Sourcing Bioactive Secondary Metabolites from Great Lakes Fungi

描述(申请人提供)：今天，许多实质性的儿科癌症预后很差，给受害者及其家人带来了巨大的身体和精神痛苦。在解决这一未得到满足的医疗需求的途径上，一个关键的发展是越来越多地认识到大多数儿童癌症的细胞基础不同于调节其成年癌症的细胞基础。因此，药物发现工作的重点是确定新的治疗线索，瞄准支撑儿童癌症的机制。任何改善儿童癌症化疗选择的努力取得成功的根本是一种方法，该方法将化学上多样化的类药物分子库中体现的发现可能性与探测疾病相关靶点的选择性/特异性的分析相匹配。天然产品满足了这一关键原则，提供了丰富的各种新颖的结构特征，自然已经演变成具有生物活性的化合物。我们的初步研究表明，来自五大湖沉积物的新真菌类群产生了具有这些吸引人的生物学特征的化合物，正如初步研究显示的对儿科癌细胞株的选择性活性所例证的那样。根据这些数据，我们假设五大湖包含一种独特和多样化的真菌组合，几乎没有被开发用于生产具有预防儿童癌症潜力的生物活性天然产品。为了实现将这种生物和化学多样性的真菌来源转化为具有治疗前景的分子的目标，我们组建了一个由拥有天然产品化学、抗癌药物发现/药理学、五大湖生态学和真菌学专业知识的研究人员组成的合作网络。我们将通过六个具体目标来验证中心假设并实现这一提议的目标：1)从不同的五大湖环境中获取沉积物样本，2)从沉积物样本中分离真菌并准备用于筛选的提取物库，3)测试提取物的活性 在一系列与罕见但致命的儿童癌症有关的新的疾病相关分析中，4)利用生物分析数据、分类亲和力和化学标记物优先选择生物活性样本进行放大研究，5)纯化生物活性化合物，以及6)在异种移植小鼠模型中验证纯化化合物的体内活性。我们的方法有几个创新功能，与生物分析(专注于选择性抑制儿童癌症表现出的酶和细胞靶标)和天然产品化学方法(半自动分离真菌的新方法、快速提取液制备和先进的去复制工具)有关。这些新技术有望加强我们识别新的生物活性化合物的方法。我们的研究意义重大，因为许多儿科癌症仍然无法治疗，需要大力努力识别具有前景的治疗方案的化合物，以满足这一未得到满足的医疗需求。我们希望我们的研究将为进一步发展儿童癌症的治疗方法提供几个新的选择。

DESCRIPTION (provided by applicant): Today, many solid pediatric cancers have a poor prognosis, contributing to an immense amount of physical and emotional suffering on the parts of the victims and their families. A key development on the pathway to addressing this unmet medical need has been growing recognition that the cellular bases of most pediatric cancers are different from those regulating their adult counterparts. Therefore, drug discovery efforts focused on the identification of new therapeutic leads that target the mechanisms underpinning pediatric cancers are needed. Fundamental to the success of any effort for improving chemotherapeutic options against pediatric cancers is an approach that matches the discovery possibilities embodied in a chemically diverse library of drug-like molecules with assays probing the selectivity/specificity of disease-relevant targets. Natural products fulfill this key criterio offering a rich assortment of novel structural features that nature has evolved into bioactive compounds. Our preliminary studies demonstrate that new fungal taxa derived from Great Lakes sediments generate compounds with these types of attractive biological profiles as exemplified in preliminary studies demonstrating selective activity against pediatric cancer cell lines. Based on these data, we hypothesize that the Great Lakes contain a unique and diverse assemblage of fungi that is virtually untapped for the production of bioactive natural products with potential against childhood cancers. To achieve the goal of transforming this fungal source of biological and chemical diversity into therapeutically-promising molecules, we have assembled a collaborative network of researchers with expertise in natural products chemistry, cancer drug discovery/pharmacology, Great Lakes ecology, and mycology. We will test the central hypothesis and fulfill the objectives of this proposal through six specific aims: 1) procuring sediment samples from diverse Great Lakes environments, 2) isolating fungi from sediment samples and preparing an extract library for screening, 3) testing extracts for activities in a suite of new and disease-relevant-assays pertaining to rare yet fatal pediatric cancers, 4) prioritizing bioactive samples for scale-up studies using bioassay data, taxonomic affinity, and chemical markers, 5) purifying bioactive compounds, and 6) verifying the in vivo activities of purified compounds in xenograft mouse models. Several innovative features have been built into our approach that pertain to both the biological assays (focus on selective inhibition of enzymatic and cell targets exhibited by pediatric cancers) and natural products chemistry approaches (new methods for the semi-automated isolation of fungi, expedited extract preparation, and advanced dereplication tools). These new techniques are expected to enhance our approach to identifying new bioactive compounds. Our research is significant because many pediatric cancers remain untreatable and vigorous efforts are needed to identifying compounds with promising therapeutic profiles that address this unmet medical need. We expect that that our studies will provide several new options for further development as therapies for childhood cancers.