Targeting Notch3 for the treatment of multiple myeloma

项目总结 多发性骨髓瘤(MM)的特征是单克隆性恶性浆细胞的生长和聚集 在骨髓中。多发性骨髓瘤由于其高复发率和耐药性的产生而仍然无法治愈。 去接受治疗。此外，多发性骨髓瘤会导致毁灭性的骨骼疾病，增加骨折风险，降低骨质量。 生活。Notch信号，一种在MM肿瘤微环境(TME)中介导细胞通讯的途径， 促进多发性骨髓瘤增殖和多发性骨髓瘤细胞存活，刺激骨质破坏。缺口抑制降低MM 在临床前模型中出现生长和骨骼疾病，但会引起不受欢迎的严重、剂量限制的副作用。这个 这项提议的长期目标是研究Notch受体3(Notch3)，一种膜结合的Notch受体 整合来自周围细胞的细胞间Notch信号作为治疗MM的靶点，这些研究的前提是 已发表的和初步的工作表明：1)TME的细胞激活Notch信号和 增加MM细胞中Notch3的表达，2)MM细胞中的Notch3信号促进MM细胞的增殖和 骨破坏，以及3)Notch3信号指示MM细胞对基于Bortezomib的治疗的反应。这个 这项应用的具体目标是评估靶向Notch3的疗效，以减少肿瘤生长，缓解 骨病，改善MM对一线治疗的反应。这一中心假设 建议是MM细胞中的Notch3整合了TME信号，导致肿瘤生长、骨破坏和药物 抵抗。这一假设将在两个具体目标上得到检验。目标1将确定 Notch3对多发性骨髓瘤生长、骨破坏的抑制作用及其对转录组的影响 TME和MM细胞。目的2将评估骨髓瘤细胞中Notch3信号在TME诱导的抗癌作用中的作用 以硼替佐米为基础的治疗并确定潜在的分子机制。为了实现这些目标，我有 组建了一个由癌症和耐药性、骨生物学、生物信息学和成像领域的领导者组成的指导团队 这将使我能够接受独特的多学科和严格的培训，为我的职业生涯做好准备 一位独立的学术科学家。

PROJECT SUMMARY Multiple myeloma (MM) is characterized by the growth and accumulation of monoclonal malignant plasma cells in the bone marrow. MM remains incurable due to its high rate of relapse and the development of drug resistance to therapy. Moreover, MM causes a devastating bone disease, increasing fracture risk and decreasing quality of life. Notch signaling, a pathway mediating cell communication in the MM tumor microenvironment (TME), promotes MM proliferation and MM cell survival and stimulates bone destruction. Notch inhibition decreases MM growth and bone disease in preclinical models, but causes unwanted severe, dose-limiting side effects. The long-term goal of this proposal is to examine Notch receptor 3 (Notch3), a membrane-bound Notch receptor integrating cell-to-cell Notch signals from surrounding cells, as a target to treat MM. The premise of these studies is supported by published and preliminary work showing that 1) cells of TME activate Notch signaling and increase Notch3 expression in MM cells, 2) Notch3 signaling in MM cells promotes MM cell proliferation and bone destruction, and 3) Notch3 signaling dictates MM cell responses to Bortezomib-based therapies. The specific goal of this application is to evaluate the efficacy of targeting Notch3 to decrease tumor growth, mitigate bone disease, and improve therapeutic responses to front-line therapies in MM. The central hypothesis of this proposal is that Notch3 in MM cells integrates TME signals leading to tumor growth, bone destruction, and drug resistance. This hypothesis will be tested in two specific aims. Aim 1 will determine the effects of the pharmacological inhibition of Notch3 on MM growth, bone destruction, and its impact on the transcriptome of TME and MM cells. Aim 2 will evaluate the role of Notch3 signaling in MM cells on TME-induced resistance to Bortezomib-based therapies and identify the underlying molecular mechanisms. To complete these aims, I have assembled a mentoring team of leaders in cancer and drug resistance, bone biology, bioinformatics, and imaging that will allow me to receive a unique multidisciplinary and rigorous training, preparing me to pursue a career as an independent academic scientist.