Targeting Brain Tumor Stem Cells

描述(由申请人提供)： 在恶性脑肿瘤中，癌症干细胞(CSCs)最近被定义为自我更新和肿瘤起始的功能分析。虽然CSCs通常只存在于人类肿瘤中的极少数，但当异种移植到动物体内时，CSCs有能力产生重现原始肿瘤的肿瘤，而其余的非CSC肿瘤块通常不能。因此，阐明对CSC生物学至关重要的分子靶点可能会产生提高患者存活率的战略疗法。尽管诱导型一氧化氮合酶(INOS)在包括恶性脑癌在内的多种癌症中都有表达，但其在肿瘤中的作用尚不清楚，因为在不同的系统中已经描述了NO和iNOS的几个促肿瘤和抗肿瘤作用。我们的初步证据表明，在各种恶性脑癌中，iNOS的表达在很大程度上局限于CSC群体，在CSC群体中的表达是对辐射的反应，iNOS活性可能对CSC在基线和放射治疗期间的生存至关重要。因此，我们假设脑肿瘤CSCs中的iNOS参与了肿瘤的恶性和辐射抵抗，靶向CSCs中的iNOS将为脑肿瘤的治疗提供有价值的途径。为此，我们将致力于以下具体目标：1)确定iNOS在正常神经干细胞和脑CSC行为中的不同作用；2)确定iNOS活性在脑肿瘤CSC辐射抵抗中的作用；3)确定药物靶向iNOS是否可以降低脑肿瘤CSC的肿瘤发生和辐射抵抗。为此，我们将使用shRNA敲除技术和一种特定的iNOS抑制剂来研究iNOS在肿瘤干细胞维持表型、辐射后生存、体内肿瘤发生和肿瘤辐射抵抗中的作用。该项目的长期目标是开发癌症干细胞特异性疗法，以提高脑瘤患者的存活率。我培训的总体目标是发展必要的技能，成为一名致力于通过将实验室和临床的研究联系起来，改善神经病学患者护理的内科科学家。公共卫生相关性：脑瘤是极其致命的，治疗后经常复发，导致患者死亡。肿瘤中的一些细胞对放射治疗具有特别的抵抗力，可能有助于肿瘤在放射治疗后再次出现。我们的目标是研究这些细胞抵抗辐射的方式，并将研究能够防止这些细胞再生肿瘤的可能治疗方法。我们预计这种方法可能会为每年数以万计的被诊断为恶性脑瘤的患者产生新的有效的治疗策略。

DESCRIPTION (provided by applicant): In malignant brain tumors, cancer stem cells (CSCs) have recently been defined in functional assays of self-renewal and tumor initiation. Though often only present in very small numbers in human tumors, CSCs have the ability to generate tumors that recapitulate the original tumor when xenotransplanted into animals, whereas the remaining non-CSC tumor bulk most often cannot. Thus, elucidating molecular targets critical to CSC biologies may generate strategic therapies which improve patient survival. Though expressed in a variety of cancers, including malignant brain cancers, the role of inducible nitric oxide synthase (iNOS) in tumors is unclear, since several pro- and anti-tumorigenic roles of NO and iNOS have been delineated in various systems. Our preliminary evidence suggests that iNOS expression is largely limited to the CSC population in a variety of malignant brain cancers, expression is induced in response to radiation in the CSC population, and iNOS activity may be crucial to the survival of CSCs at baseline and during radiation therapy. As a result, we hypothesize that iNOS in brain tumor CSCs contributes to tumor malignancy and radioresistance and targeting iNOS in CSCs will provide valuable therapeutic approaches to the treatment of brain tumors. To investigate this, we will pursue the following specific aims: 1) determine the differential role of iNOS in normal neural stem cell and brain CSC behaviors, 2) determine the role of iNOS activity in brain tumor CSC radioresistance, and 3) determine if pharmacologically targeting iNOS can decrease the tumorigenesis and radioresistance of brain tumor CSCs. To do this, we will employ both shRNA knockdown technology and a specific iNOS inhibitor to investigate the role of iNOS in cancer stem cell maintenance phenotypes, post-radiation survival, and in vivo tumorigenesis and tumor radiation resistance. The long term goal of this project is to develop cancer stem cell specific therapies to increase brain tumor patient survival. The overall goal for my training is to develop the skills necessary to become a physician-scientist dedicated to improving neurologic patient care through linking research in the laboratory and clinic. PUBLIC HEALTH RELEVANCE: Brain tumors are extremely deadly and reappear frequently after treatment, resulting in patient death. Some cells in a tumor are especially resistant to radiation therapy and probably help tumors reappear afterward. We aim to investigate the ways these cells resist radiation and will investigate possible treatments able to prevent these cells from regenerating tumors. We expect this approach may generate new and effective treatment strategies for the tens of thousands of patients diagnosed with malignant brain tumors every year.