Preclinical Testing of Galectin-3C for Multiple Myeloma

Galectin-3C 治疗多发性骨髓瘤的临床前测试

基本信息

批准号：
7615176
负责人：
Maurizio Chiriva-Internati
金额：
$ 36.39万
依托单位：
MANDALMED, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7615176
关键词：
Action Potentials Affect Age Alkylating Agents Amino Acids Animals Antibodies Antineoplastic Agents Apoptosis Autologous Autologous Stem Cell Transplantation B lymphoid malignancy B-Cell Development B-Cell Neoplasm B-Lymphocytes Binding Biodistribution Biological Factors Biological Markers Bone Marrow Bortezomib C-terminal Carbohydrates Cell Adhesion Cell Line Cells Cessation of life Characteristics Chimeric Proteins Citrus Clinical Trials Combined Modality Therapy Comorbidity Complement Complement 1q Condition Data Development Dexamethasone Dexamethasone/Thalidomide Dominant-Negative Mutation Dose Doxorubicin Drug Combinations Drug Delivery Systems Drug Kinetics Drug resistance Exposure to Extracellular Matrix Family member Fc Receptor Figs - dietary Galactose Binding Lectin Galectin 3 Genetic Goals Growth Guanosine Monophosphate Half-Life Heat Shock Protein 27 Hematopoietic Stem Cell Transplantation Human Human Cell Line IgG4 Immune Immune system Immunoglobulins In Vitro In complete remission Individual Induction of Apoptosis Inflammatory Injection of therapeutic agent Interleukin-10 Intramuscular Intramuscular Injections Intravenous Laboratories Life Ligands Liposomal Doxorubicin Lymphoma Malignant Neoplasms Mediating Melphalan Memory B-Lymphocyte Methodology Methods Modeling Multiple Myeloma N-terminal Neoplasm Metastasis Neoplasms Nuclear Numbers Osteoclasts Patients Pectins Peripheral Blood Stem Cell Phase Plasma Plasma Cells Play Polyethylene Glycols Post-Translational Protein Processing Preclinical Testing Prednisone Production Proteins Public Health Publishing Pump Regulation Relapse Reporting Research Resistance Resistance development Role SCID Mice Serum Staging Stem cell transplant Stromal Cells Structure of germinal center of lymph node Survival Rate Testing Thalidomide Therapeutic Therapeutic Agents Thinking Toxicology Transgenic Organisms Treatment Protocols United States National Institutes of Health Urine Velcade Vincristine angiogenesis base bone cancer cell cancer stem cell cancer therapy carbohydrate binding protein cell type crosslink cytochrome c effusion extracellular inhibitor/antagonist large cell Diffuse non-Hodgkin&apos s lymphoma lenalidomide malignant breast neoplasm mouse model multicatalytic endopeptidase complex multiple myeloma M Protein neoplastic cell novel novel therapeutics pre-clinical prevent response small molecule subcutaneous tumor

项目摘要

DESCRIPTION (provided by applicant): The overall goal is development of a novel human protein, Galectin-3C, as a treatment for multiple myeloma (MM) that can be given with other agents to increase the percentage of patients who are responsive to therapy, and the survival rate. MM is rarely curable despite the introduction of new therapeutic regimens and more efficacious treatments are sorely needed. The 10-year survival rate has recently increased, but is still just 17.4%. Current therapeutic agents for MM including dexamethasone, thalidomide, and bortezomib are thought to act partially through induction of apoptosis. Galectin-3C contains the carbohydrate recognition domain of Galectin-3 but lacks its N-terminal domain that functions in multimerization. Galectin-3C acts as a dominant negative inhibitor of Galectin-3 by binding to the same carbohydrate ligands but not multimerizing. Previously, we showed that Galectin-3C reduced the growth and metastasis of tumors in a mouse model of human breast cancer. Our preliminary data indicate that Galectin-3C can induce or facilitate apoptosis mediated by anticancer agents such as dexamethasone in multiple myeloma and other types of cancer cells. The Specific Aims of the Phase I research are as follows: Aim #1. To determine the ability of Galectin-3C to inhibit growth of MM cells from patients and human cell lines and to provide evidence of the mechanism of action and potential biomarkers. The effect of GAL3C on proliferation and apoptosis of MM cell lines, and patient cells will be assessed. The CD138negative MM cells that are postulated to possess the tumor-initiating and maintaining characteristics of cancer stem cells will be isolated and tested with Galectin-3C. Efficacy will be tested on MM cells adherent to immortalized human stromal cells in conditions that give rise to "extracellular matrix drug resistance" that protects MM cells from apoptosis. We will determine the expression of Galectin-3 and Bcl-2 family members, Mcl-1, Bax, Bad, and Bcl-2. Aim #2. To assess the ability of Galectin-3C to facilitate response to dexamethasone, thalidomide, and bortezomib in MM cells from patients and human cell lines. Proliferation of cell lines with Galectin- 3C and each agent will be determined, and the best combination will be tested with patient cells. Aim #3. To determine the effect of Galectin-3C alone and in combination therapy of NOD/SCID mouse models of disseminated and subcutaneous human MM. One agent will be selected based on results in Aim #2 and tested with Galectin-3C in disseminated and subcutaneous NOD/SCID mouse models of MM. Galectin-3C will be administered by intramuscular injection and continuous intravenous delivery by mini-pump in the disseminated model. The methodology producing the best response will be used for administration in the subcutaneous model. Phase II would focus on completing preclinical development towards initiation of a Phase 1 human clinical trial. PUBLIC HEALTH RELEVANCE: Multiple myeloma is rarely curable despite the introduction of new therapeutic regimens and more efficacious treatments are needed. More than 19,900 new cases and 10,700 deaths from multiple myeloma are expected in the U.S. in 2007. Although the 10-year survival rate has recently increased it is only 17.4%. The overall goal of this research is the development of a novel human protein, Galectin-3C, as a treatment for multiple myeloma that can be given with other agents to facilitate the induction of apoptosis, to increase the percentage of patients who are responsive to therapy, and the survival rate.

描述（由申请人提供）：总体目标是开发一种新型人类蛋白质galectin-3c，作为对多发性骨髓瘤（MM）的治疗，可以与其他药物一起增加，以增加对治疗有反应的患者的百分比和生存率。尽管引入了新的治疗方案，并且迫切需要MM可以治愈，但仍需要更有效的治疗方法。 10年的生存率最近有所提高，但仍然只有17.4％。当前的MM治疗剂在内，包括地塞米松，丘里度胺和硼替佐米被认为通过诱导凋亡来部分作用。 Galectin-3c包含Galectin-3的碳水化合物识别结构域，但缺乏其N末端结构域在多聚化中起作用。 Galectin-3c通过与同一碳水化合物配体结合而不是多重成分来充当Galectin-3的主要负抑制剂。以前，我们表明，甘油-3C减少了人类乳腺癌小鼠模型中肿瘤的生长和转移。我们的初步数据表明，半乳糖素-3c可以诱导或促进由多发性骨髓瘤和其他类型的癌细胞中的抗癌药（例如地塞米松）介导的凋亡。 I阶段研究的具体目的如下：AIM＃1。确定Galectin-3c抑制患者和人类细胞系MM细胞生长的能力，并提供作用和潜在生物标志物的机理。 GAL3C对MM细胞系增殖和凋亡的影响以及患者细胞的影响将评估。假定具有肿瘤发射和维持癌症干细胞特征的CD138含量MM细胞将被分离并用lectectin-3C测试。在导致“细胞外基质耐药性”的条件下，将在遵守永生的人基质细胞的MM细胞上测试功效，从而保护MM细胞免受凋亡。我们将确定Galectin-3和Bcl-2家族成员MCL-1，BAX，BAD和BCL-2的表达。目标＃2。评估Galectin-3c促进对地塞米松，丘里度胺和硼替佐米在患者和人类细胞系的MM细胞中的反应的能力。将确定用lectectin-3C和每种药物的细胞系的增殖，并将使用患者细胞测试最佳组合。目标＃3。确定单独的半乳糖素-3c以及在分布和皮下的人MM的点头/SCID小鼠模型的联合疗法中的作用。将根据AIM＃2中的结果选择一种代理，并在MM的传播和皮下点头/SCID小鼠模型中用Galectin-3C进行测试。 Galectin-3c将通过肌内注射和通过传播模型中的微型泵连续静脉注射来给药。产生最佳响应的方法将用于皮下模型中的给药。第二阶段将着重于完成临床前开发，以开始1阶段人类临床试验。公共卫生相关性：尽管引入了新的治疗方案和更有效的疗法，但多发性骨髓瘤很少可以治愈。预计在2007年，美国预计将有19,900多例新病例和10,700例多发性骨髓瘤死亡。尽管最近的10年生存率最近增加了17.4％。这项研究的总体目的是开发一种新型的人蛋白Galectin-3c，作为对多发性骨髓瘤的治疗方法，可以与其他药物一起提供促进凋亡的诱导，以增加对治疗有反应的患者的百分比和生存率。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Galectin-3C inhibits tumor growth and increases the anticancer activity of bortezomib in a murine model of human multiple myeloma.

DOI：
10.1371/journal.pone.0021811
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Mirandola L;Yu Y;Chui K;Jenkins MR;Cobos E;John CM;Chiriva-Internati M
通讯作者：
Chiriva-Internati M

Tracking human multiple myeloma xenografts in NOD-Rag-1/IL-2 receptor gamma chain-null mice with the novel biomarker AKAP-4.

DOI：
10.1186/1471-2407-11-394
发表时间：
2011-09-16
期刊：
BMC cancer
影响因子：
3.8
作者：
Mirandola L;Yu Y;Jenkins MR;Chiaramonte R;Cobos E;John CM;Chiriva-Internati M
通讯作者：
Chiriva-Internati M