CD24 Tumor-Initiating Cell as a Novel Therapeutic Target in Myeloma
Abstract
Multiple Myeloma is a blood cancer of the B cell lineage characterized by monoclonal plasma cells. Despite the recent advances in therapy, myeloma remains incurable and accounts for 19% of deaths from hematopoietic malignancies. Most patients initially respond to the therapy, but nearly all relapse and become refractory to treatment. These observations suggest that the persistence of a tumor cell population with very low proliferative capacity and very limited sensitivity to our most intensive therapies in myeloma. These myeloma cells, which escape current modes of therapy, are named tumor-initiating cells (TICs) in myeloma. Understanding the nature of myeloma-TICs will provide an opportunity to cure this disease by preventing its relapse. Through a systematical screening, our studies presented here demonstrated that CD24+ myeloma cells maintain the features of self-renewal and drug resistance in myeloma. To further determine CD24 as a biomarker in clinical myeloma samples, we will add myeloma cell markers, such as CD38+CD45–, to exclude non-myeloma cells for studying CD24+ primary myeloma cells. We predict that myeloma patients with high percentage of CD38+CD45–CD24+ myeloma cells will be relapsed rapidly and die early, and anti-CD24 antibody may eliminate myeloma tumor-initiating cells resulting in cure of myeloma disease or significant extension of patient survival. Therefore, this proposal will focus on validating CD38+CD45–CD24+ as TICs marker and its potential therapeutic role using primary myeloma samples. The first aim will determine the CD38+CD45–CD24+ phenotype in maintaining stemness and its clinical relevance in primary myeloma samples. In the second aim, tumor-initiating characteristics of CD38+CD45–CD24+ cells will be determined using in vitro and in vivo myeloma mouse models. In the third aim, we will investigate the efficacy of humanized CD24 antibodies in killing myeloma tumor-initiating cells. This proposal follows (1) the FY18 PRCRP Topic Area is myeloma; and (2) the FY18 PRCRP Military Relevance Focus Areas are chemicals associated with cancer and gaps in myeloma prevention, prognosis, and treatment for extending patient survival. In the last decade, almost 3% of United States cancer cases were reported within the military healthcare system. Myeloma is considered one of the common cancers seen among Veterans and appears to be connected to exposure to Agent Orange and other herbicides, suggesting that each year cases will increase. Because myeloma has typically spread by the time it is detected, it could greatly benefit early detection and treatment success if a marker for disease development is identified. Overall, this project has the potential to impact all myeloma patients including Veterans when we finish this project within next 4 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910500
Entities
People
- Fenghuang Zhan
Organizations
- United States Army
- University of Iowa