Microenvironmental modulation as a result of glioma therapy

描述（由申请人提供）：目前恶性胶质瘤（最常见的是多形性胶质母细胞瘤（GBM））的治疗方法包括手术切除、放疗和化疗，但由于复发和治疗耐药性而无效。无法充分治疗这些肿瘤可能部分是由于肿瘤细胞的子集，癌症干细胞，对许多常规疗法具有抗性。GBM内的癌症干细胞定位于几个区域，其中包括血管周围区室，其是已知的癌症干细胞微环境或小生境，并且已显示在治疗抗性中起作用。了解癌症干细胞如何与血管周围小生境沟通，以促进癌症干细胞表型和促进治疗抗性是直接重要的，并在设计更有效的胶质瘤治疗方法中具有意义。最近，已经在人GBM的血管周围小生境中鉴定了整合素α 6，并且高表达与具有癌症干细胞表型的细胞相关。此外，整联蛋白α 6的靶向导致受损的生长和肿瘤形成，证明整联蛋白α 6可能是有希望的治疗靶点。该提议的假设是整合素α 6是促进癌症干细胞表型的统一信号，并将通过以下方式进行评估：1）询问整合素α 6如何与血管周围微环境相互作用以维持癌症干细胞表型和2）确定整合素α 6在促进对放射和化学疗法的抗性中的作用。该提案还旨在开发一种活体成像模型，用于研究癌症干细胞与小生境之间的体内通讯。实验研究将利用人GBM标本来评估存在于小生境中的细胞外基质配体，并利用临床相关剂量的放疗和化疗来评估RNA干扰或阻断抗体给药对整联蛋白α 6靶向的影响。将通过自我更新和肿瘤起始试验评价癌症干细胞表型。该提案的长期目标是开发具有增加的治疗功效的GBM疗法，其靶向癌症干细胞与常规疗法组合。本提案中概述的这些研究将揭示癌症干细胞通过整合素16与小生境相互作用的关键作用，并评估破坏小生境相关通信的GBM的潜在疗法。任何发现和治疗进展都可能扩展到具有癌症干细胞成分的其他肿瘤类型（即结肠，乳腺）。 公共卫生相关性：多形性胶质母细胞瘤（GBM）是最常见的恶性原发性脑肿瘤，并且是最致命的肿瘤之一，这是由于它们的复发和治疗抗性，与肿瘤内存在的癌症干细胞部分相关的性质。本申请中提出的研究旨在了解GBM细胞如何通过整合素16与周围微环境相互作用，从而促进癌症干细胞表型。该提案的成功完成将阐明整合素16在维持GBM细胞和微环境之间的通信中的核心作用，并证明靶向这种相互作用用于更有效的人类GBM疗法的实用性。

DESCRIPTION (provided by applicant): Current treatments for malignant gliomas, the most common being Glioblastoma Multiforme (GBM), include surgical resection, radiation, and chemotherapy but remain ineffective due to recurrence and therapeutic resistance. The inability to adequately treat these tumors may be due in part to a subset of tumor cells, cancer stem cells, that are resistant to many conventional therapies. Cancer stem cells within GBMs are localized to several areas, among them the perivascular compartment, which is a known cancer stem cell microenvironment or niche and has been shown to play a role in therapeutic resistance. Understanding how the cancer stem cells communicate with the perivascular niche to promote the cancer stem cell phenotype and promote therapeutic resistance is of immediate importance and has implications in the design of more effective glioma therapies. Recently, integrin alpha 6 has been identified in the perivascular niche of human GBMs and high expression correlates to cells with a cancer stem cell phenotype. Additionally, targeting of integrin alpha 6 resulted in compromised growth and tumor formation, demonstrating integrin alpha 6 could be a promising therapeutic target. The hypothesis of this proposal is that integrin alpha 6 is a unifying signal that promotes the cancer stem cell phenotype and will be evaluated by: 1) interrogating how integrin alpha 6 interacts with the perivascular microenvironment to maintain the cancer stem cell phenotype and 2) determining the role of integrin alpha 6 in promoting resistance to radiation and chemotherapy. The proposal also aims to develop an intravital imaging model of study the in vivo communication between cancer stem cells and the niche. Experimental studies will utilize human GBM specimens to evaluate extracellular matrix ligands present in the niche and utilize clinically relevant doses of radiation and chemotherapy to assess the impact of integrin alpha 6 targeting by RNA interference or blocking antibody administration. The cancer stem cell phenotype will be evaluated by self-renewal and tumor initiation assays. The long term objective of this proposal is to develop GBM therapies with increased therapeutic efficacy that target the cancer stem cells in combination with conventional therapies. These studies outlined in this proposal will uncover the critical role of cancer stem cel interaction with the niche via integrin 16 and evaluate potential therapies to GBM which disrupt niche related communication. Any findings and therapeutic developments may extend to other tumor types with a cancer stem cell component (i.e. colon, breast). PUBLIC HEALTH RELEVANCE: Glioblastoma Multiforme (GBM) is the most common malignant primary brain tumor and among the most lethal due to their recurrence and therapeutic resistance, properties that are associated with a cancer stem cell fraction present within the tumor. The research proposed in this application aims to understand how GBM cell interaction with the surrounding microenvironment via integrin 16 is responsible for promoting the cancer stem cell phenotype. The successful completion of this proposal will elucidate the central role of integrin 16 in maintaining communication between GBM cells and the microenvironment and demonstrate the utility of targeting this interaction for more effective human GBM therapies.