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

摘要 多发性骨髓瘤(MM)是第二常见的血液系统癌症，虽然存活率缓慢 在最近10年的增长中，五年存活率仅略高于50%。大量的患者成为 目前的治疗方法难治是长期存活率低的核心原因。因此，有一个迫切的需要 开发对难治和耐药患者有效的独特药物。调制治疗是 开发一种一流的多肽MTI-101，它能刺激CD44/ITGA4复合体，导致 细胞内钙离子水平导致坏死。该公司已经获得了母体分子MTI-101的专利， 和衍生物(MTI-102)，涵盖物质组成和用于癌症的知识产权。 非GLP和GLP毒性测试将很快完成，为提交IND做准备 寄给FDA的包裹。因此，调制治疗公司为接受培训提供了理想的环境 需要在任何一家制药公司获得药物开发的下一级职位。女人是 高级行政职位任职人数严重不足，部分原因是缺乏取得进展所需的培训 来自入门级研究人员。这项提议的目标之一是提供研究和创业 向药品开发主任等行政职位过渡所需的技能。收到 在这项培训中，调制治疗公司的女性高级科学家将参与开发的所有阶段， 组装，并将IND包装提交给FDA。此外，领导力培训将包括 本修订中提出的一个平行研究项目的开发和作为项目负责人的作用。这项研究 该项目将研究用于调制治疗的先导化合物MTI-101的协同作用 地塞米松(Dex)，一种以联合方案治疗MM的常见药物。 101和地塞米松调节细胞内钙离子流量，地塞米松和MTI-101联合治疗可能会增加 MTI-101Ca~(2+)诱导程序性坏死。我们发现MTI-101/Dex联合治疗增加了 在MM细胞系中，地塞米松(24小时)处理后可产生最大的协同活性 额外的地塞米松/MTI-101治疗(16小时)。根据这些结果，我们假设地塞米松是 通过调节商店操作通道中涉及的蛋白质的表达来增强MTI-101 Ca~(2+)诱导的坏死。地塞米松处理的多发性骨髓瘤细胞对钙离子通量和细胞死亡的活体细胞成像 MTI-101/Dex联合治疗提供了观察到的协同作用的机制。此外， 地塞米松介导的钙离子通道蛋白表达的体外分析 RNAseq将进一步阐明促进MTI-101细胞死亡的作用机制。 地塞米松联合治疗。MTI-101/Dex联合治疗与单一药物治疗MM小鼠模型的比较 将证实体外结果将转化为更复杂的系统。随着MTI-101在药物开发方面取得进展 了解MTI-101的疗效在标准护理MM药物的背景下是至关重要的。

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.