Biology and Therapy of High Risk Neuroblastoma

高危神经母细胞瘤的生物学和治疗

• 批准号: 8506982
• 负责人: ROBERT Charles SEEGER
• 金额: $ 187.65万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-06 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506982
• 关键词: Accounting; Address; Adult; Age; Age-Months; Antibodies; Binding; Binding Proteins; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biology; Blood; Blood specimen; Bone Marrow; Bone Marrow Neoplasms; Canada; Cell Line; Cells; Cellular biology; Cephalic; Child; Childhood Solid Neoplasm; Clinical; Clinical Research; Clinical Trials; Collaborations; Consolidation Therapy; Critical Pathways; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Developmental Biology; Developmental Therapeutics Program; Diagnosis; Disease; Dose; Drug Targeting; Drug resistance; FDA approved; Femur; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Guanidines; Human; Image; Imaging technology; Immune system; Immunosuppressive Agents; Immunotherapy; In Vitro; Institution; Interleukin-12; Interleukin-2; Interleukin-6; Laboratories; Lead; MYCN gene; Malignant Neoplasms; Mesenchymal; Metastatic Neoplasm to the Bone; Modeling; Molecular and Cellular Biology; Monoclonal Antibody Ch14.18; Mouse Cell Line; Mus; Myeloid Cells; N-Myc Protein; NOD/SCID mouse; Natural Killer Cells; Neoadjuvant Therapy; Neoplasm Metastasis; Neuroblastoma; Newly Diagnosed; North America; Operative Surgical Procedures; Osteoclasts; Outcome; PIK3CG gene; Pathway interactions; Patients; Pediatric Oncology; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I/II Trial; Primary Neoplasm; Principal Investigator; Proteins; Recurrence; Recurrent disease; Refractory; Refractory Disease; Research; Research Personnel; Residual Neoplasm; Residual state; Resistance; Role; STAT3 gene; Schedule; Series; Sirolimus; Site; Staging; Subgroup; Testing; Therapeutic Human Experimentation; Transgenic Mice; Transgenic Model; Xenograft Model; antibody-dependent cell cytotoxicity; aurora-A kinase; base; bone; cell growth; chemokine; chemotherapy; clinical remission; combinatorial; cytokine; cytotoxic; cytotoxicity; density; drug testing; high risk; human STK6 protein; improved; in vivo; in vivo Model; inhibitor/antagonist; lenalidomide; mTOR Inhibitor; macrophage; monocyte; mutant; neoplastic cell; neuroblastoma cell; noradrenaline transporter; novel; novel strategies; pre-clinical; pre-clinical research; programs; radiation effect; research study; response; small molecule; therapeutic target; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): Neuroblastoma is the most common extra cranial solid tumor of childhood, and 45% of patients have aggressive tumors, nearly all of which are metastatic (stage 4) when diagnosed. Over the past 20 years, long-term survival has steadily improved to 40% with increasing intensity of non-specific cytotoxic induction and consolidation therapy and with biotherapy of minimal residual disease after consolidation. Even though long-term survival has improved, the limit of host tolerance for non-specific cytotoxic therapy has been reached. We hypothesize that improved survival for newly diagnosed patients as well as for established patients with refractory or recurrent disease will result from new combinatorial therapies that target critical pathways of tumor and host cells that promote neuroblastoma growth and survival in primary and metastatic sites. Thus, the unifying theme of this PPG is to integrate biology and developmental therapeutics research with early phase clinical trials with the overall goal of improving survival for children with high-risk neuroblastoma. Our Specific Aims are as follows: 1) Perform biologic research to identify and further understand molecules and pathways of tumor and microenvironment cells that are responsible for neuroblastoma growth. 2) Perform pre-clinical therapeutic research with drugs and biologics to develop effective strategies against neuroblastoma. 3) Perform early phase clinical trials of combinatorial strategies targeting molecules and pathways of tumor and microenvironment cells to determine appropriate dose and schedule, pharmacology and pharmacodynamics, and, within the context of such trials, anti-tumor activity. Project 1: The bone marrow microenvironment is investigated with emphasis on the role of IL-6 and STAT3 activation in bone marrow and bone metastasis and on identifying effective drugs and biologics that target this pathway. Project 2: Immunotherapy strategies focus on natural killer (NK) cells. Studies maximize NK activity with tumor cell targeting antibodies and with agents that modify the tumor microenvironment milieu to minimize NK suppressive effects of monocytes/macrophages producing IL-6 and TGF?1. Project 3: Small molecules, including PI3K, PI3K+mT0R, and Aurora Kinase A inhibitors that result in destabilization and degradation [sic] the MYCN protein, are investigated for their anti-tumor cell activity as well as their effects upon microenvironment cells. Project 4: New strategies developed in our laboratories are tested in phase I and II trials by the New Approaches to Neuroblastoma Therapy (NANT) consortium (www.nant.org), which includes 15 pediatric oncology institutions across the US and in Canada.

描述(申请人提供)：神经母细胞瘤是最常见的儿童颅外实体瘤，45%的患者有侵袭性肿瘤，几乎所有患者在诊断时都是转移性的(4期)。在过去的20年里，随着非特异性细胞毒诱导和巩固治疗强度的增加，以及巩固后微小残留病的生物治疗，长期存活率稳步提高到40%。尽管长期存活率有所提高，但宿主对非特异性细胞毒治疗的耐受性已经达到极限。我们假设，新诊断的患者以及已确诊的难治性或复发性疾病患者的生存率将来自于新的组合疗法，这些疗法针对肿瘤和宿主细胞的关键途径，促进神经母细胞瘤在原发和转移部位的生长和存活。因此，PPG的统一主题是将生物学和发育疗法研究与早期临床试验相结合，总体目标是提高高危神经母细胞瘤儿童的存活率。我们的具体目标如下：1)进行生物学研究，以确定和进一步了解与神经母细胞瘤生长有关的肿瘤和微环境细胞的分子和途径。2)开展药物和生物制剂的临床前治疗研究，以开发针对神经母细胞瘤的有效策略。3)进行针对肿瘤和微环境细胞的分子和途径的组合策略的早期临床试验，以确定适当的剂量和时间表、药理学和药效学，并在这些试验的背景下，确定抗肿瘤活性。项目1：研究骨髓微环境，重点是IL-6和STAT3的激活在骨髓和骨转移中的作用，以及寻找针对这一途径的有效药物和生物制品。项目2：免疫治疗策略侧重于自然杀伤(NK)细胞。研究使用肿瘤细胞靶向抗体和改善肿瘤微环境的药物来最大化NK活性，以最大限度地减少产生IL-6和转化生长因子？1的单核/巨噬细胞对NK的抑制作用。项目3：研究了导致MYCN蛋白失稳和降解的小分子，包括PI3K、PI3K+mT0R和Aurora Kinase A抑制剂[SIC]它们的抗肿瘤细胞活性及其对微环境细胞的影响。项目4：我们实验室开发的新策略由神经母细胞瘤治疗新方法(NANT)财团(www.nant.org)在第一和第二阶段试验中进行测试，该财团包括美国和加拿大的15家儿科肿瘤学机构。