Gene expression profiling vs MRD assessment in Myeloma

骨髓瘤中的基因表达谱与 MRD 评估

• 批准号: 7260387
• 负责人: Guido J. Tricot
• 金额: $ 25.78万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-13 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7260387
• 关键词: Acute leukemia; Address; Autologous; Autologous Transplantation; BAD gene; Bad protein; Biological Markers; Biometry; Biopsy; Blood specimen; Bone Diseases; Bone Marrow; Bone Marrow Cells; Bortezomib; Cells; Characteristics; Chromosome abnormality; Chronic; Classification; Complementary DNA; Computer software; Cytogenetics; Cytotoxic Chemotherapy; Data; Data Analyses; Diagnosis; Diffuse; Disease; Disease Progression; Disease Resistance; Disease remission; Disease-Free Survival; Doctor of Philosophy; Dose; Drug resistance; Ensure; Evolution; Exhibits; Fine needle aspiration biopsy; Gene Components; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Gold; Growth; Immunoglobulins; Individual; Infiltration; Kinetics; Lesion; Link; M-proteins (Myeloma); Magnetic Resonance Imaging; Malignant Neoplasms; Marrow; Maximum Tolerated Dose; Measurement; Measures; Metaphase; Modeling; Molecular; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Myeloproliferative disease; Nature; Needles; Neoadjuvant Therapy; Nested PCR; Newly Diagnosed; No Evidence of Disease; Osteoblasts; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma Cells; Polymerase Chain Reaction; Positron-Emission Tomography; Principal Investigator; Prior Therapy; Production; Prognostic Factor; Program Research Project Grants; Proteins; Protocols documentation; RNA; Rate; Relapse; Reliance; Reporting; Research Institute; Research Personnel; Residual Neoplasm; Residual state; Resistance; Risk; Sampling; Score; Standards of Weights and Measures; Surrogate Markers; Techniques; Technology; Testing; Thalidomide; Therapeutic Studies; Time; Transplantation; Treatment Failure; Treatment outcome; Tumor Burden; Washington; anticancer research; base; blind; cell killing; experience; follow-up; improved; inhibitor/antagonist; neoplastic cell; novel; older patient; peripheral blood; prevent; prognostic; programs; second transplant; tool; tumor

DESCRIPTION (provided by applicant): Significant progress has been made in myeloma therapy, including >20% 10 year event-free survival (EFS). However, the disease remains largely incurable, and outcome in myeloma is difficult to predict. There is no reliable early surrogate marker for long-term outcome that would allow adjustment of treatment in an individual patient to avoid excessive or inadequate treatment. To further improve outcome, we must have better tools to measure the degree of tumor reduction after intensive therapy and a better understanding of the myeloma-specific genetic features related to poor or excellent survival. As currently defined, complete remission (CR) is a poor reflection of tumor load, due in part to the focal nature of myeloma and the heavy reliance of CR on myeloma (M) protein measurements, knowing that there is a major inter- and intra-patient variability in immunoglobulin production per myeloma cell. We hypothesize that predicting treatment outcome will not only depend on accurate assessment of the remaining tumor load after therapy, but also on genetic characteristics of an individual's myeloma cells. In Aim 1, we will determine the tumor burden after tandem transplants using CDR3-PCR technology in patients with high-risk myeloma (i.e., relapsing during the first 2 years after the first transplant) and in patients with low-risk myeloma (i.e., EFS >4 years). We will assess minimal residual disease (MRD) in random bone marrow and in peripheral blood as well as in focal lesions identified by MRI/PET scan. In Aim 2, we will identify the gene expression profile (GEP) associated with high risk of early progression versus prolonged remission and describe its component genes and molecular pathways. We will also construct validated prediction models. GEP will be performed at baseline, after induction therapy, and at relapse, as well as on focal MRI/PET lesions persisting in remission. This will allow us to evaluate whether a major resistant clone is already present at diagnosis, whether induction therapy acts to select out a small subclone of resistant myeloma cells, or whether resistant myeloma develops mainly as the consequence of treatment. Key genes related to poor outcome that are thus identified and validated can be targeted by specific novel therapies to maintain remissions. Distinction between the importance of absolute tumor reduction versus genetic characteristics as the major cause of treatment failure and dissecting genetic characteristics at baseline, follow-up, and relapse will provide invaluable information about the progression of myeloma. This information could then be used to apply better treatment approaches, ensuring some patients (low-risk) are not over-treated and others (high-risk) receive adequate treatment. These findings can serve as a model for treatment approaches in other chronic lymphoproliferative and myeloproliferative malignancies, which exhibit a similar disease progression.

描述（申请人提供）：骨髓瘤治疗已取得重大进展，包括>20%的10年无事件生存率（EFS）。然而，这种疾病在很大程度上仍然是不可治愈的，骨髓瘤的结局难以预测。没有可靠的长期结局的早期替代标志物，可以调整个体患者的治疗，以避免过度或不充分的治疗。为了进一步改善预后，我们必须有更好的工具来衡量强化治疗后肿瘤缩小的程度，并更好地了解与生存不良或良好相关的骨髓瘤特异性遗传特征。根据目前的定义，完全缓解（CR）是肿瘤负荷的不良反映，部分原因是骨髓瘤的局灶性和CR对骨髓瘤（M）蛋白测量的严重依赖，已知每个骨髓瘤细胞的免疫球蛋白产生存在重大的患者间和患者内变异性。我们假设，预测治疗结果不仅取决于治疗后剩余肿瘤负荷的准确评估，还取决于个体骨髓瘤细胞的遗传特征。在目标1中，我们将使用CDR 3-PCR技术确定高危骨髓瘤患者（即，在第一次移植后的前2年内复发）和低风险骨髓瘤患者（即，EFS >4年）。我们将评估随机骨髓和外周血以及MRI/PET扫描确定的局灶性病变中的微小残留病（MRD）。在目标2中，我们将确定与早期进展与长期缓解的高风险相关的基因表达谱（GEP），并描述其组成基因和分子途径。我们还将构建有效的预测模型。将在基线、诱导治疗后和复发时以及持续缓解的局灶性MRI/PET病灶上进行GEP。这将使我们能够评估在诊断时是否已经存在主要的耐药克隆，诱导治疗是否可以选择出耐药骨髓瘤细胞的小亚克隆，或者耐药骨髓瘤的发展是否主要是治疗的结果。由此鉴定和验证的与不良结局相关的关键基因可以通过特定的新疗法靶向以维持缓解。区分绝对肿瘤缩小与遗传特征作为治疗失败主要原因的重要性，并在基线、随访和复发时解剖遗传特征，将提供有关骨髓瘤进展的宝贵信息。然后，这些信息可以用于应用更好的治疗方法，确保一些患者（低风险）不会过度治疗，而另一些患者（高风险）则得到充分的治疗。这些发现可以作为其他慢性淋巴细胞增生性和骨髓增生性恶性肿瘤的治疗方法的模型，表现出类似的疾病进展。