Clinical Evaluation of an Implantable Lab-in-a-patient microdevice that measures in-situ response to therapies in advanced ovarian cancer

项目概要： 卵巢癌（OC）是美国女性癌症死亡的主要原因。临床 OC治疗的特点是一线标准治疗（SOC）铂类/紫杉烷的初始应答率较高 治疗，但也显着复发率。在这种疾病中存在一个主要的未满足的需求，以确定最佳的 铂类耐药或难治性背景下的二线治疗选择，可产生上级结局 与目前的治疗选择相比，这在很大程度上是经验性的。 许多单药和复方制剂目前正在使用或作为二线治疗药物进行临床试验 但是几乎没有可靠的生物标志物可用于预测对这些不同类型的药物的反应。 细胞毒性或靶向化疗。最近的研究已经确定了潜在的基因组和其他标记， 包括BRCA 1/2、VEGF、MAPK、PI 3 K等。然而，生物标志物鉴定的进展 缓慢，因为每次试验仅在给定时间对每个患者进行单一治疗，因此仅 允许在给定的肿瘤状态下对一种疗法进行生物标志物/表型关联。 我们已经开发出一种技术，使我们能够测量大量的表型效应， 以快速和微创的方式在单个肿瘤内使用不同的药剂或药物组合， 无全身毒性。这项技术代表了一种新的模式， 而不是经验性的，药物在病人肿瘤中的作用。由可植入的微型装置组成， 将最多120种不同药剂或组合的微剂量平行释放到小的受限区域中， 肿瘤，它允许使用已建立的药效学直接测量药物/肿瘤相互作用 在天然肿瘤微环境内测试的每种疗法的读数。 该提案旨在通过卵巢癌的试点试验将微型设备转化为临床应用。 癌症患者。在手术前一天，将多达6个微型装置植入网膜肿瘤中， 他们预计将提供一个快速和全面的快照，肿瘤实际上是如何回应所有 可用的疗法。来自肿瘤的不同部分的6个空间上分离的读出也将提供一个 肿瘤异质性的新功能检查。所有的读数都将与基因组相关， 转录组学、免疫和组织生物标志物，有效地在每种生物标志物中进行20项或更多的生物标志物试验。 患者有六次重复，只有一个额外的活检程序，并在分钟的药物暴露水平。 这项前所未有的临床研究旨在验证安全性，使用和程序， 从患者体内的微型装置中获得多种药物表型，并显着扩大该领域的 了解卵巢癌的预测性生物标志物。如果成功，这项研究可能会奠定基础， 将这种药物筛选微型装置应用于卵巢癌以外的领域。

Project summary: Ovarian cancer (OC) is a leading cause of cancer deaths in women in the United States. The clinical treatment of OC is marked by high initial response rates to 1st line standard-of-care (SOC) platinum/taxane treatment, but also significant relapse rates. A major unmeet need in this disease exists to identify optimal 2nd line therapy options in the platinum resistant or refractory setting which yield superior outcomes compared with current treatment selection which is largely empirical. Many single and combination agents are currently in use or in clinical trials as 2nd line treatments for OC, but there are few reliable biomarkers available to predict response to these various types of cytotoxic or targeted chemotherapies. Recent studies have identified potential genomic and other markers, including BRCA1/2, VEGF, MAPK, PI3K and others. Advances in biomarker identification, however, are slow because each trial only administers a single therapy on every patient at a given time, and thus only allows biomarker/phenotype correlations on one therapy at a given tumor state. We have developed a technology that allows us to measure the phenotypic effect of a large number of distinct agents or drug combinations within a single tumor in a rapid and minimally invasive manner and without systemic toxicities. The technology represents a new paradigm for predicting proactively, rather than empirically, the effect of drugs inside a patient tumor. Consisting of implantable microdevices, which release microdoses of up to 120 distinct agents or combinations in parallel into small confined regions of tumor, it allows for direct measurement of drug/tumor interaction using established pharmacodynamic readouts for each therapy tested within the native tumor microenvironment. This proposal seeks to translate the microdevices into clinical use through a pilot trial in ovarian cancer patients. Up to 6 microdevices will be implanted into omental tumors one day prior to surgery where they are expected to provide a rapid and comprehensive snapshot of how the tumor actually responds to all the available therapies. 6 spatially separated readouts from distinct parts of the tumor will also provide a novel functional examination of tumor heterogeneity. All of the readouts will be correlated with genomic, transcriptomic, immune and tissue biomarkers, effectively performing 20 or more biomarker trials in each patient with six-fold replicates, with only one extra biopsy procedure, and at minute drug exposure levels. This unprecedented clinical study seeks to validate safety, usage and procedures for obtaining multiple drug phenotypes from microdevices within patients, and to significantly expand the field's understanding of predictive biomarkers in ovarian cancer. If successful, this research may lay the foundation for application of this drug screening microdevice beyond ovarian cancer.