Targeting Stoma-Tumor Co-Dependency for Glioma Therapy

脑肿瘤（星形细胞瘤或神经胶质瘤）是儿童癌症相关死亡的主要原因，也是成人癌症相关死亡的第四大原因。虽然我们通过靶向癌细胞内的遗传和分子变化来部分阻止其生长的能力已经取得了相当大的进展，但大量胶质瘤患者死于疾病，由于治疗而发生继发性脑功能障碍，或者尽管治疗仍未能恢复正常的神经功能。我们假设，脑肿瘤治疗改善患者预后需要治疗考虑肿瘤周围肿瘤细胞和非肿瘤细胞之间的双向相互作用。在过去的五年中，我们已经开发并验证了几种低度胶质瘤的基因工程小鼠模型（GEMM），这些模型概括了人类疾病的显著特征。在本申请中，我们将利用这些精确的GEMM系统来理解（1）肿瘤微环境的作用，包括重要的免疫系统细胞，在胶质瘤形成和肿瘤生长中，（2）胶质瘤生长对正常神经元功能的影响，以及（3）化疗和放疗对非肿瘤性脑细胞的继发性影响。使用跨学科的方法，我们的目标是解开低级别胶质瘤中肿瘤细胞和非肿瘤细胞之间双向相互作用的细胞和分子决定因素，并使用这些见解来确定旨在改善这些癌症患者预后的新策略。为此，我们组建了一个新的研究团队，他们之前参与了大规模的合作研究计划，并在小鼠模型生成（大卫古特曼博士），脑肿瘤中的基质相互作用（大卫古特曼博士，约书亚鲁宾），先进的小动物成像（乔尔加博博士），基因组对肿瘤发生的影响（Karlyne Reilly博士）和多模态成像（Mark Ellisman博士）方面具有专业知识。最后，我们分别利用华盛顿大学、加州大学圣地亚哥分校和国家癌症研究所丰富的研究环境来解决癌症生物学中的这一复杂问题。

Brain tumors (astrocytomas or gliomas) represent the leading cause of cancer-related death in children and the fourth leading cause in adults. While there have been considerable advances in our ability to partially arrest their growth by targeting the genetic and molecular changes within cancer cells, a substantial number of patients with gliomas succumb to their disease, develop secondary brain dysfunction as a result of treatment, or fail to regain normal neurologic function despite treatment. We hypothesize that improved patient outcome from brain tumor treatment requires that therapies consider the bi-directional interactions between neoplastic cells and non-neoplastic cells in the tumor surround. Over the past five years, we have developed and validated several genetically-engineered mouse models (GEMMs) of low-grade glioma that recapitulate the salient features of the human condition. In this application, we will exploit these accurate GEMM systems to understand (1) the role of the tumor microenvironment, including important immune system cells, in gliomagenesis and tumor growth, (2) the effects of glioma growth on normal neuronal function, and (3) the secondary effects of chemotherapy and radiation therapy on non-neoplastic brain cells. Using a cross-disciplinary approach, we aim to unravel the cellular and molecular determinants that underlie the bi-directional interactions between neoplastic cells and non-neoplastic cells in low-grade glioma, and use these insights to identify novel strategies aimed at improving the outcome of patients with these cancers. To this end, we have assembled a new team of investigators with prior involvement in large-scale cooperative research initiatives and expertise in mouse model generation (Dr. David Gutmann), stromal interactions in brain tumors (Drs. David Gutmann, Joshua Rubin), advanced small-animal imaging (Dr. Joel Garbow), genomic influences on tumorigenesis (Dr. Karlyne Reilly), and multi-modality imaging (Dr. Mark Ellisman). Finally, we have individually leveraged the rich research environments at Washington University, University of California-San Diego, and The National Cancer Institute to tackle this complex problem in cancer biology.