Improving current therapies for myeloma

改善当前的骨髓瘤治疗方法

基本信息

批准号：
7737741
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/7737741
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，尽管最近取得了进展，但仍然无法治愈且均致命。对恶性浆细胞代谢的理解的最新进展已确定自噬途径是治疗抵抗的重要机制，因此是潜在的治疗靶点。该提案研究了在当前有效的骨髓瘤疗法中添加自噬抑制的效用。使用新型药物硼替佐米抑制蛋白酶体现已成为骨髓瘤的标准疗法。自噬途径是降解聚集的错误折叠蛋白的主要非蛋白酶体机制，并允许细胞逃避蛋白酶体抑制的细胞毒性作用，这使得联合抑制成为一种有吸引力的策略。我的合作者最近完成的基础科学实验室工作已确定羟氯喹是恶性细胞自噬的有效抑制剂。我们还表明，在硼替佐米中添加羟氯喹可在体外协同杀死骨髓瘤细胞。这些结果证明了羟氯喹与硼替佐米联合治疗骨髓瘤患者的研究的合理性。临床前结果还确定自噬途径是暴露于各种凋亡应激（包括细胞毒性化疗）的恶性细胞的重要生存机制。化疗后原发性患者肿瘤细胞自噬增加的证明将证明未来自噬抑制与细胞毒性化疗相结合的试验是合理的。因此，本研究提案包含以下具体目标：（1）在 1 期临床试验中确定羟氯喹添加到标准硼替佐米治疗中时的最大耐受剂量。 (2) 在2期试验中确定对骨髓瘤患者给予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，确定高剂量马法兰是否会诱导从患者骨髓样本中纯化的恶性浆细胞发生自噬。此外，该指导职业发展奖专门旨在为首席研究员提供转化性骨髓瘤研究方面的全面培训，以使其能够成功过渡到独立研究职业。相关性：多发性骨髓瘤仍然是一种无法治愈的致命癌症。这项研究旨在改进目前两种最有效的骨髓瘤治疗方法：自体干细胞移植和一种名为硼替佐米的新型药物。研究结果将通过更好地了解如何提高当前有效但不足的治疗方法的疗效，直接使骨髓瘤患者受益。