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

基本信息

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
项目类别：
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

项目摘要

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-¿ 的成员MIS 受体家族的表达在胚胎学上很重要。 m 的回归男性胎儿中的伊勒氏管被睾丸分泌的 MIS（配体）激活后。我们进一步表明，妇科组织中 MISRII 表达的这种组织特异性模式在成人中持续存在。这种特定的表达模式持续存在于大多数妇科癌症中，支持其作为一种治疗手段的相关性。为此，我们一直在研究以下一般假设： MISRII 是妇科癌症中存在的一种组织特异性受体（靶标），此外，与丝氨酸/苏氨酸受体介导的途径根本相关，导致生长抑制这些概念提出了两种主要且独立的治疗策略：1）利用靶向 MISRII 的配体直接导致细胞毒性治疗增殖减少或增强，和/或 2) 使用 MISRII 受体作为靶点来特异性地提供治疗或改善成像，其中任一尽管这种方法很有吸引力，但之前的研究表明它与下游信号无关。受到关键限制：(i) 缺乏相关 T1R 和下游信号成分的描述 MIS 活动所必需的；(ii) 缺乏用相关 T1R 的表达来解释 MIS 响应的尝试；基于连续癌细胞系的表达研究未能反映原代细胞中的表达模式癌症；(iv) 缺乏模型来充分评估癌细胞模型中的 rhMIS 生物活性。对于任何基于管理信息系统的战略的合理设计和应用至关重要：如果没有这一点，有意义的解释之前使用 MIS 进行体外研究是不可能的。在这个修订后的应用程序中，我们展示了初步数据和旨在解决这些限制的实验基于我们与其他 TGF-¿家族受体我们设计了实验来确定 T1R 和 T2R 在 MIS 信号传导中的作用和状态（目标 1）。然后可以在体外测试调节 Smad 信号传导和细胞生长抑制所需的受体复合物在原发性癌症培养物中（目标 2），并允许我们定义 MIS 指导治疗的具体参数最后，我们将寻求不以 MIS 为基础的替代治疗策略。依赖性信号传导：使用 MISRII 作为高度特异性的靶点来引入其他治疗剂或成像总的来说，该应用程序将提供针对特定妇科癌症的分子（目标 3）。深入了解妇科癌症中 MIS 信号传导的生物学，并为设计和提供必要的数据针对 MISRII 的人体试验的解释。