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

摘要 本申请是根据PA-21-071的要求提交的。胶质母细胞瘤(GBM)是最常见和 致命的脑癌。治疗的标准是手术切除，然后用烷化剂治疗。 替莫唑胺(TMZ)。手术切除肿瘤块，TMZ为许多患者提供了一些好处。这个 亲本肿瘤组织工程协作计划(R01 CA256481)正在发展组织工程 加速评估克服TMZ耐药性的新型抗癌化合物的方法。这个项目 正在开发过程来创建血管周围壁龛(PVN)的工程模型，这些模型从 肿瘤进入周围实质，据信在侵袭、复发、 对TMZ耐药，存活率低。传统的块状水凝胶，即使是小型化的变种，也不能提供 大道，以量身定制或跟踪独特细胞亚群周围的当地微环境的演变。 NCI多样性行政副刊的目标是支持一名女性研究助理 化学工程系教授负责制定完全独立的研究计划 胶质母细胞瘤肿瘤微环境内及以后神经元-胶质瘤连接性的分级模型 治疗性干预。在肿瘤边缘建立的独特的微环境负责神经元 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，此项目将首先检查 利用脑部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因素 微环境(目标S1)。我们随后将确定治疗干预对 神经元-胶质瘤单位(AIM S2)。这项拟议的补编将使初级女性调查员能够制定 作为伊利诺伊大学厄巴纳分校的研究助理教授，完全独立的研究项目- 香槟。通过这项独立的研究以及主办部门、校园内的互动 伊利诺伊州癌症中心和外部高级导师，我们已经确定了一个补充但独立的 研究轨迹和指导计划，以支持模范少年的完全独立 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.