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Bone-Targeted Therapies to Improve Bone Health and Prevent Relapse in Multiple Myeloma

骨靶向治疗可改善骨健康并预防多发性骨髓瘤复发

基本信息

批准号：
10625466
负责人：
Jesus Delgado-Calle
金额：
$ 33.95万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625466
关键词：
Address Antibody Therapy Bone Diseases Bone Marrow Bone Pain Bone Resorption Bone Resorption Inhibition Bone Resorption Stimulation Brain Cells Clinic Communication Development Disease Dose Drug Kinetics Genetic Goals Growth Hematologic Neoplasms Homeostasis Immunocompetent Immunosuppression In Vitro In complete remission Intestines Lytic Lesion Lytic Metastatic Lesion Malignant - descriptor Mediating Medical Metastatic Neoplasm to the Bone Minor Morbidity - disease rate Multiple Myeloma Mus Neoplasm Metastasis Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteolytic Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Plasma Cells Play Prevention Proliferating Property Recurrent disease Role Safety Signal Pathway Signal Transduction Testing Tissues Toxic effect Toxicology Tumor Promotion WNT Signaling Pathway Work antagonist bone bone health bone preservation bone repair cancer cell chemotherapeutic agent efficacy evaluation fracture risk gamma secretase healing improved in vivo inhibitor innovation mortality mouse model neoplastic cell neutralizing antibody notch protein novel novel strategies novel therapeutic intervention novel therapeutics pharmacologic pre-clinical prevent relapse prevention repaired side effect skeletal targeted treatment therapy resistant tool tumor tumor growth tumor microenvironment tumor progression

项目摘要

Summary Current chemotherapeutic agents have improved multiple myeloma (MM) patient survival. However, MM remains incurable due to high rate of disease relapse that originate from dormant MM clones resistant to therapy. Further, anti-MM therapies have minor effects on repairing MM-induced bone disease, a leading cause of morbidity and mortality in MM patients. Thus, disease relapse and bone disease remain major unmet medical needs that require innovative approaches to effectively treat MM. The overall goal of this proposal is to evaluate the efficacy of novel bone-targeted therapies blocking key interactions between MM cells and cells of the tumor niche to stop the progression of MM in bone. We will focus on Notch and Wnt signaling, two major signaling pathways mediating tumor-host microenvironment communication. In studies leading to this application, we generated a bone-targeted Notch inhibitor (BT-GSI) that selectively decreases Notch signaling in bone. Inhibition of Notch communication in the tumor niche with BT-GSI reduced MM growth and decreased osteoclast number and bone destruction. Importantly, BT-GSI circumvented the gut toxicity that limits the use of Notch inhibitors in the clinic. Further, we found that interactions between MM cells and osteocytes increase the expression of Sclerostin, a local Wnt signaling antagonist that inhibits osteoblast bone forming function. Blockade of Sclerostin using neutralizing antibodies (Scl-Ab) prevented MM-induced bone disease by increasing osteoblasts and stimulating new bone formation. Importantly, our work leading to this application showed that interactions between MM cells and osteoblasts maintain MM cells in a dormant state, while interactions with osteoclasts promote their reactivation into proliferating MM cells. Based on these preliminary findings, we propose that combined bone- directed therapies inhibiting Notch and activating Wnt signaling will 1) decrease MM growth, 2) prevent reactivation of MM dormant cells, and 3) repair damaged bone, while reducing systemic toxic effects. This hypothesis will be advanced by pursuing specific aims that employ established mouse models of MM-induced bone disease and MM dormancy and new pharmacologic tools targeted to the tumor niche. Two aims are proposed. Aim 1 will determine the pharmacokinetic, pharmacodynamic, and safety profiles of our bone-targeted Notch inhibitor BT-GSI. Aim 2 will examine the effects of combined bone-targeted inhibition of Notch signaling (BT-GSI) and activation of the Wnt pathway (Scl-Ab) on tumor growth, bone repair, and MM cell dormancy.

总结