Targeting the Mullerian Inhibiting Substance pathway in gynecologic cancer

靶向苗勒氏管抑制物质通路治疗妇科癌症

• 批准号: 8208136
• 负责人: WILLIAM A CLIBY
• 金额: $ 31.74万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208136
• 关键词: Address; Adult; Affect; Anti-Mullerian Hormone Receptor Type II; Antibodies; Antineoplastic Agents; Area; Binding; Biological; Biological Response Modifier Therapy; Biology; Cancer cell line; Cause of Death; Cell Culture Techniques; Cell Death; Cell model; Cells; Chemosensitization; Complex; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Development; Dose-Limiting; Duct (organ) structure; Elements; Endometrial; Epithelial ovarian cancer; Family; Female; Fetus; Funding; Goals; Growth; Gynecologic; Hormones; Human; Image; In Vitro; Individual; Inhibition of Apoptosis; Intervention; Investigation; Knowledge; Language; Ligands; Link; Locales; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Membrane; Methylation; Minority; Modeling; Mullerian duct inhibiting substance; Mullerian-inhibiting substance receptor; Mus; Nature; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; Outcome; Ovarian; Ovarian Tissue; Pathway interactions; Patients; Pattern; Population; Property; Public Health; Publications; Publishing; Receptor Signaling; Recurrence; Research Personnel; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Specificity; Specimen; Staging; Stem cells; Structure of paramesonephric duct; System; T2R taste receptors; Testing; Testis; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Threonine; Tissues; Toxic effect; Treatment Efficacy; Type I Activin Receptors; United States; Uterine Cancer; Woman; Work; Xenograft Model; advanced disease; animal data; base; cancer cell; cancer therapy; cell growth; chemotherapy; cytotoxic; design; effective intervention; fetal; improved; in vitro testing; in vivo; insight; male; member; mouse model; mullerian-inhibiting hormone; novel; progenitor; programs; promoter; receptor; receptor expression; reproductive; research study; response; sarcoma; stem; stem cell population; trafficking; treatment effect

MISRII is a member of the TGF-¿ family of receptors. MIS receptor expression is embryologically important in the regression of the m¿llerian ducts in the male fetus after activation by MIS (ligand) secreted by the testis. This tissue-specific pattern of MISRII expression in gynecologic tissues persists in the adult. We further show this specific pattern of expression persists in the majority of gynecologic cancers supporting its relevance as a specific target of anti-cancer therapy. To that end we have been investigating the general hypothesis that MISRII is a tissue-specific receptor (target) present in gynecologic cancers which, additionally, is fundamentally linked to serine/threonine receptor-mediated pathway(s) resulting in growth inhibition and/or cell death. These concepts suggest two primary and independent therapeutic strategies: 1) utilize ligand to target MISRII directly resulting in decreased proliferation or potentiation of cytotoxic therapy, and/or 2) using the MISRII receptor as a target to specifically deliver therapy or to improve imaging, either of which would be independent of downstream signaling. Despite the appeal of this approach prior investigations have suffered from key limitations: (i) lack of delineation of the relevant T1R and downstream signaling components necessary for MIS activity; (ii) lack of attempt to interpret MIS response with expression of relevant T1Rs; (iii) expression studies based on continuous cancer cell lines fail to reflect the expression pattern in primary cancers; (iv) lack of models to adequately assess rhMIS bioactivity in cancer cell model. This information is vital for rational design and application of any MIS-based strategy: absent this, meaningful interpretation of prior in vitro studies using MIS is impossible. In this revised application we show preliminary data and experiments designed to address these limitations. Based on our work with other TGF-¿ family receptors we have designed experiments to determine the role(s) and status of T1R and T2R in MIS signaling (Aim 1). The required receptor complexes regulating Smad signaling and cell growth inhibition can will then be tested in vitro in primary cancer cultures (Aim 2) and allow us to define the specific parameters in which MIS directed therapy may be effective. Finally, we will pursue the alternative therapeutic strategy which is not predicated upon MIS- dependent signaling: using MISRII as a highly specific target to bring other therapeutic agents or imaging molecules to specific gynecologic cancers (Aim 3). Collectively, this application will provide the necessary insight into the biology of MIS signaling in gyncecologic cancers, and provide the essential data for design and interpretation of human trials targeting MISRII.

MISRII是TGF- - 受体家族的成员。错误的受体表达在胚胎学上很重要 睾丸分泌的MIS（配体）激活MIS（配体）后，男性胎儿中的M llerian管道的回归。 成年人中这种妇科组织中杂菌表达的组织特异性模式持续存在。我们进一步展示 大多数妇科癌症中的这种特定表达方式仍然存在于支持其相关性的大多数表达模式 抗癌治疗的特定靶标。为此，我们一直在研究一个总体假设 MISRII是妇科癌症中存在的组织特异性接收器（靶），另外是 从根本上与丝氨酸/苏氨酸受体介导的途径有关，导致生长抑制 和/或细胞死亡。这些概念提出了两种主要和独立的治疗策略：1）利用 配体直接靶向misrii，导致细胞毒性疗法的增殖或增强降低，和/或2） 使用MISRII接收器作为专门提供治疗或改进成像的目标 将独立于下游信号传导。尽管出现了这种方法，但先前的调查已经 受到关键局限性：（i）缺乏相关T1R和下游信号组件的描述 MIS活动所必需的； （ii）缺乏用相关T1R的表达来解释MIS反应的尝试； （iii） 基于连续癌细胞系的表达研究无法反映原发性的表达模式 癌症； （iv）缺乏足够评估癌细胞模型中RHMIS生物活性的模型。此信息是 对于任何基于MIS的策略的理性设计和应用至关重要的：没有此事的，有意义的解释 先前使用MIS的体外研究是不可能的。在此修订的应用程序中，我们显示了初步数据和 旨在解决这些局限性的实验。根据我们与其他TGF-家庭接收者的工作 已经设计了实验来确定T1R和T2R在MIS信号传导中的作用和状态（AIM 1）。这 然后可以在体外测试进行SMAD信号传导和细胞生长抑制的所需受体复合物 在原发性癌症培养物（AIM 2）中，允许我们定义误治疗的特定参数 可能有效。最后，我们将追求替代理论策略，这不是错误地预测的 依赖信号传导：使用MISRII作为高度特定的靶标，来带来其他治疗剂或成像 特定妇科癌的分子（AIM 3）。总的来说，本申请将提供必要的 深入了解体育馆癌症中MIS信号传导的生物学，并为设计提供基本数据 针对MISRII的人类试验的解释。