TRAIL Receptor Signaling in Human Tumors

描述（由申请人提供）：tnf相关凋亡诱导配体（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受体信号传导决定了其他药物杀死肿瘤细胞的效率。然而，肿瘤细胞通常对TRAIL具有耐药性，其发生的机制以及这种耐药性对肿瘤进展和临床结果的意义尚不清楚。我们最近发现，乳腺癌和卵巢肿瘤细胞选择性抵抗TRAIL的一种机制是通过增加同源盒转录因子Six1的表达。我们发现Six1的增加很常见，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。由于已知TRAIL信号可以抑制转移，我们假设Six1通过一种特定的机制抑制TRAIL，这导致转移增加，导致患者临床结果不佳，患者肿瘤对TRAIL产生耐药性。为了验证这一假设，我们提出了一个综合项目，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，并确定这些作用是否适用于患者的原发肿瘤细胞，以及它们是否会导致更差的临床结果。由于这项工作包括细胞水平的基本机制研究，在癌症进展和转移的动物模型中测试这些机制，以及卵巢癌和乳腺癌患者肿瘤的临床和转化研究，我们采用了一种团队方法，将包括具有TRAIL信号专长的细胞生物学家（Thorburn博士）。他是癌症发展和进展中Six1分析的先驱（Ford博士），也是具有临床和转化研究专业知识的肿瘤学家（Behbakht博士）。为实现这些目标，我们有以下目标：确定Six1如何改变卵巢癌和乳腺癌中TRAIL受体靶向治疗激动剂的信号传导。2. 2 .检测six1诱导的转移是否涉及TRAIL耐药机制；确定Six1表达是否预测肿瘤患者TRAIL敏感性和预后。总之，这些目标应该让我们了解Six1如何调节TRAIL受体信号，确定这些机制在肿瘤转移中的作用，并测试相同的机制是否适用于乳腺癌和卵巢癌患者，从而确定其临床结果。公共卫生相关性：乳腺癌和卵巢癌是妇女癌症死亡的第二大和第五大原因。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，尽管许多肿瘤细胞对这些疗法有抗药性。本项目重点研究肿瘤细胞对TRAIL产生耐药性的一种机制（Six1表达），我们的数据表明，这种机制影响了大部分转移性癌症患者（~60-90%）。通过了解这种机制如何引起对TRAIL的耐药性，如何影响疾病进展和转移，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认识，并更好地了解如何使用正在开发的TRAIL治疗方法。

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.