TRAIL Receptor Signaling in Human Tumors

人类肿瘤中的 TRAIL 受体信号转导

• 批准号: 7664007
• 负责人: Kian Behbakht
• 金额: $ 41.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664007
• 关键词: Address; Adopted; Affect; Agonist; Animal Model; Antibodies; Apoptosis; Binding; Breast; Cancer Etiology; Cancer Patient; Cell Surface Receptors; Cells; Cessation of life; Clinical; Clinical Trials; Colorado; Data; Development; Disease; Disease Progression; Disseminated Malignant Neoplasm; Goals; Grant; Homeobox; Human; Immunohistochemistry; In Vitro; Lead; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Mass Spectrum Analysis; Mediating; Metastasis Suppression; Methods; Molecular; Mus; Neoplasm Metastasis; Normal tissue morphology; Oncologist; Outcome; Ovarian; Patients; Primary Neoplasm; Prognostic Marker; Proteins; Receptor Signaling; Recombinant TNF-Related Apoptosis-Inducing Ligand; Research; Resistance; Role; Signal Pathway; Signal Transduction; TNF-related apoptosis-inducing ligand; TNFRSF10A gene; TNFRSF10B gene; TNFSF10 gene; Testing; Therapeutic; Translational Research; Universities; Woman; Work; cancer therapy; in vivo; insight; killings; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel strategies; outcome forecast; ovarian neoplasm; overexpression; public health relevance; receptor; research study; resistance mechanism; response; therapeutic target; therapy resistant; transcription factor; translational study; treatment strategy; tumor; tumor progression

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.

描述（由申请人提供）：TNF相关细胞凋亡诱导配体（TRAIL）杀死肿瘤细胞，对正常组织影响很小，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，而这种耐药性发生的机制以及这种耐药性对肿瘤进展和临床结果意味着什么，人们知之甚少。我们最近发现，乳腺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 升高很常见，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发生转移。由于 TRAIL 信号传导已知可抑制转移，因此我们假设 Six1 通过特定机制抑制 TRAIL，这会导致转移增加，从而导致患者临床结果不佳以及患者肿瘤对 TRAIL 产生耐药性。为了检验这一假设，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，测试这些机制是否导致小鼠转移增加，并确定这些效应是否适用于患者的原发性肿瘤细胞，以及它们是否会导致更差的临床结果。由于这项工作涵盖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在卵巢癌和乳腺癌患者肿瘤中进行临床和转化研究，因此我们采用了一种团队方法，其中包括一位在 TRAIL 信号传导方面具有专业知识的细胞生物学家（Thorburn 博士）、一位在癌症发生和进展中分析 Six1 的先驱者（Ford 博士）以及一位在临床和乳腺癌方面具有专业知识的肿瘤学家。 转化研究（Behbakht 博士）。为了实现这些目标，我们有以下目标： 1. 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. 测试 Six1 诱导的转移是否涉及 TRAIL 抵抗机制，以及 3. 确定 Six1 表达是否可以预测患者肿瘤中的 TRAIL 敏感性和预后。总之，这些目标应该使我们能够了解 Six1 如何调节 TRAIL 受体信号传导，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，然而许多肿瘤细胞对这些疗法有抵抗力。该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很大比例的转移性癌症患者（约 60-90%）。通过了解这种机制如何导致 TRAIL 耐药、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 疗法。