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

基本信息

批准号：
10609467
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
项目类别：
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/10609467
关键词：
Address Apoptosis Apoptotic Autologous Bone Marrow Transplantation Autologous Stem Cell Transplantation BCL1 Oncogene 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 Impaired Renal Function In Vitro In complete remission Induction of Apoptosis 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 biomarker identification cancer cell cancer type chemotherapy clinical biomarkers clinical translation heart function human model immune modulating agents 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

项目摘要

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.

抽象的免疫球蛋白轻链（AL）淀粉样变性是一种高度致死的疾病，其特征是生产和在重要器官中的纤维化免疫球蛋白光链的沉积。这些错误折叠的轻链是由dissected骨细胞的克隆人群产生，这些细胞是通过使用蛋白酶体抑制剂和免疫调节剂。但是，这些治疗方案是为较常见的浆细胞疾病多发性骨髓瘤，仅在AL淀粉样变性中的效率有限由未接受自体干细胞的患者的2 - 3年中位生存期证明移植。因此，迫切需要改善诊断患有淀粉样变性的患者的疗法，迫切需要尤其是能够促进长期减免的耐受性良好的治疗方法。我们以前有发现在体外和诊所中，细胞中细胞凋亡途径的状态都深刻地改变了它们化学敏感性和临床结果。此外，大量证据表明来自Bcl-2家族的促生存蛋白的上调，包括Bcl-2，Bcl-XL和MCL-1可能是主要的多种癌症类型的治疗抗药性驱动因素，强调了这一途径的重要性管理对化学疗法的反应。新型小分子抑制剂的最新发展 Bcl-2家族的亲生蛋白蛋白创造了一个前所未有的机会来靶向凋亡癌细胞的依赖性，该策略可能在功能失调的克隆血浆中特别有效驱动淀粉样变性的细胞。但是，Al淀粉样变性中凋亡依赖性的景观以及如何可能探索它们以改善患者反应。使用原代骨髓衍生的克隆来自未经治疗和治疗的AL淀粉样变性患者的血浆细胞，我们最近发现克隆血浆细胞对Bcl-2家族蛋白表现出很强的依赖性，这些蛋白在对现有前线疗法治疗的反应。我们的中心假设是BH3 Mimetics将是高效治疗AL淀粉样变性患者克隆浆细胞的高效药物，均为单一代理商并结合前线疗法。为了检验这一假设，我们将1）确定凋亡基线和前期治疗期间，来自Al淀粉样变性患者的克隆血浆细胞的依赖性线和实验疗法； 2）研究调节Al凋亡依赖性的分子机制淀粉样变性的克隆浆细胞以及如何用作临床生物标志物； 3）开发鼠标PDX Al淀粉样变性的模型研究疾病发育和进展以及BH3模拟效率和毒性。这项研究解决了诊断为患者的治疗选择有限的重要问题通过在该疾病中利用BH3模拟物的高效治疗方法来鉴定高效的治疗方法，Al淀粉样变性。如果成功，我们希望有意义地改善患者的结果，并更接近事件治疗方法。