Chromosomal Abnormalities in Myeloma as Detected by FISH

FISH 检测骨髓瘤染色体异常

• 批准号: 7653937
• 负责人: Rafael Fonseca
• 金额: $ 36.66万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653937
• 关键词: 17p13; Address; Allogenic; Applications Grants; Biological Assay; Bortezomib; Categories; Chromosome abnormality; Clinical; Clinical Trials; Consolidation Therapy; Cytogenetics; Development; Diagnosis; Disease; Disease-Free Survival; Eastern Cooperative Oncology Group; Gene Mutation; Genetic; Genetic Markers; Genomics; Grant; Intervention; Melphalan; Molecular; Molecular Genetics; Multiple Myeloma; NF-kappa B; Newly Diagnosed; Outcome; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Predisposition; Prognostic Factor; Randomized Controlled Clinical Trials; Research; Research Personnel; Risk; Role; Sampling; Stem cell transplant; TNF receptor-associated factor 3; Thalidomide; Therapeutic Agents; Time; Treatment Protocols; base; high risk; improved; lenalidomide; novel; novel therapeutics; outcome forecast; prognostic; public health relevance; research study; response; therapy development; treatment strategy

DESCRIPTION (provided by applicant): Understanding the impact of known and new genetic factors in the context of novel therapies is paramount to best define the optimal treatment strategy for multiple myeloma (MM) patients. Our group has been at the forefront of prognosis determination based on genetic factors. In addition, we recently discovered that up to 50% of MM cases have constitutive activation of the NF-kB pathway, through multiple genetic mutations, all leading to increased activity of the non-canonical pathway. Importantly we have shown these patients have greatly increased sensitivity to bortezomib. The treatment of MM can no longer be conducted under a "one size fits all" approach, and it is imperative that we validate genetic prognostic and predictive markers for the selection of MM treatments. While novel therapeutic agents have improved the overall prospects for patients, the net effect might be different based on the molecular subtypes. Some of the novel therapies and strategies have the potential to improve the outcome of "high risk"-MM (HR-MM). Patients with "standard risk" MM (SR- MM) might benefit from simpler, less toxic, interventions, while HR-MM patients will need the introduction of more intensive regimens such as early bortezomib and/or non-myeloablative allogeneic stem cell transplant (NM-SCT) strategies. To address these issues, and at center of this project proposal, we ask the following questions: 1. Can thalidomide and lenalidomide overcome the negative prognosis of HR-MM? 2. Can we identify new genomic markers associated with long time to progression in patients treated with lenalidomide and thalidomide? 3. Can bortezomib result in better responses and outcome in patients with HR-MM? 4. Can NF-kB hyperactivation or TRAF3 inactivation predict improved outcome with bortezomib? 5. Can NM-SCT overcome the poor prognosis of t(4;14)(p16;q32)? To address these questions we propose the following experiments, using a panel of molecular and genetic assays employing clinical samples associated with five Phase 3 clinical trials. Globally these trials include over 1500 patient treated with various combinations of lenalidomide, thalidomide and bortezomib. They include the ECOG clinical trials E1A00, E4A03, E1A05 and E1A06. In addition we propose to study the prognostic significance of t(4;14)(p16;q32) in a large randomized trial (n = 700) addressing the role of NM-SCT for newly diagnosed MM. To do so we will examine research samples associated with the clinical trial BMT CTN 0102. PUBLIC HEALTH RELEVANCE: This grant proposal aims to better define which treatments should be given to which genetic subtypes of myeloma, to provide optimal and risk adapted therapy for patients.

描述（由申请人提供）：了解已知和新的遗传因素在新疗法背景下的影响至关重要，最重要的是最好定义多发性骨髓瘤（MM）患者的最佳治疗策略。基于遗传因素，我们的小组一直处于预后确定的最前沿。此外，我们最近发现，多达50％的MM病例通过多个遗传突变对NF-KB途径进行了组成式激活，这所有突变都导致了非经典途径的活性增加。重要的是，我们已经证明这些患者对硼替佐米的敏感性大大提高。 MM的处理不再可以在“一尺寸适合所有方法”方法下进行，并且我们必须验证选择MM处理的遗传预后和预测标记。尽管新型的治疗剂改善了患者的总体前景，但根据分子亚型的净效果可能有所不同。一些新型的疗法和策略有可能改善“高风险” -MM（HR-MM）的结果。具有“标准风险” MM（SR-MM）的患者可能受益于更简单，毒性较小的干预措施，而HR-MM患者将需要引入更密集的方案，例如早期的硼替佐米和/或非甲状腺硫化性异元性干细胞移植（NM-SCT）策略。为了解决这些问题，在该项目提案的中心，我们提出以下问题：1。沙利度胺和多纳利度胺可以克服HR-MM的负面预后吗？ 2。我们能否确定与多纳拉度胺和沙利度胺治疗的患者长期发展有关的新基因组标记？ 3。硼替佐米可以在HR-MM患者中产生更好的反应和结果吗？ 4。NF-KB过度活化或TRAF3失活能否预测硼替佐米的结果？ 5。NM-SCT可以克服t（4; 14）（p16; q32）的不良预后吗？为了解决这些问题，我们提出了以下实验，该实验是使用一组分子和遗传测定面板，这些分子和遗传测定法采用了与五阶段3临床试验相关的临床样本。在全球范围内，这些试验包括1500多名用来纳替米德，沙利度胺和硼替佐米的各种组合治疗的患者。它们包括ECOG临床试验E1A00，E4A03，E1A05和E1A06。此外，我们建议在一项大型随机试验（n = 700）中研究t（4; 14）（p16; q32）的预后意义，以解决NM-SCT在新诊断的MM中的作用。为此，我们将研究与临床试验BMT CTN 0102相关的研究样本。公共卫生相关性：该赠款提案旨在更好地定义哪种治疗方法应给予哪种治疗骨髓瘤的遗传亚型，以为患者提供最佳和风险的适应性疗法。