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Mechanism underpinning synergy with combined treatment of MTI-101 and Dexamethasone in Multiple Myeloma

MTI-101 和地塞米松联合治疗多发性骨髓瘤的协同作用机制

基本信息

批准号：
10080460
负责人：
Lori Hazlehurst
金额：
$ 21.27万
依托单位：
MODULATION THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080460
关键词：
Agonist American Cancer Society Apoptosis Binding Bone Marrow Bortezomib CD44 gene Calcium Caspase Cell Death Cell Line Cell Nucleus Cell Proliferation Cell Therapy Cells Cessation of life Clinical Data Combined Modality Therapy Complex Cyclic Peptides Development Dexamethasone Disease Dose Drug Industry Entrepreneurship Environment Exposure to Extracellular Matrix Female Gene Expression Profiling Glucocorticoid Receptor Glucocorticoids Goals Hematologic Neoplasms Hematopoietic Neoplasms In Vitro Intellectual Property Investigational Drugs Investigational New Drug Application Lead Leadership Legal patent Malignant Neoplasms Mediating Multiple Myeloma Necrosis Parents Pathway interactions Patient-Focused Outcomes Patients Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacologic Substance Positioning Attribute Preparation Proteins Quantitative Reverse Transcriptase PCR Refractory Relapse Research Research Assistant Research Project Grants Resistance Response Elements Role STIM1 gene Senior Scientist Source Structure Survival Rate System Therapeutic Toxicity Tests Training Translating Treatment Protocols Western Blotting Woman Work base cytokine drug development effective therapy improved in vivo in vivo Model innovation insight live cell imaging meetings mouse model new therapeutic target novel novel strategies personalized medicine protein expression release of sequestered calcium ion into cytoplasm response skills standard of care synergism therapy resistant transcriptome sequencing treatment response treatment strategy

项目摘要

ABSTRACT Multiple myeloma (MM) is the second most common hematopoietic cancer and while survival rates have slowly increase in the last 10 years, the five-year survival is just over 50%. The high number of patients that become refractory to current therapies is the core reason for the low long-term survival. Therefore, there is a crucial need to develop unique drugs that are active in refractory and resistant patients. Modulation Therapeutics is developing a first in class peptide, MTI-101, that stimulates a CD44/ITGA4 complex resulting in an increase of intracellular Ca2+ levels inducing necrosis. The company has acquired patents for the parent molecule, MTI-101, and derivative (MTI-102) covering the intellectual property for both composition of matter and use in cancer. Non-GLP and GLP toxicity testing are slated to be done soon in preparation for the submission of an IND package to the FDA. Thus, Modulation Therapeutics provides the ideal environment to receive the training required to obtain the next level position in drug development in any pharmaceutical company. Women are greatly under-represented in upper administrative positions in part due to the lack to training needed to progress from the entry-level research workforce. One goal of this proposal is to provide the research and entrepreneurial skills underpinning the transition to administrative positions such as director of drug development. To receive that training, the female senior scientist at Modulation Therapeutics will be involved in all stages of developing, assembling, and submitting the IND package to the FDA. In addition, the leadership training will include the development and role as project leader of a parallel research project proposed in this revision. The research project will investigate the synergistic interaction of the lead compound for Modulation Therapeutics, MTI-101 and dexamethasone (Dex), a common drug administered in combination regimen for treatment of MM. Both MTI- 101 and Dex modulate calcium flux in cells and combination therapy with Dex and MTI-101 would likely increase MTI-101 Ca2+ induced programmed necrosis. We found that combination treatment of MTI-101/Dex increased cell death and resulted in greatest synergistic activity in MM cell lines pretreatment with Dex (24 h) followed by an additional Dex/MTI-101 treatment (16 h). Based on these results, we hypothesize that dexamethasone is modulating the expression of proteins involved in store-operated channels to potentiate MTI-101 mediated by Ca2+ induced necrosis. Live-cell imaging of Ca2+ flux and cell death using Dex-treated MM cells exposed to an MTI-101/Dex combination treatment provide insight into the mechanism of the observed synergy. Furthermore, in vitro analysis of Dex mediated of expression of proteins involved in calcium flux by qRT-PCR, Western Blot, and RNA seq will further elucidate the mechanism of action facilitating the cell death observed with MTI-101/ Dex combination therapy. MTI-101/ Dex combination treatment versus single agents using a MM mouse model will confirm in vitro results translate to a more complex system. As MTI-101 moves forward in drug development the understanding of MTI-101 efficacy in the context of standard of care MM agents is crucial.

摘要多发性骨髓瘤（MM）是第二常见的造血系统癌症，在过去的10年里，五年生存率刚刚超过50%。大量的病人成为目前的治疗方法难治性是长期生存率低的核心原因。因此，迫切需要开发出独特的药物，对难治性和耐药性患者有效。调制疗法是开发了第一种肽MTI-101，其刺激CD 44/ITGA 4复合物，导致增加细胞内Ca 2+水平诱导坏死。该公司已经获得了母体分子MTI-101的专利，和衍生物（MTI-102），其涵盖了物质组合物和癌症用途的知识产权。非GLP和GLP毒性试验计划很快完成，为提交IND做准备给食品药品管理局因此，调制治疗提供了理想的环境，接受培训在任何制药公司获得药物开发的下一个级别的职位。妇女高级行政职位的代表性严重不足，部分原因是缺乏进步所需的培训从入门级的研究人员。该提案的一个目标是提供研究和创业向药物开发总监等行政职位过渡所需的技能。为接收培训，女性高级科学家在调制治疗将参与所有阶段的发展，组装并向FDA提交IND包装。此外，领导力培训将包括制定并担任本修订版中提议的平行研究项目的项目领导人。研究该项目将研究调制疗法的先导化合物MTI-101的协同作用和地塞米松（Dex），一种用于治疗MM的联合方案中施用的常用药物。 MTI-101和Dex调节细胞中的钙流动，并且Dex和MTI-101的组合疗法可能增加细胞中的钙流动。 MTI-101 Ca ~（2+）诱导程序性坏死。我们发现MTI-101/Dex联合治疗增加了在用Dex预处理（24 h），然后用Dex预处理（24 h）的MM细胞系中，额外的Dex/MTI-101处理（16小时）。基于这些结果，我们假设地塞米松是调节与储存操纵通道有关的蛋白质的表达，以增强由 Ca ~（2+）诱导坏死。Ca 2+通量和细胞死亡的活细胞成像，使用暴露于 MTI-101/Dex组合治疗提供了对所观察到的协同作用的机制的深入了解。此外，委员会认为，通过qRT-PCR，Western印迹，和RNA seq将进一步阐明促进用MTI-101/ 地塞米松联合治疗。使用MM小鼠模型的MTI-101/ Dex组合治疗与单一药剂将证实体外结果转化为更复杂的系统。随着MTI-101在药物开发中的发展，理解在标准治疗MM药物的情况下MTI-101的功效是至关重要的。