Integrin regulation of brain tumor initiating cells

描述（由申请人提供）：脑肿瘤，最常见的类型是神经胶质瘤，是最致命的癌症类型之一，目前的治疗方法包括手术，放射和药物的组合，仅提供姑息治疗。因此，寻找更有效的治疗方法仍然是当务之急。脑肿瘤的新治疗方法可能源于最近鉴定出的一种具有更高形成肿瘤能力的胶质瘤细胞亚群，称为胶质瘤肿瘤起始细胞（GTIC）。肿瘤起始细胞通常占总肿瘤群体的不到5%，然而，少至几百个就可以导致肿瘤在小鼠中生长，而数百万个非肿瘤起始细胞在相同的时间范围内不形成肿瘤。实验数据表明，肿瘤起始细胞可能负责维持肿瘤生长并导致肿瘤在治疗后复发。我们相信，靶向脑肿瘤中的肿瘤起始细胞将改善患者的治疗。因此，我们正试图了解如何更好地从人类患者中分离肿瘤起始细胞，并设计针对这些细胞的疗法。实现这一目标的一种方法是确定哪些信号定位于神经胶质瘤中的肿瘤起始细胞区域。然后，这些信号可以用于肿瘤起始细胞富集和靶向。我们已经确定了一个家庭的细胞外基质受体，整合素，作为一个可能的目标。在本申请中，我们的目的是：评估整合素作为GTIC的选择标记物的效用，并确定靶向GTIC上表达的整合素的治疗潜力。为了实现这些目标，我们将利用人脑胶质瘤手术活检标本，并评估整合素富集GTIC的能力，与目前公认的方法相比，使用流式细胞术和GTIC标记物评估在RNA和蛋白质水平。将使用体内移植测定来评估整联蛋白富集的细胞级分的肿瘤起始能力。为了整合素靶向的目的，我们将单独使用慢病毒shRNA和/或嵌合适体或与其他治疗方式组合，以靶向直接从人脑胶质瘤手术活检标本中富集的GTIC，并将通过体内移植试验评估肿瘤起始能力。这些实验方法将使我们能够评估整合素作为目标细胞群中GTIC的选择标记物和靶标的潜力，并设计与胶质瘤直接相关的疗法。该项目的长期贡献将是基于肿瘤起始细胞的靶向设计更有效的脑肿瘤疗法。此外，任何发现或治疗进展都可能扩展到其他肿瘤起始细胞群，如其他癌症（即结肠癌、乳腺癌、白血病）中描述的那些。

DESCRIPTION (provided by applicant): Brain tumors, the most common type being gliomas, are among the most lethal type of cancer with current treatments consisting of a combination of surgery, radiation, and drugs offering only palliation. Hence, finding more effective treatments remains an immediate priority. New treatments for brain tumors may stem from the result from the recent identification of a subpopulation of glioma cells with a higher capacity to form tumors, called glioma tumor initiating cells (GTICs). Tumor initiating cells generally constitute less than five percent of the total tumor population, however as little as a couple hundred can cause tumors to grow in mice whereas millions of the non-tumor initiating cells do not form tumors within the same timeframe. Experimental data suggest that tumor initiating cells may be responsible for maintaining tumor growth and causing tumors to come back after therapy. We believe that targeting tumor initiating cells in brain tumors will improve patient treatment. Therefore, we are trying to understand how to better isolate tumor initiating cells from human patients and design therapies to target these cells. One such way of achieving this goal is to identify which signals are localized to the tumor initiating cell regions in gliomas. These signals can then be used for tumor initiating cell enrichment and targeting. We have identified a family of extracellular matrix receptors, integrins, as a possible target. In this application, we aim to: evaluate the utility of integrins as selection markers of GTICs and determine the therapeutic potential of targeting integrins expressed on GTICs. To achieve these aims, we will utilize human glioma surgical biopsy specimens and evaluate the ability of integrins to enrich for GTICs in comparison to currently accepted methods using flow cytometry and GTIC marker assessment at the RNA and protein levels. The tumor initiation ability of integrin enriched cell fractions will be assessed using in vivo transplantation assays. For integrin targeting purposes, we will utilize lentiviral shRNA and/or chimeric aptamers alone or in combination with other therapeutic modalities to target GTICs enriched directly from human glioma surgical biopsy specimens and will assess tumor initiation capacity with in vivo transplantation assays. These experimental approaches will allow us to evaluate the potential of integrins as a selection marker and target of GTICs in the cell population of interest and design therapies which will have direct relevance to gliomas. The long term contribution of this project will be to design more effective brain tumor therapies based on the targeting of tumor initiating cells. In addition, any findings or therapeutic developments may extend to other tumor initiating cell populations such as those described in other cancers (i.e. colon, breast, leukemia).