Humanized bone marrow-like model to study patient-derived myeloma xenografts

 描述(申请人提供)：我们已经建立了一种临床前模型，在该模型中，生物兼容的陶瓷支架填充了原代人骨髓基质细胞(BMSCs)，并可以植入小鼠体内，以构建一种矿化的类骨基质。该系统模拟了人类骨髓(BM)/骨的组织学、细胞组成和功能特性，包括多发性骨髓瘤(MM)等血液恶性肿瘤中肿瘤-间质的相互作用。事实上，这种“人性化的”骨髓样模型使我们能够在体内移植、扩大甚至连续移植来自标准和高危MM、几种类型的急性和慢性白血病以及骨髓发育不良的患者来源的异种移植(PDX)。这些肿瘤的PDX样本在常规小鼠模型中的植入率通常有限。我们最近的研究还表明，植入这种人源化模型的PDX细胞没有明显的免疫表型、自我更新特性或克隆结构的倾斜；而其临床前治疗与传统或研究治疗的结果与相应患者对这些治疗的临床反应是一致的。我们将扩展这一经验，并系统地量化这种“人性化的”类似BM的模型允许人类MM PDX细胞在这种临床前环境中概括其临床特征的程度。为了解决这一目标，我们将具体检查在这个人源化的类似BM的模型中引入的MM PDX样本是否显示出更高的植入率，改善其临床前反应与各自患者临床治疗的一致性(S)；比较它们的克隆结构是否保持不变。 直到它们被植入小鼠组织(特定目标1)。我们还将检验，当MM PDX样本被引入我们的模型中时，与使用健康供体来源的BMSCs的支架相比，将MM PDX样本引入患者来源的BMSCs的支架中，是否会改善这些翻译相关性的量化指标(特定目标2)。我们的研究将为PDX模型中的新范式提供框架，利用人类基质细胞群体功能化的生物兼容支架可以帮助建立基因多样化、易于扩展的患者来源的临床前模型，以个性化、患者特有的方式研究人类肿瘤的生物学及其治疗反应。

 DESCRIPTION (provided by applicant): We have established a preclinical model in which biocompatible ceramic scaffolds are populated with primary human bone marrow stromal cells (BMSCs) and can be implanted in mice, to engineer a mineralized bone-like matrix. This system simulates the histology, cellular composition and functional properties of the human bone marrow (BM)/bone, including the tumor-stromal interactions operating in hematologic malignancies, such as multiple myeloma (MM). Indeed, this "humanized" BM-like model has allowed us to engraft, expand and even serially transplant in vivo, patient-derived xenografts (PDX) from standard- and high-risk cases of MM, several types of acute and chronic leukemias, and myelodysplasia. PDX samples from these neoplasias typically have limited engraftment in conventional murine models. Our recent studies also show that PDX cells engrafted in this "humanized" model exhibit no substantial skewing of their immunophenotype, self-renewal properties or clonal architecture; while the outcomes of their preclinical treatments with conventional or investigational therapies are concordant with clinical responses to these treatments for the respective patients. We will extend this experience and systematically quantify the degree to which this "humanized" BM- like model allows human MM PDX cells to recapitulate their clinical features in this preclinical setting. To address this objective, we wil specifically examine whether MM PDX samples introduced in this "humanized" BM-like model exhibit higher engraftment rates, improved concordance of their preclinical responses to the respective patients' clinical treatment(s); and preservation of their clonal architecture, compared to when they are implanted in murine tissues (Specific Aim 1). We will also examine whether these quantitative metrics of translational relevance are improved when MM PDX samples are introduced in our model within scaffolds "humanized" with patient-derived BMSCs, compared to scaffolds with healthy donor-derived BMSCs (Specific Aim 2). Our studies will provide the framework for a new paradigm in PDX models, whereby biocompatible scaffolds functionalized with human stromal cell populations can help establish genotypically diverse, easily expandable patient-derived pre-clinical models to study the biology of human tumors and their therapeutic response in an individualized, patient-specific, manner.