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: 8099677
• 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/8099677
• 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; public health relevance; receptor; receptor expression; reproductive; research study; response; sarcoma; stem; stem cell population; trafficking; treatment effect

DESCRIPTION (provided by applicant): MISRII is a member of the TGF-2 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-2 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. PUBLIC HEALTH RELEVANCE: Relevance to the public health (lay language): Management of advanced ovarian and uterine cancers is inadequate and most patients with advanced disease will die of their cancer. To make progress in the management of these cancers, novel and specific targets that distinguish cancer cells from normal cells are needed. MISRII is a receptor present specifically in the majority of these cancers. This provides a unique target that distinguishes the cancer cells from normal cells. Some evidence suggests that activating this receptor by exposing it to its hormone (MIS) results in growth arrest and increased sensitivity to chemotherapy. While some work has been done in this field it has been limited by: (i) key gaps in knowledge of the underlying signaling pathways needed for activation; and (ii) lack of appropriate models to test outcomes in human cancers. We will determine the conditions necessary for this response and test the ability to treat human cancers with MIS. A second, non-overlapping approach will target the receptor directly as a 'bait' to deliver toxic agents to the cancer cells. Such specific delivery would increase treatment effect and decrease associated toxicities in normal tissues. This projects brings together two investigators with distinctly different areas of expertise to address both the fundamental biologic aspects of the pathway and the translational aspects of targeting this receptor in cancer.

描述（由申请人提供）： MISRII 是 TGF-2 受体家族的成员。 MIS 受体表达对于男性胎儿苗勒管在被睾丸分泌的 MIS（配体）激活后的退化具有重要的胚胎学意义。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。我们进一步表明这种特定的表达模式在大多数妇科癌症中持续存在，支持其作为抗癌治疗的特定靶点的相关性。为此，我们一直在研究一个普遍的假设，即 MISRII 是妇科癌症中存在的一种组织特异性受体（靶标），此外，它与丝氨酸/苏氨酸受体介导的途径有根本的联系，导致生长抑制和/或细胞死亡。这些概念提出了两种主要且独立的治疗策略：1) 利用配体直接靶向 MISRII，从而导致细胞毒性治疗的增殖减少或增强，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将独立于下游信令。尽管这种方法很有吸引力，但先前的研究仍受到关键限制：(i) 缺乏对 MIS 活动所需的相关 T1R 和下游信号成分的描述； (ii) 缺乏用相关 T1R 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未能反映原发性癌症中的表达模式； (iv) 缺乏模型来充分评估癌细胞模型中的 rhMIS 生物活性。这些信息对于任何基于 MIS 的策略的合理设计和应用都至关重要：如果没有这些信息，就不可能对使用 MIS 进行的先前体外研究进行有意义的解释。在这个修订后的应用程序中，我们展示了旨在解决这些限制的初步数据和实验。基于我们与其他 TGF-2 家族受体的合作，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，可以在原代癌症培养物中体外测试调节 Smad 信号传导和细胞生长抑制所需的受体复合物（目标 2），并允许我们定义 MIS 定向治疗可能有效的具体参数。最后，我们将寻求不以 MIS 依赖性信号传导为基础的替代治疗策略：使用 MISRII 作为高度特异性的靶点，将其他治疗剂或成像分子引入特定的妇科癌症（目标 3）。总的来说，该应用将为妇科癌症中 MIS 信号传导的生物学提供必要的见解，并为针对 MISRII 的人体试验的设计和解释提供必要的数据。 公共卫生相关性： 与公共卫生的相关性（外行语言）：晚期卵巢癌和子宫癌的治疗不充分，大多数晚期疾病患者将死于癌症。为了在这些癌症的治疗方面取得进展，需要区分癌细胞与正常细胞的新颖且特定的靶点。 MISRII 是大多数此类癌症中特有的受体。这提供了区分癌细胞与正常细胞的独特靶点。一些证据表明，通过将其暴露于激素（MIS）来激活该受体会导致生长停滞并增加对化疗的敏感性。尽管在这一领域已经开展了一些工作，但仍受到以下因素的限制：(i) 对激活所需的基础信号通路的了解存在关键差距； (ii) 缺乏适当的模型来测试人类癌症的结果。我们将确定这种反应所需的条件，并测试 MIS 治疗人类癌症的能力。第二种不重叠的方法将直接靶向受体作为“诱饵”，将有毒物质输送到癌细胞。这种特异性递送将提高治疗效果并减少正常组织中的相关毒性。该项目汇集了两位具有明显不同专业领域的研究人员，以解决该途径的基本生物学方面以及针对癌症中该受体的转化方面。