Identifying targetable apoptotic vulnerabilities for the treatment of AL amyloidosis

确定治疗 AL 淀粉样变性的靶向凋亡脆弱性

• 批准号: 10376814
• 负责人: Kristopher Andrew Sarosiek
• 金额: $ 35.09万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376814
• 关键词: Address; Apoptosis; Apoptotic; Autologous Bone Marrow Transplantation; Autologous Stem Cell Transplantation; BCL2 gene; BCL2L1 gene; Biological Markers; Bone Marrow; Bortezomib; Cells; Clinic; Clinical; Cytotoxic Chemotherapy; Data; Dependence; Deposition; Development; Diagnosis; Disease; Disease Progression; Disease remission; Elderly; Exhibits; FDA approved; Family; Hematopoietic; Immunocompromised Host; Immunomodulators; Impaired Renal Function; In Vitro; In complete remission; Injections; Investigation; Investigational Therapies; Lead; Light; Light-Chain Immunoglobulins; MCL1 gene; Malignant Neoplasms; Measurement; Measures; Molecular; Multiple Myeloma; Mus; Organ; Outcome; Pathogenesis; Pathway interactions; Patient Agents; Patient-Focused Outcomes; Patients; Plasma Cells; Population; Production; Proteasome Inhibitor; Protein Family; Proteins; Relapse; Research; Research Personnel; Resistance; Stress; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Protocols; Up-Regulation; base; cancer cell; cancer type; chemotherapy; clinical biomarkers; clinical translation; heart function; human model; improved; in vivo; individualized medicine; inhibitor; innovation; mimetics; novel; novel marker; patient derived xenograft model; patient response; prevent; primary amyloidosis of light chain type; prospective; proteotoxicity; rational design; research clinical testing; response; small molecule inhibitor; therapeutic target; therapy design; tool; treatment response; treatment strategy

ABSTRACT Immunoglobulin light chain (AL) amyloidosis is a highly lethal disorder characterized by the production and deposition of fibrillogenic immunoglobulin light chains in vital organs. These misfolded light chains are produced by a clonal population of diseased plasma cells, which are therapeutically targeted with the use of proteasome inhibitors and immunomodulatory agents. However, these treatment regimens were developed for the more common plasma cell disease multiple myeloma and have only limited efficacy in AL amyloidosis as demonstrated by the 2-3 year median survival for patients that do not receive an autologous stem cell transplant. Improved therapies for patients diagnosed with AL amyloidosis are therefore urgently needed, especially well-tolerated treatments that are able to facilitate long-term remissions. We have previously discovered that the state of the apoptosis pathway in cells, both in vitro and in the clinic, profoundly alters their chemosensitivity and clinical outcomes. In addition, a preponderance of evidence demonstrates that upregulation of pro-survival proteins from the BCL-2 family including BCL-2, BCL-XL and MCL-1 can be major drivers of therapy resistance across multiple cancer types, highlighting the importance of this pathway in governing responses to chemotherapy. The recent development of novel small-molecule inhibitors of the major pro-survival proteins from the BCL-2 family has created an unprecedented opportunity to target apoptotic dependencies in cancer cells, a strategy that may be particularly effective in the dysfunctional clonal plasma cells that drive AL amyloidosis. However, the landscape of apoptotic dependencies in AL amyloidosis and how they may be exploited to improve patient responses is not known. Using primary bone marrow-derived clonal plasma cells from both treatment-naïve and treated AL amyloidosis patients, we have recently discovered that clonal plasma cells exhibit strong dependencies on BCL-2 family proteins, which change dramatically in response to treatment with existing front-line therapies. Our central hypothesis is that BH3 mimetics will be highly effective agents for the treatment of clonal plasma cells in patients with AL amyloidosis, both as single agents and in combination with front-line therapies. To test this hypothesis, we will 1) identify apoptotic dependencies in clonal plasma cells from AL amyloidosis patients at baseline and during treatment with front- line and experimental therapies; 2) investigate molecular mechanisms regulating apoptotic dependencies in AL amyloidosis clonal plasma cells and how they may be used as clinical biomarkers; and 3) develop mouse PDX models of AL amyloidosis to study disease development and progression as well as BH3 mimetic efficacy and toxicity. This study addresses the important problem of limited therapeutic options for patients diagnosed with AL amyloidosis by identifying highly-efficacious therapeutic approaches utilizing BH3 mimetics in this disease. If successful, we expect to meaningfully improve patient outcomes and be a step closer to eventual cures.

摘要 免疫球蛋白轻链（AL）淀粉样变性是一种高度致命的疾病，其特征在于产生和 重要器官中纤维形成免疫球蛋白轻链的沉积。这些错误折叠的轻链是 由患病浆细胞的克隆群体产生，其通过使用 蛋白酶体抑制剂和免疫调节剂。然而，这些治疗方案是为 更常见的浆细胞疾病多发性骨髓瘤，而在AL淀粉样变性中仅具有有限的疗效， 未接受自体干细胞治疗的患者的中位生存期为2-3年 移植因此，迫切需要改善诊断为AL淀粉样变性的患者的疗法， 特别是耐受性良好的治疗，能够促进长期缓解。我们先前已经 发现细胞凋亡途径的状态，无论是在体外还是在临床上，都深刻地改变了它们的 化疗敏感性和临床结果。此外，大量证据表明， 来自BCL-2家族的促存活蛋白（包括BCL-2、BCL-XL和MCL-1）的上调可能是主要的 在多种癌症类型的治疗耐药性的驱动因素，突出了这一途径的重要性， 控制对化疗的反应本文综述了近年来新型小分子抗肿瘤药物的研究进展， 来自BCL-2家族的促存活蛋白为靶向凋亡创造了前所未有的机会， 依赖性的癌细胞，一种策略，可能是特别有效的功能失调克隆血浆 导致AL淀粉样变性的细胞然而，AL淀粉样变性中的凋亡依赖性以及如何 目前尚不清楚它们是否可以用来改善患者的反应。使用原代骨髓来源的克隆 从初治和已治AL淀粉样变性患者的浆细胞中，我们最近发现， 克隆性浆细胞表现出对BCL-2家族蛋白的强烈依赖性，这些蛋白在 对现有一线治疗的反应。我们的中心假设是，BH 3模拟物将是 治疗AL淀粉样变性患者克隆浆细胞的高效药物， 药物和与一线治疗联合使用。为了验证这一假设，我们将1）鉴定凋亡 AL淀粉样变性患者在基线时和在前- 线和实验性疗法; 2）研究调节AL中凋亡依赖性的分子机制 淀粉样变性克隆浆细胞以及它们如何可用作临床生物标志物;以及3）开发小鼠PDX AL淀粉样变性模型，以研究疾病发展和进展以及BH 3模拟功效， 毒性这项研究解决了诊断为糖尿病的患者治疗选择有限的重要问题。 AL淀粉样变性，通过确定在这种疾病中利用BH 3模拟物的高效治疗方法。 如果成功，我们希望有意义地改善患者的预后，并向最终治愈迈进一步。