none have the ability to perform multi-omic analysis from a single sample. This proposal addresses these issues by leveraging and advancing Exclusion-based Sample Preparation (ESP) to enable the rapid and efficient isolation of multiple analytes (cells, proteins RNA, DNA) from a single precious sample with high recovery and purity. To efficiently move this platform into the clinic, we have signed licensing agreements with Gilson and Foundation Medicine (recently acquired by Roche) industry leaders in instrumentation/manufacturing, and advanced cancer diagnostics/clinical laboratory test development respectively. Additionally our clinical collaborator, Dr. Lang (University of Wisconsin), will enable us to directly demonstrate the clinical efficacy of our multi-omic approach during the SBIR proposal period, using advanced prostate cancer as a clinical model. As illustrated by the AR model system, assays capable of measuring multi-omic biomarkers would enable clinicians to make more informed decisions about what type of therapy to use and when to use it for patients with progressive disease, informing both choice of initial treatment as well as when to switch therapy as resistance occurs. We have chosen to submit a Fast-Track SBIR Proposal and have addressed the Fast-Track requirements of clear Phase I goals and clear evidence (e.g. letters) of additional funding & resource commitments that significantly enhance the likelihood of successful commercialization.

描述（由申请人提供）：个性化医疗的前提是拥有足够的患者特定信息，以提供针对该患者的特定诊断。基因组学（例如下一代测序）现已被应用于临床实践，并能够改善患者的特定护理，特别是在医疗领域。然而，仅序列信息不足以实现个性化医疗的全部潜力，如果我们检查前列腺癌，超过一半的患者不会从阿比特龙和恩杂鲁胺等新的抗癌疗法中受益。几乎所有最初受益的患者都会在 1-2 年内出现耐药性，然而，对于临床医生来说，治疗决策很大程度上是猜测，因为他/她几乎没有定量的数据来指导治疗选择。重要的是，前列腺癌在很大程度上是由前列腺癌驱动的。雄激素受体 (AR) 包括配体结合和从细胞质到细胞核的易位，激活对肿瘤发生至关重要的转录程序，目前有多种药物可以通过不同的机制防止 AR 的核易位，但仅靠测序不足以准确指导治疗。选择并监测耐药性的发展（其他癌症和其他疾病中也存在类似情况）需要正交多组学（即蛋白质、基因组、基因表达）终点。作为一种可获取的样品，许多技术正在开发用于 CTC 分析，但没有一种技术能够从单个样品中进行多组学分析。该提案通过利用和推进基于排除的样品制备 (ESP) 来解决这些问题。为了能够以高回收率和纯度从单个珍贵样品中快速有效地分离多种分析物（细胞、蛋白质、RNA、DNA），为了有效地将这个平台推向临床，我们与 Gilson 和 Foundation Medicine 签署了许可协议（最近）。分别是仪器/制造和先进癌症诊断/临床实验室测试开发领域的行业领导者，我们的临床合作者 Lang 博士（威斯康星大学）将使我们能够直接证明我们的多组学的临床功效。期间接近SBIR 提案期间，使用晚期前列腺癌作为临床模型，如 AR 模型系统所示，能够测量多组学生物标志物的测定将使老年人能够就使用哪种类型的治疗以及何时使用做出更明智的决定。对于病情进展的患者，告知初始治疗的选择以及出现耐药性时何时转换治疗。我们选择提交快速通道 SBIR 提案，并解决了明确的 I 期目标和明确证据的快速通道要求。（例如字母）额外的资金和资源承诺，可显着提高成功商业化的可能性。