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

• 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
• 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

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.

抽象的 多发性骨髓瘤 (MM) 是第二常见的造血系统癌症，而生存率却缓慢下降 近10年增长，五年生存率刚刚超过50%。大量患者成为 目前的治疗方法难治是长期生存率低的核心原因。因此，迫切需要 开发对难治性和耐药性患者有效的独特药物。调制疗法是 开发一流的肽 MTI-101，可刺激 CD44/ITGA4 复合物，从而增加 细胞内 Ca2+ 水平诱导坏死。该公司已获得母体分子MTI-101的专利， 及其衍生物（MTI-102），涵盖物质组成和癌症用途的知识产权。 非 GLP 和 GLP 毒性测试预计将很快完成，为提交 IND 做准备 包装到 FDA。因此，Modulation Therapeutics 提供了接受培训的理想环境 需要在任何制药公司获得药物开发的下一级职位。女人是 高级行政职位的任职人数严重不足，部分原因是缺乏进步所需的培训 来自入门级研究人员。该提案的目标之一是提供研究和创业 支持过渡到药物开发总监等行政职位的技能。接收 该培训中，Modulation Therapeutics 的女性高级科学家将参与开发的所有阶段， 组装并向 FDA 提交 IND 包。此外，领导力培训将包括 发展和作为本修订中提出的并行研究项目的项目负责人的角色。研究 项目将研究调制疗法的先导化合物 MTI-101 的协同相互作用 地塞米松 (Dex) 是一种以联合治疗方案治疗 MM 的常用药物。两个 MTI- 101 和 Dex 调节细胞内的钙通量，Dex 和 MTI-101 联合治疗可能会增加 MTI-101 Ca2+ 诱导程序性坏死。我们发现 MTI-101/Dex 联合治疗增加了 MM 细胞系用 Dex 预处理（24 小时）后可导致细胞死亡，并产生最大的协同活性 额外的 Dex/MTI-101 治疗（16 小时）。根据这些结果，我们假设地塞米松是 调节与库操纵通道有关的蛋白质的表达，以增强 MTI-101 介导的作用 Ca2+诱导坏死。使用暴露于 Dex 处理的 MM 细胞对 Ca2+ 通量和细胞死亡进行活细胞成像 MTI-101/Dex 联合治疗提供了对观察到的协同作用机制的深入了解。此外， 通过 qRT-PCR、Western Blot 体外分析 Dex 介导的钙流动相关蛋白的表达 RNA seq 将进一步阐明促进 MTI-101/观察到的细胞死亡的作用机制 地塞米松联合治疗。 MTI-101/ Dex 联合治疗与使用 MM 小鼠模型的单一药物治疗 将确认体外结果转化为更复杂的系统。随着 MTI-101 药物开发的进展 在标准治疗 MM 药物的背景下了解 MTI-101 的功效至关重要。

项目成果

Emergence of Resistance to MTI-101 Selects for a MET Genotype and Phenotype in EGFR Driven PC-9 and PTEN Deleted H446 Lung Cancer Cell Lines.

MTI-101 耐药性的出现选择 EGFR 驱动的 PC-9 和 PTEN 缺失的 H446 肺癌细胞系中的 MET 基因型和表型。

• 发表时间: 2022-06-22
• 影响因子: 5.2
• 作者: Jones, Clark;Dziadowicz, Sebastian;Suite, Samuel;Eby, Ashley;Chen, Wei;Hu, Gangqing;Hazlehurst, Lori A
• 通讯作者: Hazlehurst, Lori A