Perivascular tissue models to overcome MGMT-mediated temozolomide resistance in glioblastoma

摘要 本申请是根据PA-21-071提交的。胶质母细胞瘤（GBM）是最常见的， 致命的脑癌标准治疗是手术切除，然后用烷化剂治疗 替莫唑胺（TMZ）。切除肿瘤块，和TMZ提供了一些有益的许多患者。的 癌症组织工程合作项目（R 01 CA 256481）正在开发组织工程 这是一种加速评估克服TMZ耐药性的新抗癌化合物的方法。这个项目 正在开发过程，以创建血管周围龛（PVN）的工程模型， 肿瘤进入周围的实质，并且被认为在侵袭，复发， TMZ耐药，生存率低。常规的本体水凝胶，甚至是小型化的变体，不提供微生物相容性。 这是一种定制或追踪独特细胞亚群周围局部微环境演变的途径。 该NCI多样性管理补充的目标是支持女性研究助理 教授在化学工程系开发一个完全独立的研究计划， 胶质母细胞瘤肿瘤微环境中神经元-胶质瘤连接的分级模型 治疗干预在肿瘤边缘建立的独特微环境负责神经元的生长。 过度兴奋、肿瘤侵袭和治疗干预后复发。该项目将评估 假设神经元输入是肿瘤进展的关键因素。为此，该项目将首先\检查 使用脑的工程水凝胶模型将神经元-胶质瘤连接作为肿瘤生长的主要驱动力 微环境（Aim S1）。我们随后将确定治疗干预对 神经胶质瘤单元（Aim S2）。这项拟议的补充规定将使一名初级女调查员能够制定一项 作为伊利诺伊大学厄巴纳分校的研究助理教授， 尚潘。通过这种独立的研究以及与主办部门的互动，校园 癌症中心在伊利诺伊州，和外部高级导师，我们已经确定了一个互补的，但独立的 研究轨迹以及指导计划，以支持一个示范性的初级完全独立 调查员

ABSTRACT This application is being submitted in response to PA-21-071. Glioblastoma (GBM) is the most common and lethal form of brain cancer. Standard of care is surgical resection followed by treatment with the alkylating agent temozolomide (TMZ). Resection removes the tumor bulk, and TMZ provides some benefit to many patients. The parent Cancer Tissue Engineering Collaborative project (R01 CA256481) is developing tissue engineering approach to accelerate the evaluation of new anticancer compounds that overcome TMZ resistance. This project is developing processes to create engineered models of the perivascular niches (PVNs) that extend from the tumor into the surrounding parenchyma and which are believed to play a dominant role in invasion, recurrence, TMZ resistance, and poor survival. Conventional bulk hydrogels, even miniaturized variants, do not provide an avenue to tailor, or trace the evolution of, the local microenvironment surrounding unique cell subpopulations. The objective of this NCI Diversity Administrative supplement is to support a female Research Assistant Professor within a chemical engineering department to develop a fully independent research program developing hierarchical models of neuron–glioma connectivity within the glioblastoma tumor microenvironment and after therapeutic intervention. The unique microenvironment established in the tumor edge is responsible for neuronal hyperexcitability, tumor invasion and recurrence after therapeutic intervention. This project will evaluate the hypothesis that neuronal input is a key factor for tumor progression. To do this, this project will first \inspect neuron–glioma connectivity as the main driver of tumor growth using engineered hydrogel models of the brain microenvironment (Aim S1). We will subsequently determine the repercussions of therapeutic intervention on the neuron-glioma unit (Aim S2). This proposed supplement will enable a junior female investigator to develop a fully independent research program as a Research Assistant Professor at the University of Illinois at Urbana- Champaign. Through this independent research as well as interactions within the host department, the campus Cancer Center at Illinois, and external senior mentors, we have identified a complementary but independent research trajectory as well as mentoring programs to support the full independence of an exemplary junior investigator.