Improving current therapies for myeloma

改善当前的骨髓瘤治疗方法

基本信息

批准号：
7937880
负责人：
DAN TOBY VOGL
金额：
$ 17.24万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-22 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7937880
关键词：
Alkylating Agents Amino Acid Sequence Apoptotic Autologous Autologous Stem Cell Transplantation Autophagocytosis Basic Science Bone Marrow Bortezomib Cells Clinical Clinical Trials Cohort Studies Cytotoxic Chemotherapy Development Dose Dose-Limiting Electron Microscopy Future Goals Heat shock proteins High Dose Chemotherapy Hydroxychloroquine Immunoglobulins In Vitro Investigation K-Series Research Career Programs Laboratories Lead Link Malignant - descriptor Malignant Neoplasms Maximum Tolerated Dose Medicine Melphalan Mentors Metabolism Multiple Myeloma Pathway interactions Patients Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Plasma Cell Neoplasm Plasma Cells Pre-Clinical Model Principal Investigator Process Proteasome Inhibition Refractory Relapse Research Research Personnel Research Proposals Resistance Role Sampling Stem cell transplant Stem cells Stress Thalidomide Toxic effect Training Work anticancer research cancer cell cancer therapy career chemotherapy clinical effect cytotoxic effective therapy improved in vivo inhibition of autophagy inhibitor/antagonist innovation investigator training killings lenalidomide multicatalytic endopeptidase complex neoplastic cell novel novel therapeutics pre-clinical programs prospective protein misfolding response skills training stress protein therapeutic target therapy resistant

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma is a plasma cell neoplasm that, despite recent advances, remains incurable and uniformly fatal. Recent advances in the understanding of the metabolism of malignant plasma cells have identified the autophagy pathway as an important mechanism of therapy resistance and therefore a potential therapeutic target. This proposal investigates the utility of adding autophagy inhibition to current effective therapies for myeloma. Proteasome inhibition using the novel agent bortezomib is now standard therapy for myeloma. The autophagy pathway is the major non-proteasomal mechanism for degradation of aggregated misfolded proteins and allows cells to escape the cytotoxic effects of proteasome inhibition, which makes combined inhibition an attractive strategy. Recent basic science laboratory work done by my collaborators has identified hydroxychloroquine as a potent inhibitor of autophagy in malignant cells. We have also shown that the addition of hydroxychloroquine to bortezomib results in synergistic killing of myeloma cells in vitro. These results justify investigation of the combination of hydroxychloroquine with bortezomib in patients with myeloma. Preclinical results have also identified the autophagy pathway as an important survival mechanism for malignant cells exposed to a wide variety of apoptotic stresses, including cytotoxic chemotherapy. The demonstration of increased autophagy in primary patient tumor cells after chemotherapy administration would justify a future trial of autophagy inhibition combined with cytotoxic chemotherapy. This research proposal therefore encompasses the following specific aims: (1) To determine, in a phase 1 clinical trial, the maximum tolerated dose of hydroxychloroquine when added to standard bortezomib therapy. (2) To determine, in a phase 2 trial, whether administration of hydroxychloroquine to patients with myeloma can inhibit autophagy in malignant cells and improve bortezomib efficacy. (3) To determine, in a prospective cohort study, whether administration of high-dose melphalan induces autophagy in malignant plasma cells purified from patient bone marrow samples. in addition, this Mentored Career Development Award is specifically intended to provide the Principal Investigator with comprehensive training in translational myeloma research to allow successful transition to an independent research career. RELEVANCE: Multiple myeloma remains a deadly cancer that cannot be cured. This research seeks to improve two of the current most effective treatments for myeloma: autologous stem cell transplants and a newer medicine called bortezomib. The results will directly benefit patients with myeloma through a better understanding of how to increase the efficacy of current effective but insufficient treatments.

描述（由申请人提供）：多发性骨髓瘤是一种浆细胞肿瘤，尽管最近进展，但仍无法治愈且统一致命。对恶性血浆细胞代谢的理解的最新进展已确定自噬途径是治疗耐药性的重要机制，因此是潜在的治疗靶标。该提案调查了将自噬抑制作用添加到当前有效骨髓瘤疗法的实用性。蛋白酶体使用新型抗硼替佐米的蛋白酶体抑制现在是骨髓瘤的标准疗法。自噬途径是降解聚合错误折叠蛋白的主要非头膜途径机制，并使细胞能够逃脱蛋白酶体抑制的细胞毒性作用，这使得联合抑制作用成为有吸引力的策略。我的合作者最近进行的基础科学实验室工作已将羟氯喹确定为恶性细胞自噬的有效抑制剂。我们还表明，添加羟氯喹为硼替佐米导致骨髓瘤细胞在体外的协同杀死。这些结果证明了对骨髓瘤患者中羟基氯喹与硼替佐米的组合的研究合理。临床前结果还确定了自噬途径是暴露于各种凋亡胁迫（包括细胞毒性化学疗法）的恶性细胞的重要生存机制。化学疗法给药后原发性肿瘤细胞中自噬增加的证明将证明将来的自噬抑制作用结合了细胞毒性化学疗法。因此，该研究提案涵盖了以下特定目的：（1）在第1阶段临床试验中确定添加到标准的硼替佐米治疗中时，羟基氯喹的最大耐受剂量。（2）在第二阶段试验中确定对骨髓瘤患者的羟氯喹是否可以抑制恶性细胞的自噬并提高硼替佐米的疗效。（3）在一项前瞻性队列研究中确定高剂量梅尔法兰的给药是否会诱导从患者骨髓样品中纯化的恶性血浆细胞中自噬。此外，该指导的职业发展奖专门旨在为主要研究者提供转化骨髓瘤研究的全面培训，以便成功过渡到独立的研究职业。相关性：多发性骨髓瘤仍然是一种无法治愈的致命癌症。这项研究旨在改善骨髓瘤当前最有效的两种最有效的治疗方法：自体干细胞移植和一种称为硼替佐米的新药物。结果将通过更好地理解如何提高当前有效但不足治疗的功效，直接使骨髓瘤患者受益。