Identifying targetable apoptotic vulnerabilities for the treatment of AL amyloidosis

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，其特征是产生和 重要器官中纤维蛋白免疫球蛋白轻链的沉积。这些错误折叠的轻链是 由疾病浆细胞的克隆性群体产生，这些浆细胞通过使用 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，对AL淀粉样变性的疗效有限，因为 没有接受自体干细胞的患者的2-3年中位生存期证明了这一点 移植。因此，迫切需要改进对被诊断为AL淀粉样变性的患者的治疗。 尤其是耐受性好的治疗，能够促进长期缓解。我们之前已经 发现无论是在体外还是在临床上，细胞中的凋亡途径的状态都深刻地改变了它们的 化疗敏感性和临床转归。此外，大量证据表明 BCL-2家族促生存蛋白包括BCL-2、BCL-XL和MCL-1的上调可能是主要的 跨多种癌症类型的治疗耐药的驱动因素，强调了这一途径在 管理化疗的反应。新型小分子抗癌药物的研究进展 来自bcl2家族的促生存蛋白创造了一个前所未有的机会来靶向细胞凋亡 癌细胞的依赖性，这一策略可能在功能失调的克隆性血浆中特别有效 导致AL淀粉样变性的细胞。然而，AL淀粉样变性中的细胞凋亡依赖关系及其机制 它们可能被利用来改善患者的反应尚不清楚。利用原代骨髓源性克隆 治疗前和治疗后的AL淀粉样变性患者的浆细胞，我们最近发现 克隆性浆细胞对bcl2家族蛋白有很强的依赖性，这种蛋白在 对现有一线治疗的反应。我们的中心假设是BH3模拟物将是 治疗AL淀粉样变性患者克隆性浆细胞的高效药物，两者均为单一药物 并与一线治疗相结合。为了验证这一假说，我们将1)鉴定细胞凋亡 AL淀粉样变性患者在基线和治疗过程中克隆浆细胞的依赖性 LINE和实验性治疗；2)研究AL细胞凋亡依赖性调节的分子机制 淀粉样变性克隆性浆细胞及其作为临床生物标记物的研究；3)发展小鼠PDX AL淀粉样变性模型用于研究疾病的发展和进展以及BH3模拟疗效和 毒性。这项研究解决了被诊断为慢性病患者的治疗选择有限的重要问题 通过在这种疾病中利用BH3模拟物确定高效的治疗方法来治疗淀粉样变性。 如果成功，我们预计将有意义地改善患者的预后，离最终治愈又近了一步。

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.