Beta 2-Microglobulin signaling and targeting in bone metastasis

骨转移中的 Beta 2-微球蛋白信号传导和靶向

• 批准号: 7941078
• 负责人: LELAND W.K. CHUNG
• 金额: $ 30.35万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941078
• 关键词: Address; Affect; Androgen Receptor; Androgens; Antibodies; Apoptosis; Biological; Biology; Cancer Cell Growth; Cancer Patient; Cell Death; Cell Line; Cells; Cellular Stress; Clinical; Clinical Protocols; Complex; DNA Damage; DNA Repair Enzymes; Development; Effectiveness; Exhibits; Experimental Models; Future; Gene Targeting; Genes; Gleason Grade for Prostate Cancer; Growth; Growth Factor; Hereditary hemochromatosis; Histocompatibility Antigens Class I; Hormones; Human; Immune; Immunity; Ionizing radiation; Iron; LNCaP; Laboratories; Liquid substance; Major Histocompatibility Complex; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Mediating; Metastatic Neoplasm to the Bone; MicroRNAs; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Multiple Myeloma; Mus; Normal Cell; Oxidation-Reduction; Pathway interactions; Production; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Proteins; Radiation; Reactive Oxygen Species; Recommendation; Recycling; Refractory; Regimen; Regulation; Renal Cell Carcinoma; Reporting; Role; Safety; Series; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Skeleton; Solid; Specimen; Stromal Cells; Testing; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Tissues; Toxic effect; Transferrin; Transferrin Receptor; Transgenic Mice; Translations; Work; Xenograft procedure; base; bench to bedside; beta-2 Microglobulin; biological adaptation to stress; bone; cancer cell; combinatorial; cytotoxicity; epithelial to mesenchymal transition; fascinate; improved; mortality; mouse model; multiple myeloma M Protein; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutic intervention; preclinical study; protocol development; public health relevance; receptor; response; soft tissue; survivin; synergism; tumor; tumor xenograft; uptake; urinary

DESCRIPTION (provided by applicant): In this revised application, we have taken the recommendations from the reviewers by focusing specifically on the development of anti-b2-Microglobulin (b2-M) antibody as a therapeutic agent for the treatment of human prostate cancer bone metastasis. In addition, we also provided new information on a putative b2-M receptor, a novel strategy exploiting b2-M-receptor mediated cell signaling mechanisms and combinatorial approach achieving synergism between anti-b2-M monoclonal antibody (mAb) plus radiation as a promising therapeutic regimen for prostate cancer bone metastases. The hypothesis of this proposal is that anti-b2-M mAb interferes with HFE (a hereditary hemochromatosis associated gene)-TFRC (Transferrin Receptor)-TF (Transferrin) complex and iron transport, thus provokes downstream redox signaling changes with microRNAs (miRNAs) serving as regulators for a series of cell stress response proteins and DNA repair enzymes that ultimately trigger cell death in cancer but not normal cells. Two Specific Aims are proposed in this revised application. Specific Aim 1: to develop anti-b2-M mAb as a therapeutic antibody for prostate cancer bone metastasis therapy using experimental human prostate cancer xenograft and transgenic mouse models, evaluate antibody toxicity in mice, and determine the synergistic interaction between anti-b2-M mAb plus ionizing radiation on the growth of prostate cancer cells and tumors. This Aim is based on our discovery that b2-M is a major growth factor and pleiotropic signaling molecule that confers the growth, survival, and epithelial to mesenchymal transition (EMT) of human prostate cancer cells. Successful accomplishment of this Aim will allow accelerated translation of targeting b2-M as a novel therapeutic approach for human prostate cancer bone metastasis. Specific Aim 2: to evaluate and validate a putative b2-M receptor, a non-classical major histocompatibility complex (MHC)-like molecule, the hereditary hemochromatosis associated gene, HFE. The functional role of HFE and its relationship to TFRC-TF complex, iron uptake, reactive oxygen species (ROS) production, DNA damages, and cell death will be assessed. In this aim, we will investigate the function of anti-b2-M mAb on TFRC-TF complex that could promote iron uptake via endosomal iron recycling, production of ROS and highly reactive hydroxy radicals that could cause DNA damages in cancer but not normal cells. Regulation of miRNAs, potential downstream targets of redox signaling, on cell stress response proteins and DNA repair enzymes will be specially emphasized. In summary, this revised application carefully follows the recommendations of the reviewers to develop novel approaches for targeting b2-M-mediated downstream growth and signaling pathways in human prostate cancer, which has exciting potential for clinical translation to manage prostate cancer bone metastasis. PUBLIC HEALTH RELEVANCE: Prostate cancer bone metastasis contributes to mortality and morbidity of prostate cancer patients. We have developed a new therapeutic approach by using a novel anti-b2-Microglobulin antibody plus radiation, which has been shown to completely abolish the growth of human tumors in mice. This project focuses on defining the molecular mechanism of this synergism and the appropriate preclinical studies to move these discoveries from bench to the bedside.

描述(申请人提供)：在这份修订后的申请中，我们采纳了评审者的建议，特别关注抗b2-微球蛋白(b2-M)抗体作为治疗人类前列腺癌骨转移的治疗剂的开发。此外，我们还提供了关于可能的b2-M受体的新信息，这是一种利用b2-M受体介导的细胞信号转导机制的新策略，以及实现抗b2-M单抗(MAb)与放射之间的协同作用的组合方法，作为一种有前景的前列腺癌骨转移治疗方案。这一假设是，抗b2-M单抗干扰HFE(遗传性血色病相关基因)-TFRC(转铁蛋白受体)-TF(转铁蛋白)复合体和铁的运输，从而引发下游氧化还原信号的变化，microRNAs(MiRNAs)作为一系列细胞应激反应蛋白和DNA修复酶的调节因子，最终在癌症而不是正常细胞中触发细胞死亡。在这份修订后的申请中，提出了两个具体目标。具体目的1：利用实验性人前列腺癌移植瘤和转基因小鼠模型，制备抗b2-M单抗作为前列腺癌骨转移治疗的治疗性抗体，评价其在小鼠体内的毒性，并确定抗b2-M单抗联合电离辐射对前列腺癌细胞和肿瘤生长的协同作用。这一目标是基于我们的发现，即b2-M是一种主要的生长因子和多效性信号分子，它促进人前列腺癌细胞的生长、存活和上皮向间充质转化(EMT)。这一目标的成功实现将使靶向b2-M作为治疗人类前列腺癌骨转移的新方法的加速转化成为可能。具体目的2：评估和验证一个可能的b2-M受体，一个非经典的主要组织相容性复合体(MHC)样分子，遗传性血色病相关基因HFE。HFe的功能作用及其与TFRC-TF复合体、铁摄取、活性氧物种(ROS)的产生、DNA损伤和细胞死亡的关系将被评估。为此，我们将研究抗b2-M单抗在TFRC-Tf复合体上的作用，TFRC-Tf复合体可以通过内体铁循环、ROS的产生和高活性的羟基自由基的产生来促进铁的摄取，从而在癌细胞中导致DNA损伤，而不是在正常细胞中。将特别强调miRNAs，氧化还原信号的潜在下游靶标，对细胞应激反应蛋白和DNA修复酶的调节。总之，这一修订后的应用程序仔细遵循了评审者的建议，开发了针对b2-M介导的人类前列腺癌下游生长和信号通路的新方法，这对临床治疗前列腺癌骨转移具有令人兴奋的潜力。公共卫生相关性：前列腺癌骨转移导致前列腺癌患者的死亡率和发病率。我们开发了一种新的治疗方法，使用一种新型的抗b2-微球蛋白抗体加放射，已被证明完全消除了小鼠体内人类肿瘤的生长。该项目的重点是确定这种协同作用的分子机制和适当的临床前研究，以将这些发现从试验台转移到床边。