权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
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
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/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

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.

摘要