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

 描述（由申请人提供）：我们已经建立了一个临床前模型，其中生物相容性陶瓷支架填充有原代人骨髓基质细胞（BMSC），并可植入小鼠体内，以设计矿化骨样基质。该系统模拟人骨髓（BM）/骨的组织学、细胞组成和功能特性，包括在血液恶性肿瘤（如多发性骨髓瘤（MM））中起作用的肿瘤-基质相互作用。事实上，这种“人源化”BM样模型使我们能够在体内植入、扩增甚至连续移植来自标准和高风险MM病例、几种类型的急性和慢性白血病以及骨髓增生异常的患者来源的异种移植物（PDX）。来自这些瘤形成的PDX样品通常在常规鼠模型中具有有限的植入。我们最近的研究还表明，在这种“人源化”模型中移植的PDX细胞没有表现出其免疫表型、自我更新特性或克隆结构的实质性偏斜;而其常规或研究性治疗的临床前治疗结果与相应患者对这些治疗的临床反应一致。我们将扩展这一经验，并系统地量化这种“人源化”BM样模型允许人MM PDX细胞在这种临床前环境中重现其临床特征的程度。为了解决这一目标，我们将特别检查在这种“人源化”BM样模型中引入的MM PDX样品是否表现出更高的植入率，其对相应患者的临床治疗的临床前反应的一致性改善;以及与对照组相比，其克隆结构的保留。 当它们被植入鼠组织中时（特异性目的1）。我们还将检查与具有健康供体来源的BMSC的支架相比，当MM PDX样品被引入我们的模型中时，在具有患者来源的BMSC的“人源化”支架内，这些翻译相关性的定量度量是否得到改善（具体目标2）。我们的研究将为PDX模型中的新范例提供框架，从而用人基质细胞群功能化的生物相容性支架可以帮助建立基因型多样的，易于扩展的患者衍生的临床前模型，以研究人类肿瘤的生物学及其治疗反应，以个性化，患者特异性的方式。

 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.