TRAIL Receptor Signaling in Human Tumors

描述(申请人提供)：肿瘤坏死因子相关的凋亡诱导配体(TRAIL)杀死肿瘤细胞，对正常组织几乎没有影响，重组TRAIL和识别TRAIL受体的抗体正在科罗拉多大学和其他地方进行临床试验。此外，TRAIL受体信号决定了其他药物杀死肿瘤细胞的效率。然而，肿瘤细胞经常对TRAIL产生耐药，这种耐药发生的机制以及这种耐药对肿瘤进展和临床结果的意义尚不清楚。我们最近发现，乳腺和卵巢肿瘤细胞对TRAIL选择性耐药的一个机制是通过增加同源盒转录因子SIX1的表达。我们发现SIX1的升高是常见的，发生在60%的转移性卵巢癌和90%的转移性乳腺癌中，并且与不良的临床结果相关。我们进一步发现，SIX1的表达足以使非转移性肿瘤细胞在体内转移。由于TRAIL信号通路可以抑制肿瘤转移，我们假设SIX1通过一种特定的机制抑制TRAIL，从而导致转移增加，从而导致患者不良的临床预后和患者肿瘤对TRAIL的耐药。为了验证这一假设，我们提出了一个综合项目，该项目将确定SIX1抑制TRAIL受体诱导的细胞凋亡的分子机制，测试这些机制是否与小鼠转移增加有关，并确定这些效应是否适用于患者的原发肿瘤细胞，以及它们是否会导致更糟糕的临床结果。由于这项工作包括在细胞水平上研究基本机制，在癌症进展和转移的动物模型中测试这些机制，以及在卵巢癌和乳腺癌患者的肿瘤中进行临床和翻译研究，我们采用了一个团队方法，其中将有一位在TRAIL信号方面有专长的细胞生物学家(索伯恩博士)，一位分析SIX1在癌症发生和进展中的先驱(福特博士)和一位在临床和翻译研究方面有专长的肿瘤学家(贝巴赫特博士)。为了实现这些目标，我们有以下目标：1.确定SIX1如何通过TRAIL受体靶向治疗激动剂在卵巢癌和乳腺癌中改变信号。2.检测SIX1诱导的转移是否涉及TRAIL耐药机制；3.确定SIX1的表达是否预测患者肿瘤对TRAIL的敏感性和预后。总之，这些目标应该能让我们了解SIX1是如何调节TRAIL受体信号的，确定这些机制在肿瘤转移中的作用，并测试同样的机制是否适用于乳腺癌和卵巢癌患者，从而决定他们的临床结果。公共卫生相关性：乳腺癌和卵巢癌是女性癌症死亡的第二和第五大原因。治疗这些(和其他)癌症的一种令人兴奋的新方法是使用直接激活TRAIL受体的疗法，但许多肿瘤细胞对这些疗法具有抵抗力。该项目主要关注肿瘤细胞对TRAIL产生耐药性的一种机制(SIX1表达)，我们的数据表明，这一机制影响了高比例的转移性癌症患者(~60-90%)。通过了解这种机制如何导致对TRAIL的抵抗，如何影响疾病的进展和转移，以及如何改变患者的临床结果，我们应该对SIX1作为预后标志物的价值有新的见解，并更好地了解如何使用正在开发的TRAIL疗法。

DESCRIPTION (provided by applicant): TNF-Related Apoptosis Inducing Ligand (TRAIL) kills tumor cells with little effect on normal tissues and recombinant TRAIL and antibodies that recognize TRAIL receptors are in clinical trials at the University of Colorado and elsewhere. In addition, TRAIL receptor signaling determines the efficiency with which other agents kill tumor cells. However, tumor cells are often resistant to TRAIL and the mechanisms by which this occurs and what this resistance means for tumor progression and clinical outcomes is poorly understood. We recently discovered that one mechanism by which breast and ovarian tumor cells can become selectively resistant to TRAIL is through the increased expression of the homeobox transcription factor Six1. We found that increased Six1 is common, occurring in >60% of metastatic ovarian cancers and 90% of metastatic breast cancers, and associated with poor clinical outcomes. We further found that Six1 expression is sufficient to make non-metastatic tumor cells metastasize in vivo. Because TRAIL signaling is known to suppress metastasis, we hypothesize that Six1 inhibits TRAIL by a specific mechanism and this leads to increased metastasis resulting in poor clinical outcomes in patients and resistance of patient's tumors to TRAIL. To test this hypothesis we propose an integrated project that will determine the molecular mechanism by which Six1 inhibits TRAIL receptor-induced apoptosis, test if these mechanisms are responsible for increased metastasis in mice and determine whether these effects apply in primary tumor cells from patients and if they lead to worse clinical outcomes. Because this work encompasses research on basic mechanisms at the cellular level, testing those mechanisms in animal models of cancer progression and metastasis and clinical and translational studies in ovarian and breast cancer patients' tumors, we have adopted a team approach that will involve a cell biologist with expertise in TRAIL signaling (Dr. Thorburn), a pioneer in the analysis of Six1 in cancer development and progression (Dr. Ford) and an oncologist with expertise in clinical and translational research (Dr. Behbakht). To achieve these goals we have the following aims: 1. Determine how Six1 alters signaling by TRAIL receptor-targeted therapeutic agonists in ovarian and breast cancer. 2. Test if Six1-induced metastasis involves the TRAIL resistance mechanism, and 3. Determine if Six1 expression predicts TRAIL sensitivity and prognosis in patient tumors. Together, these aims should allow us to understand how Six1 regulates TRAIL receptor signaling, determine the role of these mechanisms in tumor metastasis and test if the same mechanisms apply in breast and ovarian cancer patients and thus determines their clinical outcomes. PUBLIC HEALTH RELEVANCE: Breast and ovarian cancer are the second and fifth leading causes of cancer death in women. One exciting new approach to treating these (and other) cancers is to use therapies that directly activate TRAIL receptors, however many tumor cells are resistant to these therapies. This project focuses on one mechanism (Six1 expression) by which tumor cells become resistant to TRAIL that our data indicate affect a high proportion of metastatic cancer patients (~60-90%). By understanding how this mechanism causes resistance to TRAIL, how this affects disease progression and metastasis and how this alters clinical outcomes in patients, we should gain new insights into the value of Six1 as a prognostic marker and better understand how to use the TRAIL therapeutics that are being developed.