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

 描述(由申请人提供)：个性化医疗的前提是有足够的患者特定信息来提供针对该患者的诊断。基因组学(例如，下一代测序)现在正被应用到临床实践中，并使患者特别是癌症患者的护理得到改善。然而，仅靠序列信息将不足以实现个性化医学的全部潜力。如果我们检查前列腺癌，超过一半的患者没有从阿比拉特龙和恩扎鲁胺等新的抗癌疗法中受益，而且几乎所有最初受益的患者在1-2年内都会产生耐药性。然而，对于临床医生来说，治疗决定在很大程度上是猜测，因为他/她几乎没有量化的机制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雄激素受体(AR)驱动的，包括配体结合和从细胞质到细胞核的转位，激活了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的核转位，但仅有测序将不足以准确指导治疗选择和监测耐药性的发展(类似的情况在其他癌症和其他疾病中也存在)。预测和监测靶向治疗需要正交的多组(即，蛋白质、基因组、基因表达)终点。循环肿瘤细胞(CTCs)作为一种可获得的样本具有巨大的潜力，许多CTC分析技术正在开发中，但没有一种技术能够从单个样本进行多组分析。这项建议通过利用和推进基于排除的样品制备(ESP)来解决这些问题，以实现从单个珍贵样品中快速高效地分离多个分析物(细胞、蛋白质、RNA、DNA)，并具有高回收率和高纯度。为了有效地将该平台转移到临床，我们分别与Gilson和Foundation Medicine(最近被罗氏收购)在仪器/制造和先进癌症诊断/临床实验室测试开发方面的行业领先者签署了许可协议。此外，我们的临床合作者Lang博士(威斯康星大学)将使我们能够在SBIR建议书期间以晚期前列腺癌为临床模型，直接展示我们的多组学方法的临床疗效。如AR模型系统所示，能够测量多组生物标志物的分析将使临床医生能够就对进展性疾病患者使用哪种类型的治疗以及何时使用它做出更明智的决定，从而在出现耐药时通知初始治疗的选择以及何时切换治疗。我们选择提交快速通道SBIR提案，并满足了快速通道的要求，即明确的第一阶段目标和可显著提高成功商业化可能性的额外资金和资源承诺的明确证据(例如信件)。

 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.